The regulation of protein translation in skeletal muscle by androgens

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DESCRIPTION (provided by applicant): I am in pursuit of this career development award to foster a translational research career focused on elucidating the mechanisms and developing strategies to attenuate skeletal muscle wasting. The age- and disease-related loss in muscle mass is associated with substantial social and economic costs and evidenced by impairments in strength, limitations in function, physical disability and loss of independence. Regrettably, there is a paucity of therapies to combat muscle wasting and the means by which existing therapeutics exert their effects remain poorly understood. The primary objective of this career development award is to investigate a plausible mechanism by which the prototypical androgen, testosterone, may coordinately regulate anabolic and catabolic processes in skeletal muscle; namely, through regulation of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. This will be pursued with the help of an interdisciplinary team consisting of a sponsor with expertise in the biology of androgens, and co-sponsors who have made significant contributions to the science of Akt and protein translation. First, in cell-based models, I will characterize the regulation of PI3-kinase, Akt and key effector kinases that modulate protein translation, by testosterone. Next, the effects of testosterone on these molecular targets, muscle mass and muscle function will be analyzed in a novel conditional, muscle-specific Akt1 overexpressing transgenic mouse. Lastly, the molecular basis for androgen action will be investigated in humans using muscle biopsies acquired in an ongoing study of testosterone administration in older men with low testosterone levels and mobility limitations. In addition to the support of sponsors and co-sponsors, the environment at Boston Medical Center provides rich intellectual and technical resources to ensure the success of this proposal and my development as an independent investigator. Relevance: The age-related loss in muscle mass is associated with substantial social and economic costs. With the continued growth of our aged population, there is merit in exploring the underlying mechanisms by which anabolic therapies, such as testosterone, promote muscle growth. Potentially, this work will contribute to the development of novel, safer and more effective therapies for muscle wasting.