Sex-specific Determinants of Early-phase Recovery From Skeletal Muscle Disuse

Study Overview
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Brief Summary
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This project is a 2-phase, randomized clinical trial that includes 7 days of unilateral leg disuse (Phase 1), immediately followed by 14 days of bilateral leg rehabilitation (Phase 2). The investigators will recruit cohorts of healthy middle-aged men and women to address their aims: Demonstrate the sex-specific effects of skeletal muscle disuse (Phase 1) Identify key molecular determinates of susceptibility of skeletal muscle atrophy (Phase 1) Map the early, sex-specific molecular time-course of rehabilitation (Phase 2) Determine if disused and healthy muscle respond similarly to exercise (Phase 2) Healthy, middle-age men and post-menopausal women (50-65 years) will be recruited from the greater Houston/Galveston area. This under-represented research demographic demonstrate few negative metabolic or phenotypic signs of advanced age, but are at increased risk of being hospitalized and experiencing accelerated loss of lean mass and muscle function that parallels a much older population. The goal of this study is to characterize phenotypic and molecular skeletal muscle changes in middle-aged men and women during critical periods of disuse and rehabilitation and ultimately direct the development of targeted and effective prevention and treatment strategies.

Detailed Description
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The negative health consequences of muscular disuse in aging populations are unequivocal. While descriptive, outcome data on disuse and recovery are abundant, key knowledge gaps limit researcher's ability to implement evidence-based, rehabilitation strategies. Limiters include: i) an inability to identify individuals most susceptible to disuse, ii) insufficient information to differentiate between, and respond to, disuse atrophy in men and women, iii) limited insight into the mechanisms driving adaptation to early rehabilitative exercise, and iv) the assumption that disused and healthy skeletal muscle will have a similar, positive response to resistance exercise. The investigators will complete a 2-phase, randomized clinical trial at the University of Texas Medical Branch (UTMB). The protocol includes 7-days of unilateral leg disuse (ULD; Phase 1), immediately followed by 14-days of bilateral leg rehabilitation (Phase 2). Healthy, middle-aged men (n=40) and (post-menopausal) women (n=40), (50-65 y) will be recruited; a neglected research demographic who present with a largely youthful phenotype, but are at risk of accelerated disuse atrophy. This project will provide a highly powered, detailed phenotypic characterization of the continuum of adults most and least susceptible to muscular disuse. Clinical outcomes will be supported by RNA deep sequencing and pathway analysis to establish a platform that: i) improves scientists' ability to identify higher-risk individuals and ii) provides insight into time-sensitive, sex-specific and effective rehabilitation strategies. Findings and reposed molecular data from this study, may help identify future therapeutic targets and serve as an uncomplicated/comorbidity-free baseline for clinical trials in populations experiencing disuse atrophy.

Official Title
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Sex-specific Determinants of Early-phase Recovery From Skeletal Muscle Disuse

Conditions
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Atrophy of Muscle Due to Disuse, Rehabilitation

Intervention / Treatment
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* Other: Resistance Exercise Rehabilitation
* Other: Walking-based rehabilitation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All races and ethnic backgrounds Men and women, age 50-65 years Generally healthy (see exclusion criteria) Able and willing to provide informed consent Ability to speak and read English Post-menopausal women (no menses within the last 12 months) Body mass index: 18.5-35 kg/m2 or BMI>35 if thigh adiposity does not impair muscle biopsy Exclusion Criteria: Compromised musculoskeletal function that precludes safe participation or use of crutches Pre-menopausal women Hypogonadal men (testosterone <300 ng/dL) Women taking hormone replacement therapy (HRT) Sarcopenia (European Working Group on Sarcopenia in Older People, EWGSOP102) Clinically significant heart disease (e.g. New York Heart Classification greater than grade II; ischemia) Peripheral vascular disease History of claudication Pulmonary disease History of systemic or pulmonary embolus Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg) Impaired renal function (creatinine >1.5 mg/dl) Anemia (hematocrit <33) Untreated thyroid disease (abnormal TSH) A recent history (<12 months) of GI bleed Diabetes mellitus or other untreated endocrine or metabolic disease Electrolyte abnormalities Any history of stroke, hypo- or hyper-coagulation disorders Employment requiring long (>1 h) uninterrupted period of standing Inability to meet study travel requirements (e.g. manual geared car) Recent history of balance issues or falls. Recent (3 years) treated cancer other than basal cell carcinoma Systemic steroids, anabolic steroids, growth hormone or immunosuppressant use within 12 months Recent (2 months) adherence to a weight-loss or weight-gain diet Weight change of 5% or more in previous 6 months Body mass index >30 or excess body fat that compromises muscle biopsy collection Acute infectious disease or chronic infection Alcohol or drug abuse Any other condition or event considered exclusionary by study physician

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Male Rehabilitation (M-REHAB)<br>Disuse + resistance exercise rehabilitation | Other: Resistance Exercise Rehabilitation<br>* Following disuse, the REHAB groups (M-REHAB, F-REHAB) will complete monitored resistance exercise rehabilitation sessions using an isokinetic dynamometer at a similar relative load at each rehab visit.<br>|
| Experimental: Male Control (M-CON)<br>Disuse + ambulatory control rehabilitation | Other: Walking-based rehabilitation<br>* Following disuse, the CON groups (M-CON, F-CON) will complete 30 minutes of monitored walking at a moderate intensity at each rehab visit.<br>|
| Experimental: Female Rehabilitation (F-REHAB)<br>Disuse + resistance exercise rehabilitation | Other: Resistance Exercise Rehabilitation<br>* Following disuse, the REHAB groups (M-REHAB, F-REHAB) will complete monitored resistance exercise rehabilitation sessions using an isokinetic dynamometer at a similar relative load at each rehab visit.<br>|
| Experimental: Female Control (F-CON)<br>Disuse + ambulatory control rehabilitation | Other: Walking-based rehabilitation<br>* Following disuse, the CON groups (M-CON, F-CON) will complete 30 minutes of monitored walking at a moderate intensity at each rehab visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study day 1 (before starting leg disuse) | 
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study day 7 (after finishing leg disuse) | 
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study day 7 (after 1 bout of rehabilitation) | 
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study day 9 (after 2 bouts of rehabilitation) | 
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study Day 11 (after 3 bouts of rehabilitation) | 
| Quantitative RNA-sequencing | RNA deep sequence analysis on muscle tissue taken from a muscle biopsy to measure transcriptome | Study Day 21 (after finishing 7 bouts of rehabilitation) | 
| Muscle function | Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque) | Study day 1 (before starting leg disuse) | 
| Muscle function | Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque) | Study day 7 (after 1 bout of rehabilitation) | 
| Muscle function | Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque) | Study day 9 (after 2 bouts of rehabilitation) | 
| Muscle function | Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque) | Study Day 11 (after 3 bouts of rehabilitation) | 
| Muscle function | Each leg will be individually tested on an isokinetic dynamometer to determine muscle strength (peak torque) | Study Day 21 (after finishing 7 bouts of rehabilitation) | 
| Body (leg) composition | Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry | Study day 1 (before starting leg disuse) | 
| Body (leg) composition | Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry | Study day 7 (after finishing leg disuse) | 
| Body (leg) composition | Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry | Study day 9 (after 2 bouts of rehabilitation) | 
| Body (leg) composition | Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry | Study Day 11 (after 3 bouts of rehabilitation) | 
| Body (leg) composition | Leg lean mass will be assessed via segmental dual energy x-ray absorptiometry | Study Day 21 (after finishing 7 bouts of rehabilitation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle fiber cross sectional area | Muscle biopsy samples will be evaluated for muscle fiber cross sectional area | Study day 1 (before starting leg disuse) | 
| Muscle fiber cross sectional area | Muscle biopsy samples will be evaluated for muscle fiber cross sectional area | Study day 7 (after finishing leg disuse) | 
| Muscle fiber cross sectional area | Muscle biopsy samples will be evaluated for muscle fiber cross sectional area | Study day 9 (after 2 bouts of rehabilitation) | 
| Muscle fiber cross sectional area | Muscle biopsy samples will be evaluated for muscle fiber cross sectional area | Study Day 11 (after 3 bouts of rehabilitation) | 
| Muscle fiber cross sectional area | Muscle biopsy samples will be evaluated for muscle fiber cross sectional area | Study Day 21 (after finishing 7 bouts of rehabilitation) | 
| Muscle fiber type | Muscle biopsy samples will be evaluated for muscle fiber type distribution | Study day 1 (before starting leg disuse) | 
| Muscle fiber type | Muscle biopsy samples will be evaluated for muscle fiber type distribution | Study day 7 (after finishing leg disuse) | 
| Muscle fiber type | Muscle biopsy samples will be evaluated for muscle fiber type distribution | Study day 9 (after 2 bouts of rehabilitation) | 
| Muscle fiber type | Muscle biopsy samples will be evaluated for muscle fiber type distribution | Study Day 11 (after 3 bouts of rehabilitation) | 
| Muscle fiber type | Muscle biopsy samples will be evaluated for muscle fiber type distribution | Study Day 21 (after finishing 7 bouts of rehabilitation) | 
| Diet recall | A multi-pass 24-hour dietary recall using the Automated Self Assessment 24-h dietary assessment tool to determine habitual food intake | Familiarization session ( 1 week before starting leg disuse) | 
| Diet recall | A multi-pass 24-hour dietary recall using the Automated Self Assessment 24-h dietary assessment tool to determine habitual food intake | Study day 11 (after two bouts of rehabilitation) | 
| Physical activity | Accelerometers will placed on the waist and ankle to measure physical activity | Study Days -7 to Day 0 (1 week prior to starting leg disuse) | 
| Physical activity | Accelerometers will placed on the waist and ankle to measure physical activity | Study Days 1-6 (1 week of disuse) | 
| Physical activity | Accelerometers will placed on the waist and ankle to measure physical activity | Study Days 7-21 (2 weeks of rehabilitation) |