HORMONAL REGULATORS OF MUSCLE AND METABOLISM IN AGING

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DESCRIPTION: (provided by applicant) Elderly persons experience progressive loss of skeletal muscle mass, muscle strength, and functional capacity for activities of daily living. Aging is also associated with a loss of gonadal function and integrity of the growth hormone (GH)/IGF-1 axis. However, the relationship of deficiencies in these hormonal axes to sarcopenia and functional impairment in aging has not been established or whether there is an interaction of these two hormone systems in maintaining normal skeletal muscle mass and physical function. We hypothesize that both hormone systems regulate musculoskeletal protein mass and contractile fibers by different and complimentary mechanisms and that optimal levels of both testosterone and GH are necessary to maintain skeletal muscle mass, muscular strength and power, and full functional activities of daily living during the aging process. This proposal has been revised and entails a controlled, 16 week study to evaluate the independent effects and interaction of these two anabolic hormone systems in community dwelling elderly men 65-90 years of age who are hyposomatotropic (IGF-1 in lower tertile) with low eugonadal status (total testosterone of 250-550 ng/dL). The study will utilize a factorial design (2X3) with a two tiered randomization in which 108 study subjects will first be randomized to either the low or high eugonadal level of testosterone using a novel Leydig cell clamp method (GnRH agonist plus topical testosterone supplementation) to achieve target levels of testosterone. Low gonadal status (250-550 ng/dL) will be maintained with 5 g daily doses of topical testosterone, whereas high gonadal status (650-950 ng/dL) will be achieved with 10 g daily doses. Within these two groups, subjects will be randomized to receive placebo or one of two doses of rhGH therapy (0, 3.0, 5.0 mug/kg/day) in a double blinded fashion. The direct effects of study interventions will be assessed by measuring the fractional synthetic rates of mixed and contractile (actin and myosin heavy chain [MHC]) skeletal muscle proteins and degradation of skeletal muscle (ubiquitin, and proteasome sub-units) and by analyzing local regulators of skeletal muscle synthesis (e.g. IGF- I, IGFBP4, myostatin). The clinical effects resulting from the study interventions will be assessed by measuring change in skeletal muscle strength, muscle mass, power and fatigability (endurance), physical performance, and markers of safety. The findings of this study should result in important mechanistic understanding of the relative contributions of androgen deficiency and hyposomatotropism in elderly persons with or who are at risk for frailty due to decreased muscle mass and strength. The results should also provide valuable information for future testing of new, novel treatment strategies, which are more tolerable and convenient than parenteral therapies for age associated sarcopenia.