A number of important health-related conditions including, but not limited to, aging, physical inactivity, nutrient imbalance or insufficiency, hormonal imbalance or insufficiency, and a number of disease states are associated with a dramatic loss of skeletal muscle mass due largely to development of an imbalance between rates of protein synthesis and degradation, particularly in those muscles composed of a high proportion of fast-twitch fibers. In order to better understand the causes of the imbalance for each of these conditions and to begin to develop therapeutic strategies for abrogating or reversing the loss of muscle mass, the long-term objectives of the project described in this competitive renewal application are to identify and characterize the signaling pathways and effector mechanisms through which the initiation of mRNA translation is regulated in skeletal muscle. The studies proposed for the next grant period are designed to test the following hypothesis: alterations in protein expression patterns and global rates of protein synthesis in skeletal muscle in response to amino acids (e.g. leucine), hormones (e.g. insulin, glucocorticoids, and catecholamines), and/or resistance exercise are governed in part by a dynamic interplay of regulatory inputs acting through the mammalian target of rapamycin (mTOR) signaling pathway to mediate control of effector mechanisms involved in the selection of mRNAs for translation.
The specific aims of the project are: (1) to identify how leucine acts to stimulate mTOR-mediated signaling to effector mechanisms involved in the selection of mRNAs for translation; (2) to identify how agents such as glucocorticoids and catecholamines act to repress mTOR-mediated signaling to effector mechanisms involved in the selection of mRNAs for translation; (3) to identify for selected agents molecular targets within the mTOR-mediated signaling pathway that when activated produce a dominant effect over inputs to other components of the pathway; and (4) identify how mTOR-mediated signaling acts to stimulate translation of elF2B? mRNA, locate the functional elements in the e-subunit message that confer regulation, and analyze the functional effects of increased elF2Be expression on protein synthesis and cell growth. Overall, the proposed studies should provide new insights into the signaling pathways and effector mechanisms through which nutrients, hormones, and resistant exercise act to modulate protein expression patterns and global rates of protein synthesis in skeletal muscle. ? ? ? ?
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