Androgen-Mediated Reversal of Muscle Wasting

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DESCRIPTION (provided by applicant): Muscle wasting is a prevalent health care problem that has a high morbidity in the adult population and causes a loss of muscle strength, increased vulnerability to falls, increased health care utilization and a reduced quality of life. In order to develop novel therapies that will achieve optimal reversal of muscle wasting, it is important to understand cellular and molecular changes to the muscle fiber during both catabolic and anabolic processes. Testosterone (and presumably selective androgen receptor modulators or SARMs) has been shown to induce satellite cell activation as a first step in muscle fiber hypertrophy/new fiber formation, but the mechanism is unknown. A more complete understanding of satellite cell activation would be a significant contribution towards our long term goal of developing novel strategies for reversal of muscle wasting. The goals of the proposed studies are: (1) to compare and contrast the cellular and molecular effects of androgen deprivation and subsequent testosterone or SARM supplementation on muscles with varying responsiveness to androgens; and (2) to examine the hypothesized role of androgens in mediating satellite cell activation through a NOS/HGF pathway. Methods include muscle fiber assays to evaluate the changes in myonuclear number and protein synthesis; protein assays of specific factors involved in satellite cell activation; and molecular assays to determine changes in RNA message for expression of factors related to androgens and satellite cell activation. Understanding the signaling and subsequent activation of muscle satellite cells by androgen is an important milestone towards the predictable management of muscle wasting conditions. Pathways leading to satellite cell activation are likely to be complex and may vary according to a particular stimulus. The significance of the proposed research will be to explore a known stimulus, androgen, and identify a pathway that can be valuable for the development of novel therapeutic interventions. Muscle wasting is a widespread health care problem causing a loss of muscle strength, increased chance of falls, increased health care use and a reduced quality of life. Testosterone treatment reverses muscle wasting but has many side effects. In order to develop new treatments that will reverse muscle wasting, it is important to understand cellular and molecular changes to the muscle fiber during both wasting and hypertrophy. The proposed research will explore a known stimulus, testosterone or testosterone-like compound (SARM), to identify the pathway of action and allow for the development of new treatments for muscle wasting.