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

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

This project is a 2-phase, randomized clinical trial that includes 7 days of unilateral leg disuse (Phase 1), immediately followed by 1 week 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.

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. The protocol includes 7-days of unilateral leg disuse (ULD; Phase 1), immediately followed by 1 week 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.

Inclusion Criteria:

1. All races and ethnic backgrounds
2. Men and women, age 50-65 years
3. Generally healthy (see exclusion criteria)
4. Able and willing to provide informed consent
5. Ability to speak and read English
6. Post-menopausal women (no menses within the last 12 months)
7. Body mass index: 18.5-35 kg/m2 or BMI>35 if thigh adiposity does not impair muscle biopsy

Exclusion Criteria:

1. Compromised musculoskeletal function that precludes safe participation or use of crutches
2. Pre-menopausal women
3. Hypogonadal men (testosterone <300 ng/dL)
4. Women taking hormone replacement therapy (HRT)
5. Sarcopenia (European Working Group on Sarcopenia in Older People, EWGSOP102)
6. Clinically significant heart disease (e.g. New York Heart Classification greater than grade II; ischemia)
7. Peripheral vascular disease
8. History of claudication
9. Pulmonary disease
10. History of systemic or pulmonary embolus
11. Uncontrolled blood pressure (systolic BP>170, diastolic BP>95 mmHg)
12. Impaired renal function (creatinine >1.5 mg/dl)
13. Anemia (hematocrit <33)
14. Untreated thyroid disease (abnormal TSH)
15. A recent history (<12 months) of GI bleed
16. Diabetes mellitus or other untreated endocrine or metabolic disease
17. Electrolyte abnormalities
18. Any history of stroke, hypo- or hyper-coagulation disorders
19. Employment requiring long (>1 h) uninterrupted period of standing
20. Inability to meet study travel requirements (e.g. manual geared car)
21. Recent history of balance issues or falls.
22. Recent (3 years) treated cancer other than basal cell carcinoma
23. Systemic steroids, anabolic steroids, growth hormone or immunosuppressant use within 12 months
24. Recent (2 months) adherence to a weight-loss or weight-gain diet
25. Weight change of 5% or more in previous 6 months
26. Body mass index >30 or excess body fat that compromises muscle biopsy collection
27. Acute infectious disease or chronic infection
28. Alcohol or drug abuse
29. Any other condition or event considered exclusionary by study physician