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Skeletal Muscle Adaptations to Low-Load Resistance Exercise Combined with Blood Flow Restriction in Older Adults with Knee Osteoarthritis

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Skeletal Muscle Adaptations to Low-Load Resistance Exercise Combined with Blood Flow Restriction in Older Adults with Knee Osteoarthritis
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Layne, Andrew S
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[Gainesville, Fla.]
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Doctorate ( Ph.D.)
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University of Florida
Degree Disciplines:
Health and Human Performance
Applied Physiology and Kinesiology
Committee Chair:
BORSA,PAUL A
Committee Co-Chair:
BUFORD,THOMAS W
Committee Members:
BORST,STEPHEN EDWARD
ANTON,STEPHEN D

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exercise -- kaatsu -- osteoarthritis
Applied Physiology and Kinesiology -- Dissertations, Academic -- UF
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government publication (state, provincial, terriorial, dependent) ( marcgt )
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Health and Human Performance thesis, Ph.D.

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Abstract:
Skeletal muscle weakness is a primary contributor to pain, functional decline and disease progression among older persons with knee osteoarthritis (OA). Thus, resistance exercise is commonly used as a preventative and rehabilitative intervention in this population. High-load resistance exercise performed with >60% of one-repetition maximum (1RM) is the best-known intervention for improving skeletal muscle strength. However, persons with OA may be unable to perform high-load exercise due to pain and joint compression. As a result, interventions are needed that are capable of increasing strength while utilizing low loads. One potential strategy is the addition of blood-flow restriction (BFR) to low-load training. This strategy is effective for increasing skeletal muscle strength relative to low-load training alone in healthy adults. Thus, the objective of this randomized, single-masked pilot trial was to evaluate the efficacy and feasibility of BFR training for improving skeletal muscle strength and physical function among older adults with knee OA. A total of 30 participants aged 60 or more years with symptomatic knee OA were randomly assigned to twelve weeks of center-based, traditional resistance exercise (CNTRL, 60% 1RM to volitional fatigue) or BFR (20% 1RM). Study outcomes included changes in 1) 1RM 2) isokinetic knee extensor strength 3) objective (Short Physical Performance Battery (SPPB), 400m walk) and subjective measures of physical function (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Late Life Function and Disability Instrument (LLFDI)) 4) body composition 5) gait parameters and 6) serum markers of muscle hypertrophy. Changes in 1RM and isokinetic knee extensor strength were not statistically significantly different between groups (time*condition interactions p>0.05) but tended to favor the CNTRL intervention. Similarly, changes in 400m walk and subjective function as assessed by LLFDI tended to favor the CNTRL intervention, whereas changes in WOMAC stiffness favored the BFR intervention. Changes in SPPB and gait parameters were similar between groups. Furthermore, changes in total lean mass, fat mass and body fat percentage tended to favor CNTRL. Serum P3NP was significantly higher in CNTRL relative to BFR, while serum IGF1 was similar between groups. Serum TWEAK tended to be lower CNTRL relative to BFR. Finally, P3NP demonstrated moderate to strong correlations with eccentric knee extensor force characteristics, while TWEAK was positively associated with 400m walk speed and negatively associated with changes in body fat. These findings indicate that the CNTRL intervention tended to be more efficacious for strength and function in persons with knee OA. However, results should be interpreted with caution as this trial was not fully powered to detect differences in these outcomes. ( en )
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Thesis (Ph.D.)--University of Florida, 2017.
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Adviser: BORSA,PAUL A.
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Co-adviser: BUFORD,THOMAS W.
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by Andrew S Layne.

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SKELETAL MUSCLE ADAPTATIONS TO LOW LOAD RESISTANCE EXERCISE COMBINED WITH BLOOD FLOW RESTRICTION IN OLDER ADULTS WITH KNEE OSTEOARTHRITIS By ANDREW STEVEN LAYNE A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2017

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2017 Andrew Steven Layne

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To my family

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4 ACKNOWLEDGMENTS I am deeply grateful to my family and friends for their unwavering support and encouragement during this grueling period. I would not have been successful in this endeavor without them. I would also like to thank Dr. Thomas Buford for his patience and expe rt instruction. I have greatly improved as a thinker, writer and person thanks to his leadership. I am also appreciative of my committee including Dr. Paul Borsa, Dr. Stephen Anton and Dr. Stephen Borst -for their time, availability and feedb ack during thi s process. Each has greatly contributed to my academic development. Finally, I would like to thank Dr. David Criswell for the opportunity to come to the University of Florida and my instructors from East Tennessee State University, Dr. Michael Stone, Dr. M ichael Ramsey, Dr. Charles Stuart and Meg Stone for laying the foundation for my success.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ........ 4 LIST OF TABLES ................................ ................................ ................................ .................. 7 LIST OF FIGURE S ................................ ................................ ................................ ................ 8 LIST OF ABBREVIATIONS ................................ ................................ ................................ .. 9 ABSTRACT ................................ ................................ ................................ .......................... 11 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .......... 13 2 L ITERATURE REVIEW ................................ ................................ ................................ 18 Backgrou nd ................................ ................................ ................................ ................... 18 Literature Search Methodology ................................ ................................ .................... 19 Skeletal Muscle Function and OA ................................ ................................ ................ 19 Efficacy of Exercise for Management of OA ................................ ............................... 22 Skeletal Muscle Adaptations to BFR Exercise ................................ ............................ 24 Recent Studies Relevant to BFR Exercise for OA ................................ ...................... 27 Conclusions and Perspectives ................................ ................................ ..................... 29 3 METHODOLOGY ................................ ................................ ................................ .......... 31 Research Design ................................ ................................ ................................ .......... 31 Participant Characteristics ................................ ................................ ............................ 31 Interventions ................................ ................................ ................................ .................. 32 Study Outcomes ................................ ................................ ................................ ........... 33 Skeletal Muscle Strength ................................ ................................ ....................... 33 Measures of Functional Status ................................ ................................ .............. 34 Gait Analysis ................................ ................................ ................................ ........... 34 Self Assessed Pain and Physical Function ................................ .......................... 35 Body Composition ................................ ................................ ................................ .. 35 Serum Biomarkers ................................ ................................ ................................ 36 Statistical Analyses ................................ ................................ ................................ ....... 37 4 RESULT S ................................ ................................ ................................ ...................... 40 Demographic Characteristics ................................ ................................ ....................... 40 Intervention Adherence and Perceived Exertion ................................ ........................ 40 Skeletal Muscle Function ................................ ................................ ............................. 41 Meas ures of Physical Function ................................ ................................ .................... 42

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6 Gait ................................ ................................ ................................ ................................ 42 Self Assessed Pain and Function ................................ ................................ ................ 43 Body Composition ................................ ................................ ................................ ......... 43 Serum Measures of Muscle Hypertrophy ................................ ................................ .... 43 Correlations ................................ ................................ ................................ ................... 44 5 DISCUSSION ................................ ................................ ................................ ................ 73 Limitations ................................ ................................ ................................ ..................... 80 Conclusions ................................ ................................ ................................ ................... 82 APPENDIX A WESTE RN ONTARIO AND MCMAS TER UNIVERSITIES OST EOARTHRITIS INDEX ................................ ................................ ................................ ............................ 84 B LATE LIFE FUNCTION A ND DISABILITY INSTRU MENT ................................ ........ 85 LIST OF REFERENCES ................................ ................................ ................................ ..... 92 BIOGRAPHICAL SKETCH ................................ ................................ ............................... 111

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7 LIST OF TABLES Table page 3 1 Inclusion and exclusion criteria ................................ ................................ ............... 38 3 2 Data collection summary by study visit ................................ ................................ ... 39 4 1 Participant characteristics ................................ ................................ ........................ 45 4 2 One repetition maximums ................................ ................................ ........................ 46 4 3 Objective measures of physical function ................................ ................................ 47 4 4 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) ...... 48 4 5 Late Life Function and Disability Instrument ................................ ........................ 49 4 6 Body composition ................................ ................................ ................................ ..... 50 4 7 Correlations between serum markers of skeletal muscle hypertrophy and isoki netic knee extensor strength at 60 degrees/s ................................ ................. 51 4 8 Correlations between serum markers of skeletal muscle hypertrophy and isokine tic knee extensor strength at 90 degrees/s ................................ ................. 52 4 9 Correlations between serum markers of skeletal muscle hypertrophy and isokinetic knee extensor strength at 120degrees/s ................................ ................ 53 4 10 Correlations between serum markers of skeletal muscle hypertrophy and isokinetic knee extensor endurance ................................ ................................ ........ 54 4 11 Correlations between serum markers of skeletal muscle hypertrophy, 400m walk and SPPB ................................ ................................ ................................ ......... 55 4 12 Correlations between serum markers of skeletal muscle hypertrophy and GAITRite parameters ................................ ................................ ............................ 56 4 13 Correlations between serum markers of skeletal muscle hypertrophy and WOMAC ................................ ................................ ................................ .................... 57 4 14 Correlations between serum markers of skeletal muscle hypertrophy and LLFDI ................................ ................................ ................................ ........................ 58 4 15 Correlations between serum markers of skeletal muscle hypertrophy and body composition ................................ ................................ ................................ ..... 59

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8 LIST OF FIGURES Figure page 4 1 Change in ratings of perceived exertion (RPE) across sets ................................ .. 60 4 2 Change in ratings of perceived exertion (RPE) across weeks 1 4, 5 8, and 9 12 of the intervention f ................................ ................................ ............................. 61 4 3 Concentric isokinetic knee extensor average peak torque. ................................ ... 62 4 4 Eccentric isokinetic knee extensor average peak torque ................................ ...... 63 4 5 Concentric isokinetic knee extensor average peak power ................................ .... 64 4 6 Eccentric isokinetic knee extensor average peak power ................................ ....... 65 4 7 Concentric isokinetic knee extensor total work ................................ ...................... 66 4 8 Eccentric isokinetic knee extensor total work ................................ ......................... 67 4 9 Change in gait parameters assessed by GAITRite.. ................................ .............. 68 4 10 Change in gait parameters assessed by GAITRite. ................................ ............... 69 4 11 Change in gait parameters assessed by GAITRite. ................................ ............... 70 4 12 Change in gait parameters assessed by GAITRite.. ................................ .............. 71 4 13 Change in serum markers of skeletal musc le hypertrophy ................................ .... 72

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9 LIST OF ABBREVIATION S 1RM One repetition maximum 31 P NMR 31 Phosphatate nuclear magnetic resonance spectroscopy BFR Blood flow restriction CAF C terminal agrin fragment CI Confidence interval CNTRL Control group (traditional exercise) DBP Diastolic blood pressure DEXA Dual energy x ray absorptiometry ELISA E nzyme linked i mmunosorbent assay EMG Electromyography GH Growth hormone IGF 1 Insulin like growth factor 1 K/L Kellgren Lawrence grading scale KOOS Knee Osteoarthritis Outcome Score LLFDI Late Life Function and Disability Instrument MAPK Mitogen activated protein kinase MMSE Mini mental State Exam mTOR Mammalian target of rapamycin OA Osteoarthritis P3NP N terminal peptide of procollagen type III SBP Systolic blood pressure SMD Standard mean difference SPPB Short Physical Performance Battery

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10 TWEAK Tumor necrosis like weak inducer of apoptosis VAS Visual analog scale WOMAC Western Ontario and McMaster Universities Osteoarthritis Index

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11 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SKELETAL MUSCLE ADAPTATIONS TO LOW LOAD RESISTANCE EXERCISE COMBINED WITH BLOOD FLOW RESTRICTION IN OLDER ADULTS WITH KNEE OSTEOARTHRITIS By Andrew Steven Layne August 2017 Chair: Paul Borsa Cochair: Thomas W. Buford Major: Health and Human Performance Skeletal muscle weakness is a primary contributor to pain, functional decline and disease progression among older persons with knee osteoarthritis (OA). Thus, resistance exercise is commonly used as a preventative and rehabilitative intervention in this population. High load resistance exercise performed with >60% of one repetition maximum (1RM) is the best known intervention for improving skeletal muscle strength. However, persons with OA may be unab le to perform high load exercise due to pain and joint compression. As a result, interventions are needed that are capable of increasing strength while utilizing low loads. One potential strategy is the addition of blood flow restriction (BFR) to low load training. This strategy is effective for increasing skeletal muscle strength relative to low load training alone in healthy adults. Thus, the objective of this randomized, single masked pilot trial was to evaluate the efficacy and feasibility of BFR traini ng for improving skeletal muscle strength and physical function among older adults with knee OA. A total of 30 participants aged 60 years with symptomatic knee OA were randomly assigned to twelve weeks of center based,

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12 traditional resistance exercise (CNT RL, 60% 1RM to volitional fatigue) or BFR (20% 1RM). Study outcomes included changes in 1) 1RM 2) isokinetic knee extensor strength 3) objective (Short Physical Performance Battery (SPPB), 400m walk) and subjective measures of physical function (Western O ntario and McMaster Universities Osteoarthritis Index (WOMAC) and Late Life Function and Disability Instrument (LLFDI)) 4) body composition 5) gait parameters and 6) serum markers of muscle hypertrophy. Changes in 1RM and isokinetic knee extensor strength were not statistically significantly different between groups (time*condition interactions p>0.05) but tended to favor the CNTRL intervention. Similarly, changes in 400m walk and subjective function as assessed by LLFDI tended t o favor the CNTRL interventi on, whereas changes in WOMAC stiffness favored the BFR intervention. Chan ges in SPPB and gait parameters were similar between groups. Furthermore, changes in total lean mass, fat mass and body fat percentage tended to favor CNTRL. Serum P3NP was signific antly higher in CNTRL relative to BFR, while serum IGF1 was similar between groups. Serum TWEAK tended to be lower CNTRL r elative to BFR. Finally, P3NP demonstrated moderate to strong correlation s w ith eccentric knee extensor for ce characteristics, while T WEAK was positively associated with 400m walk speed and negatively associated with changes in body fat. These find ings indicate that the CNTRL intervention tended to be more efficacious for strength and function in persons with knee OA. However, results sh ould be interpreted with caution as this trial was not fully powered to detect differences in these outcomes.

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13 CHAPTER 1 INTRODUCTION The primary purpose of this project was to fill critical gaps in our understanding of how resistance training combined with mild blood flow restriction to the working muscles (BFR) influences skeletal muscle hypertrophy among older adults with knee osteoarthritis. These data provide information critical to our long term goal of evaluating the efficacy of BFR training for improving physical function among clinically relevant populations. Hig h load resistance exercise (~ 60 % of maximal strength) is the best known intervention for impr oving skeletal mus cle strength and hypertrophy 1 As a result, resistance exercise is strongly recommended for a wide range of clinical populations, particularly those with the greatest risk of disa blement due to declines in skeletal muscle mass and function. 2 Unfortunately, many of these populations -such as frail older adults, and those with musculoskeletal disorders such as osteoarthritis (OA) -are typically unable to perform resistance exercise wit h optimal loads due to pain fatigue or a lack of self efficacy 3 Consequently, current recommendations include the performance of low or moderate load resistance exercise d espite the fact that these training paradigms are sub optimal for improving skeletal muscle function. Therefore, alternative interventions are needed for improving skeletal muscle strength while utilizing low loading paradigms 4 Low load resistance exercise performed with blood flow restriction (BFR) is superior to low load resistance exercise alone for improving skeletal muscle strength and hypertrophy 5 and in some c ases BFR may be comparable to high load training for this purpose 6 Therefore, BFR is an attractive alternative training paradigm for

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14 populations in which high load exercise is contraindicated. Prior studies have demo nstrated that BFR exercise induces skeletal muscle hypertrophy under a variety of conditions, including alone or in combination with exercise not typically shown to induce skeletal muscle growth (e.g. walking 7,8 ). While the exact mechanisms are unclear, BFR is thought to induce these changes through multiple mechanisms including metabolic stress, cell swelling and increased skeletal muscle activation 9 Rece nt evidence suggests that BFR may have benefits for bone and joint health as well, 10 further increasing its potential value for persons with OA. To date, the majority of BFR studies have utilized healthy young adults, with few examining older adults and scarcely any evaluating older adults with chronic health conditions. In addition, the majority of these studies are short term (<6 weeks) and few d ata exist regarding functional outcomes. As a result, relatively little is known about the potential efficacy of BFR as a therapeutic intervention among older adults with chronic conditions such as OA. Furthermore, to our knowledge, no study to date has ex amined the molecular mechanisms underlying the effects of BFR exercise in older persons with OA (e.g. skeletal muscle growth pathways, neuromuscular activation, cartilage and bone turnover, inflammation). These markers will be critical for optimizing the d osage (exercise load, volume, cuff width and pressure) and determining the safety of BFR exercise for persons with OA. Therefore, the overarching objective of this work was to evaluate, amongst a clinically relevant population, the molecular mechanisms und erlying skeletal muscle adaptations to chronic BFR training 4 We evaluate d these adaptations in 30 participants from a recently completed, NIH funded trial comparing the efficacy of BFR to traditional resistance training among

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15 was that 12 weeks of BFR training would beneficially alter concentrations of serum markers indicative of chronic skeletal muscle adaptations, and these adaptations would be assoc iated with improvements in objective and subjective measures of skeletal muscle strength and function. We leverage d the existing resources and infrastructure of the recently completed trial to address the gaps in the current literature by assessing the ske letal muscle adaptations to 12 weeks of BFR (20% 1RM) to those of high intensity resistance training ( CNTRL 60% 1RM) according to the following aims: Aim 1. To determine the extent of change in serum biomarkers of skeletal muscle hypertrophy and function in response to BFR and HIRT We used commercially available enzyme linked immunosorbent assay (ELISA) kits to determine serum concentrations of the following biomarkers from serum collected at baseline, week six and week twelve of the trial. Insulin like g rowth factor 1 (IGF 1): Increases with resistance training and is associated with increased protein synthesis and lean mass. 11 Tumor necrosis like weak inducer of apoptosis (TWEAK): Associated with inflammati on and skeletal muscle regeneration. 12 Lower TWEAK expression is associated with skeletal muscle hypertrophy and greater force production. 13 N terminal peptide of procolla gen type III (P3NP): Product of the formation of skeletal muscle specific isoform of collagen. Serum P3NP expression is positively associated with changes in lean body mass. 14 C terminal agrin fragment (CAF): P roduct of agrin cleavage. Agrin is produced by neurons and stimulates acetylcholine receptor clustering at the neuromuscular

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16 junction. High serum concentrations of CAF are associated with poorer physical function. 1 5 Aim 2: To assess changes in clinically relevant gait parameters in response to the training interventions During ambulation, skeletal muscle acts to reduce shock and provides stability to the joints. 16 Skeletal mu scle weakness results in an inability of the muscle to counteract the external forces placed on the joint during movement which may contribute to OA disease initiation and progression. Additionally, a number of gait abnormalities have been identified in pe rsons with OA and are thought to be associated with OA disease severity 17 In particular, persons with OA demonstrate slower overall step cadence, shorter step length and reduced single leg stance time relative to he althy counterparts. These and other gait abnormalities are associated with reduced lower extremity strength 18 and greater pain and physical disability 19 among persons with OA. Therefore, we evaluated these gait parameters at baseline, six and twelve weeks using the GAITRite system ( GAITRite, Franklin, NJ) Aim 3: To determine if observed training derived changes in serum biomarkers are significantly asso ciated with changes in strength, physical function and skeletal muscle mass Skeletal muscle weakness is one of the earliest manifestations of OA, and is more closely associated with physical disability among persons with OA than pain or joint space narrow ing. 20 As skeletal muscle size a major determinant of skeletal muscle strength, we hypothesize d that serum biomarkers of skeletal muscle hypertrophy would be associated with changes in lean mass and physical function. Physical function was

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17 objectively assessed using walking speed over 400m, the Short Physical Performance Battery (SPPB), and knee extensor strength measured at 60 degrees/s 90 degrees/s and 120 degrees/s Subjective measures of pain and physical function were assessed using the Late Life Disability and Function Instrument (LLFDI) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Lean mass was determined using dual energy x ray absorptiometry (DEXA). We correlated these variab les and the GAITRite analysis ( A im 2) with the change in serum biomarkers in response to the intervention.

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18 CHAPTER 2 LITERATURE REVIEW Background Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is a leading cause of disability among older adults. 21,22 Estimates indicate that up to 80% of 22 with hand, knee and hip joints being the most commonly affected. Pai n due to OA -particularly of the hip and knee is strongly associated with the incidence of physical disabili ty 23 25 Given the increasing prevalence of OA and rapid aging of the population, OA associated disability among older adults is a growing public health concern. 26,27 Skeletal muscle weakness represents an important modifiable risk factor that is a primary contributor to the exacerbation of OA and its symptoms. 28,29 As a result, phys ical activity designed to increase skeletal muscle strength is oft en used in rehabilitation and management of OA. Indeed, increased skeletal muscle strength is associated with reduced pain and improved physical function and quality of life among persons wi th OA. 30,31 To maximize gains in skeletal muscle strength, resistance exercise performed with a heavy external load (>60% of one repetition maximum) is considered to be most effective. 1,32 However, training with high compressive loads may not be feasible for many persons with OA due to potential exacerbations of joint pain and lack of self efficacy. 33 Therefore, alternative training strategies are needed capable of improving skeletal muscle strength while utilizing low loads. One potential strategy is the use of blood flow restriction (BFR) in combination with low load exercise. Blood fl ow restriction is achieved through the use of a pressure cuff placed proximal to the working skeletal muscles. In brief, the pressure cuff is

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19 inflated during exercise so that arterial flow is turbulent while venous return is mildly restricted. 34,35 Prior studies have demonstrated that BFR exercise is capable of increasing skeletal muscle hypertrophy and strength. 5 However, t o date, the majority of BFR studies have utilized healthy young adults, with few examining older adults and scarcely any evaluating older adults with chronic health conditions. As a result, relatively little is known about the potential efficacy of BFR as a therapeutic intervention among older adults with chronic conditions such as OA. As such the purpose of this review is to examine the extant evidence related to the potential for using BFR exercise as a therapeutic intervention for preserving skeletal mus cle strength and function among older adults with osteoarthritis. Literature Search M ethodology The National Library of Medicine (PubMed) database, the Cochrane Database of Systematic Reviews and Web of Science were used to search for relevant articles, a nd reference lists were reviewed for additional relevant articles. Specific search terms used Skeletal Muscle F unction and OA Skeletal muscle weakness is a common clinical feature of OA patients. 36,37 Weakness of the knee extensors and flexors in particular is associated with hip and knee OA. Although a direct relationship between skeletal muscle weakness and OA disease initiation and progression in humans has not yet been elucidated, 38 increased strength is associated with a reduction in pain and improved physical function and

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20 quality of life among persons with OA. 31,39 42 In addition, skeletal muscle strength may modulate several peripheral causes of pain and disease progression associated with OA, including joint space narrowing, 43 gait abnormalities, 44,45 and joint loading during ambulation. 46,47 Skeletal muscle size may also play a ro le, as muscle cross sectional area is related to muscle force production. 48 Indeed, longitudinal data suggest that thigh muscle volume is positively associated with knee cartilage volume and negatively associated with cartilage volume loss over two years of follow up. 49 As a result, interventions capable of increasing skeletal muscle size and strength (e.g. resistance training) are likely to benefit persons with OA. Skelet al muscle weakness is one of the earliest manifestations of OA, and is more closely associated with physical disability among persons with OA than pain or joint space narrowing. 20,50 Aside fro m acute injury, cartilage degeneration of the weight bearing joints is thought to largely result from excessive chronic joint loading. 51,52 During ambulation, skeletal muscle acts to reduce shock and provides stability to the joints. 16,53 Skeletal muscle weakness results in an inability of the muscle to counteract the external forces placed on the joint during movement which may con tribute to OA disease initiation and progression. 53 Additionally, a number of gait abnormalities have been identified in persons with OA and are thought to contribute to joint degeneration. 17,54 One of the most studied measures is the external knee adduction moment, which is often used as a proxy for medial knee compartment loading during ambulation. 55 However, a number of studies have failed to show an association between increased quadriceps strength and reductions in the knee adduction moment during walking. 56 59

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21 Thus, a direct role of skeletal muscle weakness in OA disease initiation and progression in humans is yet to be established. 38 Still studies utilizing a rabbit model of Botulinum toxin A induced quadriceps weakness provide evidence that skeletal muscle weakness leads to cartilage degeneration independent of gait biomechanics. 60,61 Furthermore, Leumann and colleagues 62 demonstrated that skeletal muscle weakness induced changes in knee structural tissue mRNA expression of collagens I and III and matrix metalloproteinases 1, 3, and 13, thus providing evidence that skeletal muscle weakness result s in altered metabolism of joint tissues in rabbits. 62 In humans, evidence for the role of skeletal muscle weakness in OA comes primarily from observational studies. Persons with OA display concentric quadriceps streng th deficits of 11 56% relative to aged matched healthy controls. 63 Skeletal muscle weakness in persons with OA is primarily caused by reduced muscle mass and/or reduced muscle activation secondary to pain, anxiety, neural inhibition and altered joint biomechanics. 64 A meta analysis of studies using electrical stimulation to elicit maximal contraction of the quadriceps found activation deficits of approximately 20% in the invol ved and contralateral limbs of persons with OA relative to healthy controls. 65 Local anesthesia is capable of improving skeletal muscle activation by ~12%, suggesting that pain or fear of pain is a major cont ributor to muscle activation deficits in persons with OA. 66 Skeletal muscle atrophy also likely contributes to skeletal muscle weakness among persons with OA. Hart et al. 67 found that quadriceps volume was ~10 15% lower among persons with OA relative to aged matched controls. Similar deficits of 12% were reported by Ikeda et al. 68 when comparing women with OA to age matched

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22 controls and by Petterson et al. 69 when comparing muscle volume between the involved and uninvolved limbs of persons with unilateral OA. Furthermore, Fink et al. 70 obtained biopsies from t he vastus medialis of persons with OA undergoing knee replacement surgery and found evidence of type II muscle fiber atrophy (defined as fiber diameter <30 m in females or <40 m in males) in all participants studied. Longitudinal data suggest that an inc rease in skeletal muscle cross sectional area from baseline to two years was associated with a decreased risk of joint replacement surgery at two and 4.5 years. 71 Due to the proposed benefits of improving skeletal muscle function (size and strength) in persons with OA, exercise training is a cornerstone of rehabilitation and management of the disease. Efficacy of E xercise for M anagement of OA Indeed, numerous studies indicate that exercise training is efficacious fo r persons with OA. Various forms of exercise including strength training, aerobic training, water based exercise and tai chi all appear to reduce pain and disability among persons with OA. 31,42,72 78 For example, Juhl et al. 74 analyzed results from 47 trials and 4028 patients and found that regardless of training modality, exercise training significantly reduced pain (standard mean difference [SMD] 0.50, 95% CI 0.39 0.62) and disability (35 trials, 2732 patients, SMD 0.49, 95% CI 0.35 .063). These effects equated to a 9% (95% CI 7 11%) reduction in pain and an 8% (95% CI 6 11%) reduction in physical disability according to self assessment using Visual Analog Scales (VAS). Similar results were reported in a recent Cochrane review of exercise interventions for knee OA. In this analysis, exercise training resulted in a 12% (95% CI 10 15%) reduction in pain and a 10% (95% CI 8 13%) reduction in perceived physical disability relative to non exercise controls. 31

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23 Although sufficient evidence exists to show exercise training is capable of reducing pain and improving physical function in OA, it is less clear which training modalities are most effective. Meta analyses comparing the effects of resistanc e and aerobic exercise on pain and physical disability among persons with OA were equivocal, with some showing greater efficacy of resistance exercise 74 and others showing no difference. 73 It is also unclear whether combined training improves outcomes relative to aerobic or resistance training alone, as some analyses concluded that combined training was less effective for improving pain 74,75 and physical function, 74 while another showed combined training (resistance, flexibility, and land or water based aerobic exercise) to be more effective. 72 As a result, published guidelines for exercise in the management of OA vary considerably in terms of recommended training modalities. However, low impact aerobic exercise, resistance exercise, and flexibility training are often recommended. 79 For improving skeletal muscle strength, high load exercise appears to be more effective than lower load exercise modalities in persons with OA. 78,80 A recent meta analysis by Zacharias et al. 80 compared low load resistance exercise to non exercise controls (10 studies, 768 participants) and found evidence for small increases in knee extension strength at short term f ollow up (6 1 3 weeks, Standard Mean Difference [SMD] 0.47, 95% CI 0.56 0.92) but no significant effect at intermediate term (20 24 weeks, SMD 0.08. 95% CI 0.16 0.32) or long term follow up (>24 wks, SMD 1.05, 95% CI 1.02 3.12). However, this group found moderate effect sizes for increased knee extension strength following high load resistance exercise relative to non exercise controls at short term (4 studies, 195 participants, SMD 0.76, 95% CI 0.47 1.06) and

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24 long term follow up (3 studies, 129 participan ts, SMD 0.80, 95% CI 0.44 1.17). 80 Similarly, a recent Cochrane review comparing high load exercise to low load exercise found a significant effect size for overall lower body strength favoring high load exercise (SMD 1.01, 95% CI 0.74 1.27). 81 However, while heavy loads may be optimal for improving skeletal muscle size and strength and reducing OA symptoms, these loads are not always well tolerated among persons with OA. 82 Thus, alternative strategies such as BFR combined with low load exercise may be warranted in persons with OA. Skeletal Muscle Adaptations to BFR E xercise Blood flow restriction is capable of improving skeleta l muscle size and strength when combined with exercise, even with loads and exercise modalities not typically associated with such improvements (e.g. low load resistance exercise, 83 86 walking 7,8 ). The mechanisms by which BFR augments the adaptive response to low load exercise are not completely understood. However several recent reviews detailed the possible molecular mechanisms, 9,34,87,88 which include local and systemic hormone release, increased motor unit recruitment, increased muscle protein synthesis and decreased protein degradation secondary to metabolic stress and cellular swelling. Metabolic stress characterized by increased blood lactate concentration, inorganic phosphate accumulation, lowered intramuscular pH an d phosphocreatine depletion is a primary signal for skeletal muscle hypertrophy following resistance exercise. 89 High metabolic stress, specifically an increase in blood lactate concentration, is associated with a n increase in post exercise testosterone 90 92 and growth hormone (GH) synthesis and release. 90,93,94 Exercise with BFR (160 230mmHg, 20 40% 1 RM) increases lactate concentration and intramuscular inorganic phosphate while lowering pH relative to low load exercise alone, 95 99 and induces similar acute metabolic stress

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25 relative to high load exercise (65% 1 RM). 97 Subsequently, BFR exercise increases systemic GH expressi on relative to low and high load exercise without BFR. However, most studies show no change in total testosterone, 7,100 102 free testosterone 100,103 or IGF 1 102 104 following BFR exercise. Furthermore, the relationship between post exercise changes in syste mic hormone expression and muscle hypertrophy is still under debate 105 106 107 leading to speculation that other factors are primarily responsible for signaling skeletal muscle growth in response to BFR training. 9,35 Metabolic stress may also mediate the skeletal muscle hypertrophic response following BFR by increasing cellular swelling. Accumulating metabolites particularly lactate 108 -create an osmotic gradient favoring fluid flow into the cell. This increase in cellular hydration is thought to activate growth s ignaling pathways 109 (e.g. mammalian target of rapamycin [mTOR] and mitogen activated protein kinase [MAPK]) and inhibit proteolysis 110,111 secondary to mechan ical stretch of the sarcolemma, 112 ultimately resulting in a net increase in protein synthesis. Cellular swelling may also stimulate skeletal muscle hypertrophy by increasing activation and proliferation of skel etal muscle satellite cells. 113 Although many of these molecular responses are augmented by the addition of BFR to low load exercise, 114 117 it should be noted that a recent investigation by Gundermann et al. 118 failed to show an increase in skeletal muscle protein synthesis or mTOR and MAPK signaling using a pharmacologically induced increase in post exercise blood flow. However, the peak pharmacologically induced post exercise blood flow and plasma lactate concentrations were lower relative to BFR exercise. Thus, the pharmacological increase in post exercise blood flow may not have been sufficient to mimic the physiological responses to BFR exercise. Furthe r studies are needed to

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26 elucidate the role of cellular swelling in stimulating skeletal muscle hypertrophy following BFR exercise. Blood flow restriction may also augment the hypertrophic response to low load exercise by increased activation of type II mot or units secondary to hypoxia and metabolic stress. 9,87,119,120 Low load exercise performed under normal conditions is generally not a sufficient stimulus to activate higher threshold (type II) motor units. 121 However, BFR exercise (130% SBP, 20% 1 RM) is capable of stimulating similar type II fiber activation relative to higher load resistance exer cise (65% 1 RM) as measured by 31 Phosphatate nuclear magnetic resonance spectroscopy ( 31 P NMR) 95,122 As Type II skeletal muscle fibers have a higher capacity for hypertrophy than type I fibe rs, 123 this increased activation of type II fibers is a possible mechanism for augmented skeletal muscle growth with BFR exercise. Furthermore, BFR exercise (100 160mmHg, 20% 1 RM) increases skeletal muscle activatio n relative to low load exercise alone as measured peripherally 124 126 (surface electromyography [EMG]) and centrally. 127 Giv en the activation deficits typically seen in persons with OA, this may be an important mechanism for skeletal muscle strength gains and improvements in physical function with BFR exercise. However, it should be noted that some studies failed to show an inc rease in skeletal muscle activation with BFR exercise relative to work matched low load exercise without BFR 128,129 or low load exercise performed to volitional fatigue. 130 Furthermore, Cook et al. demonstrated that high load exercise (70% peak torque) elicited greater skeletal muscle activation relative to low load exercise (20% peak torque) performed to volitional fatigue and BFR exercise (20% peak torque, 180mm Hg). 130 However, although the neuromuscular adaptations to BFR exercise may

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27 be dissimilar to higher load resistance exercise, BFR exercise may still be beneficial for persons with OA due to a reduced capacity to train with heavier loads or to maintain sufficient output to reach volitional fatigue. Recent S tudies R elevant to BFR E xercise for OA Despite the possible benefits of BFR combined with low load exercise, to our knowledge only three studies to date have utilized this exercise modality for persons with or at risk for OA. Segal et al. 131 compared low load intensity exercise (30% 1 RM ) with or without BFR (65mm wide cuff inflated to 160 200mmHg) in 45 women aged 45 65 years (average age 54.66.9 yrs control group and 56.15.9 yrs BFR) with at least one risk factor for symptomatic knee OA. Risk factors included 1) body mass index 2 2) history of knee joint injury or surgery 3) pain, aching or stiffness on most of the last 30 days 4) being told that they have radiographic knee OA. Participants had not participated in resistance train ing during the last three months. The exercise intervention consisted of bilateral leg presses performed three times per week over four weeks. Outcomes included bilateral leg press isotonic strength and power, stair climb power, and knee pain (Knee Osteoar thritis Outcome Score, KOOS). Additionally, a subset of participants (n=6 from each group) were randomly selected for analysis of quadriceps muscle volume measured by MRI. Both groups significantly improved in leg press 1 RM strength and stair climb power relative to baseline. The BFR group also significantly improved on leg press power assessed at 40% of 1 RM and isokinetic knee extensor torque relative to baseline. The increase in knee extensor torque was significantly different from the control group ( 0 .050.03 Nm/kg control vs. 0.07 0.03 Nm/kg BFR, p=0.0048). Knee pain and quadriceps volume were unchanged relative to baseline in both groups.

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28 In a separate study, Segal et al. 132 used a similar protocol to assess the effects of low load exercise and BFR in 42 men aged 45 90 years (average age 56.17.7 yrs). Outcomes included isotonic leg press strength, isokinetic knee extension strength at 60/s and knee pain (KOOS). Following the exercise intervention, leg press 1 RM was significantly improved in both groups relative to baseline (4.71.3%, p<0.002 control, 3.10.9%, p=0.003 BFR), but was not significantly different between groups (p=0.322). Isokinetic knee extensor strength was only improved relative to baseline i n the control group (6.72.3%, p=0.062 control vs. 0.42.4%, p=0.883 BFR, p=0.066 between groups). Neither group improved KOOS scores following the intervention (14.27.2%, p=0.062 control vs. 4.93.3%, p=0.155 BFR). Finally, Bryk et al. 133 compared high load resistance exercise (70% 1 RM) to low load resistance exercise with BFR (30% 1 RM, cuff pressure 200 mmHg, cuff width not reported) in 34 women (average age 60.46.7 yrs control vs. 62.37.0 yrs BFR) w ith diagnosed knee OA based on American College of Rheumatology criteria. Participants had a K/L grade score of two or three in one of the knees. Exclusion criteria included previous surgery or invasive procedure on the affected knee, previous physical the rapy, participation in any knee strengthening program. The training program combined flexibility (static hamstring stretches) and sensorimotor training (standing on a mini trampoline) with midsection and lower body strengthening exercises. The primary exer cise was seated knee extensions (3 sets of 10 repetitions with 70% 1 RM for control, 3 sets of 30 repetitions at 30% 1 RM for BFR). The exercise intervention was performed three times per week for six weeks. Outcomes included quadriceps maximum isometric v oluntary contraction, anterior knee pain assessed during exercise

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29 and at the pre/post intervention, and physical function (Lequesne functional scale and timed up and go). Both groups improved significantly relative to baseline in isometric strength, physic al function and knee pain, Although not statistically significant, the magnitude of isometric quadriceps strength gain tended to be greater following BFR (+42% for BFR vs. +30% for control). Furthermore, the BFR group reported less anterior knee pain durin g exercise relative to the control group (p=0.01), indicating that low load exercise combined with BFR may be better tolerated than high load exercise in this population. Conclusions and P erspectives Resistance training may reduce pain and improve physical function secondary to improved skeletal muscle function in persons with OA. However, a number of factors including joint pain and diminished self efficacy may limit the performance of resistance exercise with optimal loads. Resistance exercise combined wi th BFR is capable of improving skeletal muscle function while utilizing low loads. As a result, exercise with BFR is a promising alternative intervention for management of OA as well as other clinical conditions in which skeletal muscle function is compro mised including inflammatory myopathies, 134,135 ligament 136 and bone 137 injury rehabilitation, and sarcopenia. 85,138 Although BFR exercise holds considerable promise for management of OA, there are several knowledge gaps in the current literature that will need to be addressed in future trial s. To our knowledge, no study to date has examined the molecular mechanisms underlying the effects of BFR exercise in persons with OA (e.g. skeletal muscle growth pathways, neuromuscular activation, cartilage and bone turnover, inflammation). These markers will be critical for optimizing the dosage (exercise load,

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30 volume, cuff width and pressure) and determining the safety of BFR exercise for persons with OA. Furthermore, recent evidence suggests that there is significant molecular cross talk between skelet al muscle and other joint structures, 139 suggesting that exercise may directly modulate OA disease progression. Indeed, exercise alters cartilage expression of many genes associated with inflammation and cart ilage metabolism. 140 Moreover, intermittent hypoxia also reduces inflammation in synovial tissues, 141 suggesting that the addition of BFR may further modulate the inflammatory respon se compared to resistance exercise alone. This may be of particular importance for early OA disease management. 142 While speculative, future research on the direct disease modifying effects of BFR exercise may be warranted. While BFR exercise has many potential advantages over traditional high load resistance exercise for persons with OA, there are several limitations. Logistically, BFR exercise requires considerable investments in equipment and technical expert ise. Also, while BFR exercise is generally well tolerated, certain parameters (cuff pressure, cuff width) may influence perceived exertion and discomfort. These issues may potentially limit widespread applicability. Additionally, BFR can only be applied to the limb musculature. As a result, supplementary training for proximal and midsection muscle groups may be necessary to maximize the benefits of BFR exercise. In conclusion, BFR exercise appears to be a promising alternative to high load resistance exerci se among older adults with OA, however well controlled studies identifying the mechanisms of action as well as investigating the clinical viability are needed.

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31 CHAPTER 3 METHODOLOGY Research Design The purpose of this study was to evaluate the skeletal muscle adaptations to 12 weeks of resistance exercise either with (BFR) o r without BFR (CNTRL) among older adults with knee osteoarthritis. This study was an ancillary study utilizing a subset of participant s from a r andomized, single masked pilot trial de signed to evaluate the safety and efficacy of BFR exercise for improving physical function among older adults with symptomatic knee osteoarthritis. Prior to randomization in the study, interested individuals participated in an initial screening visit to de termine eligibility (Table 2 1 ). This included a review of medical history, physical activity habits, medication use, and the Mini mental State Exam 143 to ensure participants had normal cognitive function Following these procedures, the 400 m walk test 144 and Short Physical Performance Battery (SPPB) 145 were performed as well as a medical exam that included assessment of OA rel ated symptoms. Participant Characteristics Data from a total of t hirty previously sedentary were included in the present analysis (n=14 BFR, n=16 CNTRL). Eligibilit y criteria are listed in Table 3 1 Briefly, eligible participants had objective signs of functional limitations or walking speed <1.2 m/sec ), had OA of the knee defined by (1) radiographic evidence of osteophytes, (2) pain classification > grade 0 on Graded Chronic Pain Scale, (3) and bilateral standing ante rior posterior radiograph demonstratin g Kellgren and Lawrence grade > 1 of the affected knee. Persons with contraindications to tourniquet use, including those with peripheral vascular disease,

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32 systolic blood pressure (SBP) >160 or < 100 mm Hg, diastolic blo od pressure (DBP) >100 mm Hg, absolute contraindications to exercise training, 146 or with other medical conditions that would preclude safe participation were excluded. All participants provided wr itten informed consent before randomization, and all study procedures were approved by the University of Florida Institutional Review Board. Interventions Participants in each study arm performed center based resistance exercise three days per week throug hout the 12 week study period (36 total sessions). Following a brief warm up (stationary cycling or walking), participants performed machined based lower body strength exercises followed by a brief cool down routine consisting of balance exercises and st re tching. Resistance exercises leg press, leg extension, leg curl and calf extension -were performed using standard resistance training equipment (Life Fitness, Schiller Park, IL). Participants performed three sets on each machine with a one minute rest be tween sets and five minutes of rest between machines. All exercises were performed to volitional fatigue -defined as the inability to complete a pain free range of motion after strong verbal encouragement. Ratings of perceived exertion were obtained follow ing each set using the modified Borg scale (0 10) 147 Participants in the CNTRL exercise group performed the resistance exercises at an intensity of 60% of one repetition maximum (1RM) according to exercise gu ide lines for seniors with OA. 1,146 For the KAATSU intervention, resistance exercises were performed using 20% of 1RM with external compression applied to the proximal thigh of each leg. Compression was applied according to published tourniquet guidelines 148 and maintained by

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33 pneumatic cuffs (TD 312 calculating cuff inflator, Hokanson, Bellevue, WA) Cuff pressure was set according to the equation [pressure=0.5*(SBP)+2*(thigh circumference)+5]. 149 Cuffs remained inflated during performance of each exercise (i.e. between sets) but were deflated for five minute rest periods b etween exercises. All exercise sessions were supervised by trained and American Heart Association Basic Life Support certified exercise interventionists. Load was adjusted based on subsequent RM testing at week three, week six and week nine. To determine 1RM, participants performed brief general warm up and subsequently completed 4 6 sets of each exercise with a progressively increasing load. Participants then performed as many repetitions as possible and 1RM was calculated 150 according to the formula 1RM load*(1.0278 (0.0278*repetitions)) 1 Study Outcomes Skeletal M uscle S trength Participants performed muscle strength testing on both limbs at baseline, week six and week twelve. Maximal isokinetic strength of the quadriceps extensors was assessed using a Biodex System 3 (Biodex Medical Systems, Inc., Shirley, NY). Participants perfo rmed three submaximal trial repetitions of seated leg extensions at an estimated effort of 25%, 50%, 75% and two maximal (100% effort) repetitions followed by a rest period of one minute. Subsequently, participants performed five maximal (100% effort) repe titions at 60 degrees/s, 90 degrees/s, and 120 degrees/s. Finally, participants completed an endurance protocol consisting of 50 repetitions at 120 degrees/s. Outcomes obtained included 1) average peak torque (N*m) 2) average power (W) and 3) average total work (N*m).

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34 Participants also completed 1 RM testing for each machine use d for the training intervention at baseline and week 12 Following a brief general warm up, participants completed 4 6 sets of each exercise with a progressively increasing load. Participants rested for ~3 minutes between sets. Load was increased until the participant could only perform one repetition through the full range of motion, and this load was determined to be 1RM. M easures of Functional S tatus F unctional outcomes inclu ded usual paced gait speed measured during a 400 m test and performance on the SPPB ( Table 3 2 ) These tests have high clinical relevance as they have proven reliable and valid for predicting adverse health outcomes among seniors. 151 154 During the 400m walk test, participants were asked to complete 10 laps around a 40m course. T ime and distance walked were recorded, and gait speed was determined in m/s For the SPPB p articipants performed a time d standing balance test, a four meter walk, and a repeated chair stand. A score ranging from zero (inability to complete the task) to four (best performance) was recorded for each test, and the scores were summed for a final score ranging from 0 12 Gait A nalysis Gait analysis was performed at baseline and week twelve using the GAITRite system. This system employs a n 8 m long mat equipped with fifteen sensor arrays. The system record ed location of activate d sensors and time of activation/deactivation during a self paced walk test. The walk test was repeated six times and the values of specific parameters were averaged for the six trials. GAIT Rite software was used to examine the g ait parameters. Gait param eters collected included 1 ) velocity ( cm/s ) 2) velocity normalized to leg length (leg length/sec, leg length measured from greater trochanter to

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35 the floor, bisecting the medial Malleolus 3) step cadence 4) step length differential (left:right ratio) 5) ste p time differential (elapsed time from first contact of one foot to first contact of opposite foot) 6) cycle time differential (elapsed time between first contacts of two consecutive steps of same foot) 7) single leg support stance time (time elapsed between last contact of current footfall to first contact of next footfall of the same foot) and 8) toe in/toe out angle (angle between line of progression and midline of the foot). Self Assessed Pain and P hysical F unction The WOMAC is a multidimensional, self administered functional health status instrument for patients with lower limb OA. 155 The WOMAC index is a 24 item questionnaire divided into three subscales, which measure pain (WOMAC pain; 5 questions), stiffness (WOMAC stiffness; 2 questions), and physical function (WOMAC function; 17 questions). Each question is rated on a 0 4 scale, with 0 indicating no difficulty performing the task and 4 indicating extreme difficulty. The WOMAC total scor e was the s um of the three subscale scores The WOMAC has demonstrated validity as well as sensitivity to treatment effects in patients with knee pain. 156,157 The Late Life Function and Disab ility I nstrument (LLFDI) includes 16 tasks representing a broad range of disability indicators that assesses both frequency of doing a task and perceived limitation. The instrument uses a scale from 0 to 100, with higher scores indicating higher levels of function. The scale has strong concurrent and predictive validity with physical performance. 158 Body C omposition Body composition was assessed at baseline and week twelve using dual energy x ray absorptiometry (DEXA) (Hologic, Waltham, MA ). Outcomes assessed included 1) android/gynoid ratio ( %fat waist/%fat hip ) 2) total mass 3) fat mass 4) total lean mass

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36 (muscle and soft organ tissue) 5) total bone mineral content (BMC) and 6) body fat percentage Serum B iomar kers Bood was collected from the antecubital vein according to standard laboratory practices at baseline, week six and week twelve. Serum was s eparated by centrifugation and stored at 80C for later analysis. Serum levels of insulin like growth factor 1 ( IGF 1, R&D Systems, Minneapolis, MN), t umor necrosis like weak inducer of apoptosis (TWEAK, R&D Systems, Minneapolis, MN), N terminal peptide of procollagen type III (P3NP MyBioSource, San Diego, CA ), and C terminal agrin fragment (CAF Neurotune, Zurich, Switzerland ) were determined using commercially available enzyme linked i mmunosorbent assay (ELISA) kits. Concentrations of each target protein were determined using the colorimetric method at an optical density of 450 nm with a microplate reader ( Biotek, Winooski, VT ). Standard curves were generated using a commercially available microplate reader compatible statistical software ( Biotek Gen5, Winooski, VT ). These standard curves were generated for all measures using commercially developed standards with s pecific antigens with reported r values in the range of 0.948 0.999. Intra assay coefficients of variation for each assay were determined for each duplicate for all participants and resulted in a mean coefficient of variation of 3.4% For TWEAK, a spike recovery control experiment was performed according to manufacturer instructions to validate the kit for use with human serum. Briefly, two 1 mL aliquots of serum sample were prepared. One 980L aliquot was spiked with 20L of kit standard TWEAK concentrat e (20 ng/mL) and the other aliquot was analyzed without spiking. A control sample was prepared by adding 20 L of TWEAK standard to 980 L

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37 of the supplied reagent diluent. These samples were serially diluted in reagent diluent (neat, 1:2, 1:4, and 1:8) and analyzed relative to the standard curve. Spike recovery was determined as % Recovery = Observed value (pg.mL) x 100/(Expected value ol spiked sample value. Linearity was determined as % Recovery (dilution) = Observed value (pg/mL) *100/Expected value (pg/mL)*dilution factor. All values for spike recovery and linearity were within the acceptable range of 80 120% ( %Recovery = 99.8%, line arity 88.9 95.9%), indicating that the TWEAK ELISA kit is valid for analysis of human serum. Statistical Analyses Repeated measures analysis of covariance (ANVOCA) was used to determine d ifferences in mean outcome measures between intervention groups B as eline outcome measure, age, gender, baseline pain rating on the visual analog scale and the intervention group assignment were included in the model. Hypothesis tests for intervention effects at assessment visits were performed using simple contrasts of the 6 and 12 week intervention means. Overall comparisons between groups for the outcome measure across follow up visits were obtained using a contrast to compare average effects across follow up visits. For aim 3, correlations between serum markers of myogenesis and measures of physical function were analyzed using rank correlation coefficients for non parametric data and Pearson correlation coefficients for parametric data.

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38 Table 3 1. Inclusion and exclusion criteria Inclusion Criteria Males or females a ge 60 years and older Radiographic evidence of osteophytes Pain classification > Grade 0 on Graded Chronic Pain Scale Bilateral standing anterior posterior radiograph demonstrating Kellgren and Lawrence grade > 1 of t he target knee Physical limitations evidenced by either: OR Walking speed < 1. 2 m/sec during or inability to complete 400 m usual paced test Willingness to participate in all study procedures Exclusion criteria Failure to provide informed consent Regular participation in progressive, lower body resistance exercise training within the past 3 months Current involvement in supervised rehabilitation program Absolute contraindication(s) to exercise training according to American College of Sports Medicine guidelines Diagnosed peripheral vascular disease Ankle brachial index < 0.95 Resting office SBP > 160 mm Hg or < 90 mm Hg DBP > 100 mm Hg Complicated hypertension indicated by active use of > 2 antihypertensive medications Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically significant aortic stenosis, history of cardiac arrest or stroke, use of a car diac defibrillator, or uncontrolled angina; History of Deep venous thrombosis Known peripheral neuropathy History of rheumatoid arthritis Lower limb amputation Residence in a nursing home; (persons living in assisted or independent housing will not be ex cluded) Significant cognitive impairment, defined as a known diagnosis of dementia or a Mini Mental State Examination exam score < 24 Inability to communicate because of severe hearing loss or speech disorder Severe visual impairment, which would preclude completion of the assessments and/or intervention Other significant co morbid disease that would impair ability to participate in the exercise intervention Residence outside of the study site or is planning to move out of the area during the study timefr ame Simultaneous participation in another intervention trial

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39 Table 3 2. Data collection summary by study visit Study Phase Pre randomization Randomization Visit description (FU=follow up, CO=close out) Screen Baseline FU CO Visit number 1 2 3 4 Visit week 2 0 6 12 Informed consent, review inclusion/exlusion criteria x Personal intervie w, medical history, MSSE x Monitor vital signs x x x x Physical exam x 400 m walk x x x SPPB x x Randomization x Late Life Disability Questionnaire x x Blood collection (CBC, chemical chemistries) x x x Muscle function x x x G AIT Rite x x x

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40 CHAPTER 4 RESULTS Demographic C haracteristics Participant characteristics are presented in Table 4 1. Briefly, the mean age of the sample was 67.8 5.6 years, 62% of the sample was female, and the mean BMI was 29.7 5.0 kg*m 2 The mean 400m walking speed was 1.01 0.13 m/s and the mean SPPB score was 10.4 1.8. Importantly, baseline VAS pain score was statistically significantly higher in the CNTRL group at baseline (28.5 17.9 mm CNTRL vs. 13.8 17.5 mm BFR, p=0.02). No other statistically significant differences were observed between groups at baseline. Intervention Adherence and Perceived E xertion Overall attendance to the intervention was 74.1 2.7 % for CNTRL vs. 70.0 3.1% for BFR (p=0.691). Overall RPE for the 12 week intervention was similar between groups (8.1 0.5 vs 7.3 0.5, p=0.318). When comparing across sets, overall RPE was higher fo r the CNTRL intervention (Figure 4 1) However, RPE increased significantly from set one to set three in the BFR group (time condition interactions for each exercise p<0.05, Figure 4 1 ). To assess perceptual changes over the course of the intervention, ove rall RPE was calculated for each month of the intervention (i.e. weeks 1 4, weeks 5 8, and weeks 9 12 Figure 4 2 ). Overall monthly RPE increased significantly in BFR relative to CNTRL over the course of the intervention for leg press (F(1,21)= 14.906, time *condition interaction p=0.001) and leg extension (F(1,16)=17.726, p=0.001) but was similar for leg curl and calf flexion.

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41 Skeletal Muscle F unction One repetition maximum testing was performed for each exercise at baseline and week twelve ( Table 4 2 ). Time*condition interactions were not statistically significant for leg press (F(1,16)=3.44, p=0.082), leg extension (F(1,12)=4.54, p=0.054), leg curl (F(1,14)=3.60, p=0.078) or calf flexion (F(1,16)=0.159, p=0.695). However, increases in leg press (30.3 6.2 kg CNTRL vs. 13.4 6.2 kg BFR) leg extension (17.7 3.9 kg vs. 6.2 3.5 kg) and leg curl (7.8 2.7 kg vs. 0.4 2.7 kg) in response to the intervention tende d to favor the CNTRL condition Isokinetic k nee extensor strength, power and en durance we re tested at baseline, week six and week twelve ( Figures 4 3 through 4 8 ) Time*condition interactions revealed no statistically significant differences in knee extensor strength parameters between groups (p>0.05). Although not statistically significant, t he BFR group demonstrated slightly increased concentric total work at 60 degrees/sec (63.5 32.7 N*m CNTRL vs. 65.2 35.0 N*m BFR F(1,23)=0.43, p=0.837 ) 90 degrees/sec (36.9 24.6 N*m vs. 55.3 26.5 N*m F(1,23)=0. 25 p=0 .625 ) 120 degrees/sec (24.6 26.4 N*m vs. 26.5 28.5 N*m F(1,23)=0.45, p=0.835 ) and endurance total work (272.2 135.7 N*m vs. 317.8 132.9 N*m F(1,21)=0.05, p=0.818 ) relative to CNTRL. The BFR group also demonstrated a non statistically significant increase in concentric avera ge power at 90 degrees/sec relative to CNTRL (6.2 4.3 W for CNTRL vs. 11.6 4.6 W for BFR, F (1,23)=1.293, p=0.409). However, concentric average power tended to favor the CNTRL condition at 60 degrees/sec (11.0 3.5 W CNTRL, 9.1 3.8 W BFR, F( 1,23)=0. 226, p=0.639) 120 degrees/sec (9.7 6.5 W CNTRL vs.8.6 7.0 W BFR, F(1,23)=0.01, p=0.912) and endurance (8.3 3.2 W CNTRL vs. 6.8 3.1 W BFR, F(1,23)=0.11, p=.0744)

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42 M easures of P hysical F unction Gait speed over 400m was assessed at baseline, week six and week twelve. Change in 400m gait speed was not statistically significantly different between groups, but tended to favor the CNTRL intervention ( 0.01 0.03 m/s for CNRL vs. 0.06 0.03 m/s for BFR, group*time interaction F(1,24)=3.72, p=0.065) ( Table 4 3 ). In contrast, c hange in gait speed over 4m (0.08 0.02 m/s CNTRL vs. 0.08 0.02 m/s BFR, F(1,24)=0.01, p=0.936) and change in total balance score ( 0.14 0.20 points CNTRL vs. 0.32 0.20 points BFR, F(1,24)=0.373, p=0.547) were similar betw een groups in response to the intervention. Finally, total SPPB score tended to increase in both groups at week twelve relative to baseline (0.45 0.35 points CNTRL vs. 0.09 0.35 points BFR, main effect of time F( 1,24)=1.966 p=0. 174 ) but the this chang e was not statistically significant between groups ( time* condition interaction F(1,24)=0.479, p=0.496) Gait Gait parameters were assessed using the GAITRite system at baseline, week six and week twelve. Change in average velocity (5.7 2.4 cm/s CNTRL vs. 4.7 2.4 cm/s BFR, time*condition interaction F(1,23)=0.256, p=0.618) and normalized velocity (0.07 0.03 leg lengths/s CNTRL vs.0.05 0.03 leg lengths/s F(1,23)=0.455, p=0.507) were similar between groups in response to the interventi on (Figure 4 9). Similarly, changes in the ratio of left to right foot step length were similar between groups ( 0.39 0.37 CNTRL vs. 0.01 0.37 BFR, F(1,23)=0.484, p=0.494) but tended to favor the CNTRL intervention (Figure 4 10) While not statistical ly significant, changes in single leg stance time tended to favor the BFR group (0.02 0.24% CNTRL vs. 0.30 0.25% BFR, F( 1,23)=0.576, p 0.456, Figure 4 11). Finally, changes in toe in/out angle were

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43 similar between groups for the left (F(1,23)=0.266, p =0.611) and right feet (F(1,23)=0.316, p= .579, Figure 4 12). Self Assessed Pain and F unction Subjective measures of pain and physical function were assessed using the WOMAC and LLFDI questionnaires at baseline and week 12. Changes in WOMAC total score, p ain and physical function were similar between groups (all time*interaction p values >0.05, Table 4 4 ). While not statistically significant, change in stiffness score tended to favor the BFR group (0.45 0.54 points CNTRL vs. 0.61 0.56 points BFR, F(1,25)=1.536, p=0.227). In contrast, changes in LLFDI tended to favor the CNTRL intervention (Table 4 5). In particular, change in perceived functional limitation total score was significantly higher in CNTRL vs. BFR (11.0 3.3 points C NTRL vs. 5.0 3.0 points BFR, F(1,13)=9.064, p=0.010). Body C omposition Body composition was assessed using DE XA at baseline and week twelve ( Table 4 6 ). Change in total mass was similar between groups ( 0.39 0.71 kg CNTRL vs. 0.55 0.75 kg BFR, F(1 ,15)=0.020, p=0.889). However, while not statistically significant, changes in total lean mass (0.36 0.65 kg CNTRL vs. 0.70 0.69 kg BFR, F(1,15)=1.050, p=0.321), fat mass ( 1.07 0.56 kg CNTRL vs. 0.37 0.58 kg BFR, F(1,15)=1.808, p=0.199) and body fat percentage ( 1.25 0.55% CNTRL vs. 0.37 0.58% BFR, F(1,15)=3.565, p=0.079) tended to favor the CNTRL intervention. Serum Measures of Muscle H ypertrophy Serum IGF 1, TWEAK and P3NP were assessed at baseline, week six and week twelve (Figure 4 13) Change in IGF 1 in response to the intervention was similar between groups ( 0.009 0.019 arbitrary units CNTRL vs. 0.011 0.019 units BFR,

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44 F(1,23)=0.189, p=0.878). Se rum P3NP expression was significantly reduced from baseline in BFR relative to CNTRL following the intervention ( 0.03 0.08 units CNTRL vs. 0.23 0.08 units BFR, F(1,23)=5.228, p=0.032). Finally, while not statistically significant, serum TWEAK expression was slightly reduced from baseline in CNTRL relative to BFR following the intervention ( 19.0 22.4 pg/mL CNTRL vs. 3.7 20.5 pg/mL BFR, F(1,20)=0.489, p=0.493) Correlations To determine the relationship between skeletal muscle adaptations and functional outcomes in response the intervention, changes in seru m markers of muscle hypertrophy were correlated with study outcomes (Tables 4 7 through 4 15). Serum expression of P3NP, a marker of skeletal muscle collagen synthesis, was demonstrated moderate to strong significant correlations with eccentric isokinetic knee extensor peak torque, power, and work at weeks six and twelve (Tables 4 7 through 4 10) Serum TWEAK was negatively correlated with body fat percentage and total fat mass at baseline and week twelve (Table 4 15).TWEAK also demonstrated a strong, posit ive correlation with 400m walk speed at baseline and week 12 (Table 4 11).

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45 Table 4 1. Participant characteristics CNTRL N=19 BFR N=16 p value Age (years) 69.17.1 67.25.2 0.390 Female 15 (78.9%) 10 (62.5%) 0.2833 BMI (kg*m 2 ) 29.85.3 31.75.9 0.327 Minority 3 (15.8%) 2 (12.5%) 0.633 Education 0.102 High school or equivalent 2 (10.5%) 2 (12.5%) Technical degree 1 (6.3%) Some college 6 (31.6%) College degree 4 (21.1%) 7 (43.8%) Professional or grad degree 6 (31.6%) 6 (37.5%) MM SE score 28.21.3 28.31.5 0.831 VAS pain score (mm) 28.517.9 13.817.5 0.020* WOMAC pain 33.619.0 30.613.7 0.597 Daily moderate activity time (3.0 6.0 METs) 56.164.2 32.622.9 0.210 400m walk speed (m/s) 1.010.11 1.040.12 0.455 SPPB score 10.21.9 10.41.9 0.742 All values presented as mean standard error or n(%). Abbreviations: BMI=Body mass index. M MSE=Modified mini mental state examination. VAS=Visual analog scale. WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index. MET=metabolic equivalent of task. SPPB=Short physical performance battery.

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46 Table 4 2. One repetition maximums CNTRL BFR Exercise Baseline Wk 12 Change Wk 12 Change Time*condition (p value) Leg press 67.5 0 97.8 6.2 30.3 6.2 80.8 6.2 13.4 6.2 0.082 Leg extension 45.4 0 63.1 1.0 17.7 4.0 51.6 1.1 6.2 3.5 0.054 Leg curl 45.9 0 53.7 10.3 7.8 2.7 46.3 11.6 0.4 2.7 0.078 Calf flexion 72.6 0 102.5 4.7 29.9 7.6 98.1 5.3 25.5 7.6 0.090 Values are expressed in kg and expressed as mean standard error Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable.

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47 Table 4 3. Objective measures of physical function CNTRL BFR Variabl e Baseline Wk 12 Change Wk 12 Change Time*condition (p value) 400m walk speed (m/s) 1.05 0 1.05 0.01 0.01 0.02 0.99 0.02 0.06 0.02 0. 065 SPPB gait speed (m/s) 0.93 0 1.02 0.02 0.08 0.02 1.01 0.02 0.08 0.02 0.936 Chair stand score 2.9 0 3.3 0. 2 0.4 0.2 3.2 0. 2 0 3 0. 2 0. 809 Total balance score 3.8 0 3.7 2.0 0.1 0.2 3.5 0.2 0.3 0.2 0.547 Total SPPB score 10.5 0 10.9 0.3 0.4 0.3 10.6 0.3 0.1 0.3 0.496 Values are expressed as mean standard error. Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable. Abbreviations: SPPB=Short physical performance battery.

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48 Table 4 4. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) CNTRL BFR Variable Baseline Week 12 Change Week 12 Change Time*conditio n p value Total score 31.9 0 29.9 3.3 2.0 3.3 28.9 3.5 3.0 3.5 0.850 Pain 6.9 0 5.8 0.9 1.1 0.9 6.4 0.9 0.5 0.9 0.673 Stiffness 3.6 0 4.0 0.5 0.5 0.5 3.0 0.6 0.6 0.6 0.227 Function 21.3 0 20.1 2.2 1.2 2.2 18.4 2.3 2.9 2.3 0.632 Values are expressed as mean standard error Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable.

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49 Table 4 5. Late Life Function and Disability Instrument CNTRL BFR Variable Baseline Week 12 Change Week 12 Change Time*condition p value Frequency total scale 53.0 0 54.9 1.6 1.9 1.6 50.6 1.5 2.5 1.5 0.111 Frequency social scale 48.8 0 51.1 2.0 2.3 2.0 45.4 2.0 3.4 1.9 0.111 Frequency personal scale 63.9 0 68.1 5.4 4.2 5.4 70.0 5.0 2.9 5.0 0.430 Limitation total scale 68.8 0 79.8 3.3 11.0 3.3 63.8 3.0 5.0 3.0 0.010* Limitation instrumental scale 68.4 0 80.8 4.0 12.4 4.0 63.7 3.7 4.7 3.7 0.022* Limitation management scale 82.8 0 92.7 4.5 9.9 4.5 77.4 4.2 5.4 4.2 0.055 Values are expressed as mean standard error Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable. *indicates statistical significance at p<0.05.

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50 Table 4 6 Body composition CNTRL BFR Variable Baseline Wk 12 Change Wk 12 Change Time*condition (p value) Total mass (kg) 82.4 0 82.0 0.7 0.4 0.7 81.8 0.8 0.5 0.8 0.889 Total lean mass (kg) 47.1 0 47.4 0.6 0.4 0.6 46.4 0.7 0.7 0.7 0.321 Lean mass BMC (kg) 49.3 0 49.8 0.6 0.6 0.6 48.7 0.6 0.5 0.6 0.235 Fat mass (kg) 33.1 0 32.1 0.6 1.1 0.6 33.2 0.6 0.1 0.6 0.199 Body fat (%) 40.0 0 38.8 0.5 1.2 0.5 40.4 0.6 0.4 0.6 0.079 Android/gynoid ratio 1.06 0 1.05 0.02 0.01 0.02 1.06 0.02 0.01 0.02 0.847 Values are expressed as mean standard error Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable. Abbreviations: BMC=Bone mineral content.

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51 Table 4 7 Correlations between serum markers of skeletal muscle hypertrophy and isokinetic knee extensor strength at 60 degrees/s BL 6wk 12wk IGF1 P3NP T WEAK IGF1 P3NP Tweak IGF1 P3NP T WEAK Variable Avg. PT extension 0.139 0.038 0.174 0.022 0.293 0.163 0.037 0.218 0.013 Avg. PT flexion 0.058 0.214 0.214 0.089 0 .517 0.151 0.194 0 .482 0.037 Avg power extension 0.102 0.034 0.146 0.065 0.296 0.034 0.057 0.022 0.086 Avg. power flexion 0.069 0.123 0.172 0.148 0 .534 0.040 0.212 0 .410 0.066 Total work extension 0.139 0.028 0.143 0.114 0.242 0.155 0.022 0.193 0.016 Total work flexion 0.075 0.143 0.193 0.092 0 .537 0.110 0.224 0 .468 0.035 Values presented as Pearson correlation coefficient (r). *I ndicates statistical significance (p<0.05). Abbreviations: PT=Peak torque. IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III TWEAK=Tumor necrosis like weak inducer of apoptosis

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52 Table 4 8 Correlations between serum markers of skeletal muscle hypertro phy and isokinetic knee extensor strength at 90 degrees/s BL 6wk 12wk IGF1 P3NP T WEAK IGF1 P3NP Tweak IGF1 P3NP T WEAK Variable Avg. PT extension 0.161 0.029 0.057 0.060 0.263 0.214 0.112 0.040 0.158 Avg. PT flexion 0.096 0.125 0.136 0.209 0 .503 0.115 0.247 0 .429 0.032 Avg power extension 0.102 0.034 0.146 0.065 0.296 0.034 0.057 0.022 0.086 Avg. power flexion 0.069 0.123 0.172 0.148 0 .534 0.040 0.212 0 .410 0.066 Total work extension 0.193 0.043 0.069 0.129 0.201 0.160 0.083 0.012 0.111 Total work flexion 0.069 0.084 0.172 0.138 0 .511 0.075 0.231 0 .386 0.032 Values presented as Pearson correlation coefficient (r). *Indicates statistical significance (p<0.05). Abbreviations: PT=Peak torque. IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III TWEAK=Tumor necrosis like weak inducer of apoptosis

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53 Table 4 9 Correlations between serum markers of skeletal muscle hypertrophy and isokinetic knee extensor strength at 120degrees/s BL 6wk 12wk IGF1 P3NP Tweak IGF1 P3NP T WEAK IGF1 P3NP T WEAK Variable Avg. PT extension 0.202 0.121 0.003 0.118 0.059 0.014 0.076 0.010 0.013 Avg. PT flexion 0.138 0.009 0.103 0.020 0.248 0.029 0.121 0 .411 0.069 Avg power extension 0.193 0.012 0.031 0.105 0.199 0.082 0.062 0.153 0.209 Avg. power flexion 0.141 0.058 0.131 0.151 0.348 0.003 0.005 0 .424 0.018 Total work extension 0.145 0.025 0.147 0.051 0.325 0.029 0.109 0 .402 0.006 Total work flexion 0.193 0.044 0.019 0.212 0.121 0.095 0.027 0.111 0.080 Values presented as Pearson correlation coefficient (r). *Indicates statistical significance (p<0.05). Abbreviations: PT=Peak torque. IGF1=Insulin like growth factor 1. P3NP= N terminal pept ide of procollagen type III. TWEAK=Tumor necrosis like weak inducer of apoptosis

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54 Table 4 10 Correlations between serum markers of skeletal muscle hypertrophy and isokinetic knee extensor endurance BL 6wk 12wk IGF1 P3NP T WEAK IGF1 P3NP Tweak IGF1 P3NP T WEAK Variable Avg. PT extension 0.004 0.106 0.028 0.007 0.353 0.305 0.171 0.209 0.042 Avg. PT flexion 0.096 0.044 0.249 0.031 0.316 0 .409 0.126 0 .457 0.128 Avg power extension 0.030 0.066 0.010 0.022 0.352 0.257 0.151 0.240 0.024 Avg. power flexion 0.019 0.150 0.162 0.114 0.340 0.247 0.111 0 .437 0.112 Total work extension 0.045 0.057 0.000 0.112 0.210 0.258 0.066 0.141 0.055 Total work flexion 0.023 0.144 0.186 0.071 0.302 0.303 0.077 0 .453 0.178 Values presented as Pearson correlation coefficient (r). *Indicates statistical significance (p<0.05). Abbreviations: PT=Peak torque. IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III. TWEAK=Tumor necrosis like weak induce r of apoptosis

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55 Table 4 11 Correlations between serum markers of skeletal muscle hypertrophy, 400m walk and SPPB BL 12wk IGF1 P3NP T WEAK IGF1 P3NP T WEAK Variable Fastest walk time 0.004 0.125 0.213 0.076 0.063 0.186 Chair stand time 0.179 0.070 0.263 0.137 0.139 0.318 SPPB Gait speed 0.003 0.145 0.294 0.119 0.105 0.149 400m walk speed 0.281 0.104 0 561 0.243 0.040 0 .508 Total Balance score 0.106 0.008 0.066 0.103 0.042 0.008 Speed score 0.104 0.137 0.255 0.068 0.054 0.068 Chair score 0.107 0.032 0.201 0.141 0.028 0.013 Total score 0.004 0.036 0.249 0.099 0.017 0.057 Values presented as Pearson correlation coefficient (r). *indicates statistical significance (p<0.05). Abbreviations: SPPB=Short physical performance battery. IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III. TWEAK=Tumor necrosis like weak inducer of apoptosis

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56 Table 4 1 2 Correlations between serum markers of skeletal muscle hypertrophy and G AITRite parameters BL 6wk 12wk IGF1 P3NP T WEAK IGF1 P3NP Tweak IGF1 P3NP T WEAK Variable Velocity 0.159 0.008 0.060 0.006 0.039 0.097 0.096 0.014 0.133 Normalized velocity 0.159 0.008 0.060 0.006 0.039 0.097 0.145 0.239 0.151 Step length differential 0.106 0.176 0.085 0.211 0.048 0.149 0.063 0.008 0.189 Cycle time differential 0.084 0.114 0.502 0.291 0.060 0.150 0.166 0.039 0.195 Toe in/out right foot 0.048 0.025 0.219 0.175 0.185 0.178 0.015 0.229 0.170 Toe in/out left foot 0.065 0.071 0.264 0.108 0.050 0.267 0.066 0.150 0.280 Single leg support 0.054 0.113 0.272 0.047 0.086 0.210 0.007 0.190 0.252 *Indicates statistical significance (p<0.05). Abbreviations: IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III. TWEAK=Tumor necrosis like weak inducer of apoptosis

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57 Table 4 13. Correlations between serum markers of skeletal muscle hypertrophy and WOMAC BL 12wk IGF1 P3NP T WEAK IGF1 P3NP T WEAK Variable Pain 0.092 0.135 0.020 0.052 0.016 0.059 Stiffness 0.035 0.081 0.091 0.190 0.163 0.270 Physical function 0.125 0.018 0.168 0.211 0.195 0.012 Total 0.104 0.045 0.149 0.044 0.096 0.010 *Values presented as coefficient (r ho ). *indicates statistical significance (p<0.05). Abbreviations: WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index. IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III. TWEAK=Tumor necrosis like weak inducer of apoptosis

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58 Table 4 1 4 Correlations between serum markers of skeletal muscle hypertrophy and LLFDI BL 12wk IGF1 P3NP T WEAK IGF1 P3NP T WEAK Variable Frequency total 0.074 0.033 0.319 0.039 0.011 0.259 Frequency social 0.159 0.006 0.321 0.355 0.013 0.417 Frequency personal 0.184 0.085 0.270 0.171 0.035 0.301 Limitation total 0.130 0.118 0.123 0.009 0.040 0.164 Limitation instrumental 0.192 0.126 0.035 0.008 0.051 0.184 Limitation management 0.143 0.096 0.292 0.118 0.051 0.282 *Values presented as Pearson correlation coefficient (r). LLFDI=Late Life Function and Disability In strument IGF1=Insulin like growth factor 1. P3NP= N terminal peptide of procollagen type III. TWEAK=Tumor necrosis like weak inducer of apoptosis

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59 Table 4 1 5 Correlations between serum markers of skeletal muscle hypertrophy and body composition BL 12wk IGF1 P3NP T WEAK IGF1 P3NP T WEAK Variable Body fat % 0.030 0.087 0 .392 0.183 0.257 0.417 Android/gyn oid ratio 0.267 0.178 0.186 0.270 0.180 0.180 Appendicular lean mass/height 0.136 0.257 0.094 0.136 0.018 0.145 Total fat mass 0.087 0.005 0 .457 0.028 0.236 0 .489 Total lean mass + BMC 0.094 0.134 0.092 0.388 0.118 0.075 Values presented as Pearson correlation coefficient (r). *indicates statistical significance (p<0.05).

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60 Figure 4 1. Change in ratings of perceived exertion (RPE) across sets for A) leg press B) leg extension C) leg curl D) calf flexion exercises. Model was adjusted for age, sex, baseline pain rating

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61 Figure 4 2. Change in ratings of perceived exertion (RPE) across weeks 1 4, 5 8, and 9 12 of the intervention for A) leg press B) leg extension C) leg curl and D) calf flexion exercises. Model was adjusted for age, sex, and baseline pain rating

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62 Figure 4 3. Concentric isokinetic knee extensor avera ge peak torque (Newton*meters) measured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) across 50 repetitions (endurance) at 120 degrees/s. Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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63 Figure 4 4. Eccentric isokinetic knee extensor average peak torque (Newton*meters) measured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) across 50 repetitions (endurance) at 120 degrees/s Model was adjusted for ag e, sex, baseline pain rating and baseline value of the corresponding variable

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64 Figure 4 5. Concentric isokinetic knee extensor average peak power (Watts) measured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) acr oss 50 repetitions (endurance) at 120 degrees/s Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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65 Figure 4 6. Eccentric isokinetic knee extensor average peak power (Watts) me asured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) across 50 repetitions (endurance) at 120 degrees/s Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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66 Figure 4 7. Concentric isokinetic knee extensor total work (Newton*meters) measured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) across 50 repetitions (endurance) at 120 degrees/s Model was adjusted for age, sex, baseline pain rating and baseline v alue of the corresponding variable

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67 Figure 4 8. Eccentric isokinetic knee extensor total work (Newton*meters) measured at A) 60 degrees/s B) 90 degrees/s C) 120 degrees/s and D) across 50 repetitions (endurance) at 12 0 degrees/s Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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68 Figure 4 9. Change in gait parameters assessed by G AITRite A) Velocity measured in meters/s B) Velocity normal ized to leg length and expressed as leg length/s. Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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69 Figure 4 10 Change in gait parameters assessed by G AITRite A) Cycle time differential expressed as the ratio of left:right foot cycle time. B) Step length differential express ed as the ratio of left:right foot step length. Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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70 Figure 4 11. Change in gait parameters assessed by G AITRite A) Cycle time differential expressed as the ratio of left:right foot cycle time. B) Step length differential express as the ratio of left:right foot step length. Model was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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71 Figure 4 12. Change in gait parameters assessed by G AITRite A) Toe in/out angle of left the left foot expressed as degrees of deviation from midline B) Toe in/out angle of left the right foot expressed as degrees of deviation from midline M odel was adjusted for age, sex, baseline pain rating and baseline value of the corresponding variable

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72 Figure 4 13. Change in serum markers of skeletal muscle hypertrophy. A) Serum N terminal peptide of procollagen type III (P3NP) B) Serum insulin like growth factor 1. C) Serum tumor necrosis like weak inducer of apoptosis Model was adjusted for age, sex, baseli ne pain rating and baseline value of the corresponding variable

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73 CHAPTER 5 DISCUSSION The primary objective of the present analysis was to assess the physical and skeletal muscle functional adaptations to twelve weeks of lower body resistance e xercise alone or combined with BFR among older adults with knee OA. Secondarily, we assessed changes in serum markers of skeletal muscle hypertrophy and determined their relationship to changes in muscle function, body composition and physical function. Th e primary findings from the present analysis indicate that changes in lower body strength assessed by 1RM and isokinetic knee extensor strength parameters tended to favor the CNTRL group. Furthermore, 400m walk speed, subjective measures of physical functi on (LLFDI) and changes in body composition (body fat mass, lean mass) also tended to favor the CNTRL group. Other measures including objective measures of physical function (SPPB), subjective measures of pain (WOMAC) and gait parameters were similar betwee n groups. Additionally, serum P3NP expression was significantly higher in CNTRL compared to BFR at week 12, while serum total IGF 1 tended to be higher in CNTRL. Serum TWEAK tended to be lower in CNTRL at week 12. Finally, we found that serum P3NP was posi tively associated with eccentric isokinetic knee extensor strength parameters, while serum TWEAK demonstrated a strong, positive association with 400m walk speed and a moderate, negative association with body fat mass. The addition of BFR to low load resi stance exercise was previously shown to increase skeletal muscle strength relative to low load exercise alone. 5 However, the majority of studies in healthy adults report greater increased strength from traditio nal high load exercise compared to BFR. 5,159 Our findings indicate that strength changes

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74 were not statistically significantly different between BFR and CNTRL. However, the majority o f isokinetic knee extensor strength measures and changes in 1RMs tended to favor CNTRL over BFR. To our knowledge, only one other study has compared BFR to high load exercise in persons with knee OA. In contrast to the present study, Bryk et al. 133 reported greater isometric knee extensor strength gains in BFR (30% 1RM, 200mmHg cuff pressure) relative to high load training (70% 1RM). However, some key differences between these studies may explain this discrep ancy. For example, the training protocol utilized by Bryk et al. was similar between groups with the exception of seated knee extensions which were performed with or without BFR. These additional exercises (e.g. hip and thigh adduction abduction) performed with similar loads may have augmented the BFR training response. Furthermore, the BFR group used a higher load for training (30% vs 20% in the present study). Finally, Bryk et al. prescribed a set number of repetitions as opposed to performing exercises t o volitional fatigue 204 More research is needed to determine optimal training variables to elicit knee extensor strength adaptations, as knee extensor strength is associated with risk of symptomatic knee OA, 160 pain, 31,40 joint space narrowing 161 163 cartilage thickness 43,49,164 and physical function 165 in persons with OA. Additionally, the knee extensors play an important role in shock absorption and gait stability during ambulation. 46,47,166 As a result, knee extensor weakness may lead to altered gait mechanics, 44,45 which can inc rease OA risk or accelerate joint damage. 167 Specifically, the knee extensors are activated eccentrically during the contact phase of the gait cycle and prevent forward excursion of the knee, 168 such that persons with greater ability to produce eccentric force have less knee damage over time. 169

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75 Furthermore, knee extensor eccentric force is associated with knee pain, function 170 and balance in persons with OA. 171 Although these associations were not explored in the present analysis, several objective (gait speed) and subjective measures of phy sical function (LLFDI) tended to favor the CNTRL intervention. Although speculative, these findings may be at least partially explained by the tendency to increase knee extensor eccentric force characteristics in the CNTRL group relative to BFR. Interesti ngly, we found moderate to strong correlations between P3NP -a serum marker of skeletal muscle hypertrophy produced during skeletal muscle collagen formation 14 -and knee extensor eccentric peak torque, power, a nd total work. This finding suggests that the relative increase in knee extensor eccentric force production may be due to increased skeletal muscle hypertrophy. In support of this hypothesis, we found that the CNTRL group tended to increase lean body mas s relative to BFR over the course of the intervention. However, this remains speculative as we did not directly measure changes in knee extensor skeletal muscle CSA or thigh mass. Furthermore, it is unclear why P3NP expression is correlated only with eccen tric knee extensor force characteristics. While speculative, it is likely that the lower load used for the BFR intervention was not a sufficient stimulus to evoke optimal adaptations for eccentric force production. For example, Yasuda et al. 172 compared eccentric only BFR exercise to concentric eccentric BFR exercise. The concentric eccentric training evoked significant increases in skeletal muscle CSA and strength, while these measures were unchanged after eccen tric only exercise. T hese findings may warrant future research, as knee extensor eccentric strength is a major determinant of physical function in persons with knee OA. 173

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76 Although changes in strength tended to favor the CNTRL intervention, it is also important to consider the perceptual responses to the interventions as higher perceived exertion may result in lower adherence over time Previous studies have shown higher load training may have lower adherence rates tha n lighter load training in persons with OA. 80 In the present analysis, overall RPE was significantly lower in BFR relative to CNTRL. This is consistent with numerous BFR studies showing that RPE is lower for BFR compared to high load training. 174 177 However, RPE increased significantly across sets (set 1 to set 3) and over time (month 1 to month 3) relative to CNTRL. This finding is in contrast to a longitudinal study showing that RPE significantly decreases with subsequent training sessions with BFR (20% 1RM) relative to high load training (85% 1RM). 174 However, this study was performed in recreationally active young males which may partially explain this discrepancy. Nonetheless, our findings indicate that while BFR appears to be better tolerated overall relative to high load training, the re are marked perceptual changes over time that could potentially limit the long term applicability of BFR training in older adults with knee OA. Despite this potential limitation, BFR may be particularly appropriate as a short term intervention for impro ving strength in lower functioning patients or patients awaiting joint replacement. Furthermore, RPE in BFR training can be impacted by numerous factors including cuff size and material, 178,179 occlusion pressure, 180 type of pressure application (i.e. continuous vs. intermittent), 176 load, 174 and exercise modal ity. Thus clinicians looking to implement BFR training long term for persons with musculoskeletal disorders may consider varying these factors to offset changes in perceptual responses with training. However, more work is needed to confirm the validity of this approach.

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77 Persons with OA are at significantly greater risk of becoming disabled. 21,22 Thus assessment of physical function is critical for determining the e fficacy of interventio ns in older adults with knee OA. Functional tests such as the SPPB and 400m walk have been validated among older adults for testing physical function and are highly associated with disability risk and mortality. 145,154,181 In the present analysis, while not statistically significant, 400m walk speed tended to decrease in BFR. Furthermore, this decrease was clinically significant ( 0.05 m/s). 182 In contrast, gait speed over 4m tended to increase to a similar extent in both groups following the intervention. It is unclear what caused this discrepancy, as related knee extensor strength parameters 183 185 including peak torque, power, and peak torque to body mass (not shown) tended to increase over the course of the intervention in both groups. However, it should be noted that while both the 4m and 400m walk tests are measures of lower extremity function, the 400m walk test is likely influenced by aerobic fitness and capacity and therefore may be more sensitive to factors that affect endurance (e.g. c ardiovascular comorbidities or sarcopenic obesity 186 ). In support of this hypothesis, the BFR group tended to increase fat mass and lose lean mass over the course of the intervention, whereas the CNTRL group tended to lose fat mass and gain lean mass. Alt hough knee extensor peak torque relative to body weight tended to increase in the BFR group (not shown), these changes in body composition may have negatively impacted the endurance capabilities of participants in the BF R group, resulting in lower gait spe ed over 400m. Interestingly, we also found that serum TWEAK demonstrated a strong, positive correlation with 400m gait speed both at baseline and at 12 weeks. While acute increases in TWEAK signaling following

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78 exercise are associated with skeletal muscle m signaling, 187 chronically elevated TWEAK expression is associated with skeletal muscle atrophy, 188,189 cardiovas cular morbidities 190 and obesity. 191 However, we found that serum TWEAK demonstrated a moderate, negative correlation with total fat mass and body fat percentage at b aseline and week 12. These correlations and changes in body composition and function correspond with a t r end toward a decrease in serum TWEAK in CNTRL versus no change in BFR. Although we cannot establish a causal relationship between changes in serum TWEA K and these outcomes, these findings indicate that persons with higher serum TWEAK have lower body fat mass and higher gait speed over 400m. However, as this relationship is in contrast to much of the published literature, extensive follow up will be neede d to confirm this association and determine the efficacy of serum TWEAK as a biomarker of physical function in persons with OA. In addition to slower walking speed and reduced physical function, persons with knee OA tend to have altered gait parameters re lative to healthy controls. 192 These alterations appear to become more pronounced with increasing disease severity. 167 For example, persons with OA have greater step l ength and cycle time differential, which are indicative of gait asymmetry. In turn, gait asymmetry is associated with physical function, fall risk 193,194 and joint degradation 195 on older adults. In the present study, cycle time differential tended to decrease in both groups, while step length differential only tended to decrease in the CNTRL group at week 12 While step length differential was decreased at week 6 in B FR it returned to baseline levels at week 12. Although the reason for this reversal is unclear, it may be important to follow up with future studies to determine the role of strength training for improving gait asymmetry in per sons with OA.

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79 To our knowledge, no study to date has explored this relationship. However, Laroche et al. 196 observed greater gait asymmetry in persons with knee extensor strength asymmetry between legs. Thus, targe ting strength asymmetry with resistance exercise may be a potential preventative or rehabilitative intervention for persons with knee OA. Another gait abnormality associated with knee osteoarthritis is the toe in/out angle. Specifically, greater toe out an gle reduces knee adduction moment (KAM) in the coronal plane during ambulation 197 However, it has been suggested that patients with knee OA are unable to toe out effectively due to knee and shank misalign ment. 197 Greater toe out angle is associated with lower symptomatic OA 198 and a reduced risk of OA disease progression, likely due to reduction of KAM and other loading forces on the knee during gait. 199 In the present study, toe out angle tended to decrease at week 6 in the BFR group (left foot), but returned to baseline at week 12. In contrast, toe out angle tended to increase slig htly in the CNTRL group. Toe out angle tended to decrease to a similar extent in both groups for the right foot. To our knowledge, the impact of resistance training on toe out angle has not been explored in the literature. However, increases in toe out ang le were observed in persons recovering from knee arthroplasty, and this increase corresponded with recovery of knee and hip musculature strength 200 Furthermore, targeted gait interventions have demonstrated tha t toe out angle can be adapted. 198 Future studies may explore the use strength training to augment targeted gait training for increasing toe out angle in persons with knee OA. We also evaluated changes in single leg st ance (SLS) in response to the intervention. This gait parameter measures the percentage of the gait cycle spent supported on one leg (i.e. while the opposite leg swings forward). Persons with OA have

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80 smaller SLS relative to healthy controls, 201 and this appears to be a compensation strategy to reduce joint loading on the affected side. 19 In healthy adults, SLS is reportedly 38 40%. 2 02 Participants in our study had slightly lower SLS than healthy adults (34.4% at baseline), which is consistent with a previous study. 203 While SLS did not change over the course of the intervention for the CN TRL group, SLS decreased at week 6 but recovered to near baseline levels at week 12 in the BFR group. While it is unclear why SLS initially decline in the BFR group, this change may be partially explained by changes in pain and self assessed function. 204 Although we showed a trend toward a decrease in WOMAC st iffness in the BFR group relative to CNTRL phy sical limitations on the LLFDI significantly increase d in CNTR L relative to BFR, indicating lower fu nction in the BFR group. While speculative, these changes in self assessed pain and function may partially explain the unfavorable changes in gait speed, step length differential and SLS in BFR observed in the present study. 205 Thus, t hese associations and their underlying causes may warrant future research Furthermore, while changes in SLS with resistance exercise have not been explored, patients recovering from hip arthroplasty increased SLS on the affected limb tw o years after surgery, and this increase corresponded with recovery of knee musculature strength. 18 This suggests that improving muscle strength may improve SLS, possibly by redu cing pain and guarding behavior durin g ambulation. Limitations The strengths of the present study include a clinically relevant population and outcomes, good adherence to the exercise interventions, and a relatively long period of intervention and follow up. However, this trial was designed a s a pilot trial to determine

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81 the efficacy and feasibility of BFR training for older adults with knee OA, with the intention of performing a larger, fully powered trial in the future. Thus the present study was not statistically powered to detect difference s in study outcomes and results must be interpreted with caution. Another potential limitation is that the participants performed all exercises to volitional fatigue. We chose this method of training to account for differences in workload resulting from th e use of a fixed repetition prescription with different loading paradigms between groups. Indeed, performance of resistance exercise to volitional fatigue results in similar strength and skeletal muscle hypertrophic responses between high and low load exer cise. 206,207 However, we cannot rule out that differences in workload may have significantly influenced outcomes such as body composition. Another limitation of the present study involves tec hnical limitations with the C terminal agrin fragment (CAF) analysis. We had planned to evaluate changes in serum CAF, a serum marker of skeletal muscle hypertrophy and neuromuscular adaptations. 208 However, due to technical problems with the analysis kits this analysis could not be completed. The addition of serum CAF measurements could have helped to clarify the mechanisms linking skeletal muscle adaptations such as hypertrophy with changes in knee extensor stre ngth and other functional outcomes. This objective could have been further augmented by direct measurement of skeletal muscle CSA and related hypertrophy markers (e.g. TWEAK receptor FN14, satellite cell activity, and myogenic regulatory factors) from skel etal muscle tissue Future studies are needed to evaluate these possibilities. A final limitation with the present study involves the methods used to induce BFR. As discussed previously, a number of factors may dictate the outcomes to BFR

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82 training, including cuff width and material, occlusion pressure, intermittent vs. continuous pressure application, exercise modality and load (%1RM). At the present time, no optimal combination of these factors has been identified for maximizing skeletal m uscle strength and functional outcomes, particularly in persons with knee OA. As a result, caution is advised when comparing the results of this study with other trials utilizing different training protocols. While experimentally difficult, outcomes may be further optimized by introducing variation of these and other factors throughout the intervention. For example, knee extensor power 209 and eccentric strength 210 are imp ortant determinants of function and disease progression in persons with knee OA Thus inclusion of power training and/or eccentric accentuated exercises may be beneficial for improving knee extensor strength parameters when using BFR training in this population. Conclusions We found that changes in skeletal muscle strength, walking speed, subjective measures of physical function and body composition tended to favor the CNTRL group following twelve weeks of either high load resistance exercise (C NTRL) or low load resistance exercise combined with BFR in older adults with knee OA. Other outcomes objective measures of physical function (SPPB) and self assessed pain and stiffness were similar between groups. Furthermore, we found that serum expressio n of TWEAK and P3NP were associated with numerous outcomes including eccentric knee extensor strength parameters, walking speed over 400m and changes in body fat mass. Thus, these measures have potential utility as biomarkers of functional changes in respo nse

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83 to exercise interventions. However, results from the present study must be interpreted with caution as the trial was not designed to assess changes in these outcomes.

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84 APPENDIX A WESTERN ONTARIO AND MCMASTER UNIVERSITIE S OSTEOARTHRITIS IND EX

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85 APPENDIX B LATE LIFE FUNCTION A ND DISABILITY INSTRU MENT

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111 BIOGRAPHICAL SKETCH Andrew Steven Layne earned a Bachelor of Science degree in exercise science from East Tennessee State University in 2008 and a Master of Arts in exercise physiology in 2010. Andrew then received a graduate school fellowship award to begin his doctoral studies in exercise physiology at the University of Florida, which he has been on improving physical performance through resistance exercise. Andrew has worked with a wide range of populations from athletes to the elderly in research, commercial and corporate settings.