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

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

• 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