Growth and maintenance of skeletal muscle mass is critical for long-term health and quality of life. Muscle is important for mobility but it is also crucial for metabolic health because of its contribution to glucose uptake and fat metabolism. Our lab and others have demonstrated that signaling through the mammalian target of rapamycin (mTOR) is necessary for skeletal muscle growth but the molecular links between signal input and downstream function are far from understood. In our previous studies we showed that a) prolonged activation of mTOR signaling is specific to growth inducing contractions, b) mechanical strain activates mTOR signaling in skeletal muscle but not in non-muscle cells, c) strain-induced mTOR signaling is independent of the IGFl/insulin/PI3 kinase signaling pathways, and d) cell cycle genes, such as cyclin D1 and c-myc, are induced during mTOR dependent growth and they likely function, in the differentiated muscle cell, to induce ribosomal biogenesis/protein synthesis. The overall goal of this research is to use in vitro and in vivo models of skeletal muscle growth with molecular tools to identify the necessary upstream regulators and downstream effectors of mTOR. I) mechanical strain acts synergistically with IGF1 to prolong activation of mTOR signaling and II) mTOR kinase activity is necessary for translational-regulation of critical growth mRNAs including cyclin D1 and c- myc. These hypotheses will be tested by the following specific aims:
Specific Aim 1. To determine the molecular signals by which mechanical strain regulates mTOR signaling.
Specific Aim 2. To demonstrate whether mechanical signaling acts synergistically with IGF1 to regulate growth-related mTOR function.
Specific Aim 3. Specific Aim 3. To determine whether the kinase activity of mTOR is necessary for growth, protein synthesis and increased c-myc and cyclin D1 protein levels in response to mechanical overload in vivo. The results of these studies will provide novel insight for the field of mTOR regulation and the role of mechanical strain in the growth process of skeletal muscle. The clinical implications of this work are also significant and will contribute to development of strategies to attenuate or ameliorate muscle atrophy associated with disuse, aging, bed rest and cachexia. ? ? ? ?
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