SIRTI and Adaptive Muscle Growth

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PROJECT SUMMARY Skeletal muscle mass and function are inversely associated with chronic disease risk and mortality. Understanding the molecular mechanisms underlying the regulation of muscle growth and mass, particularly as it relates to adaptive muscle growth, holds therapeutic promise. The long-term objective of this research is to define the mechanisms underlying adaptive skeletal muscle growth. Currently, phosphorylation-based signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway is considered the principal mechanism underlying adaptive muscle growth (i.e. growth changes in response to loading). We believe however, that reversible lysine acetylation of proteins comprising the mTORC1 complex and/or its downstream targets provide an additional level of control of adaptive growth. Accordingly, for this application our primary objective is to elucidate the importance of sirtuin 1 (SIRT1), a well-described protein deacetylase, to adaptive muscle growth and to identify potential growth-related signaling molecules regulated by SIRT1. Our central hypothesis is that SIRT1 restricts protein synthesis and adaptive muscle growth through coordinated deacetylation of S6K1 and downstream targets that control mRNA translation. This innovative hypothesis is contrary to current thinking contending that SIRT1 is a positive regulator of muscle growth. To address our hypothesis, our approach will be to measure skeletal muscle protein synthesis, mass and fiber area, in response to adaptive growth stimuli in novel mouse models in which we have manipulated SIRT1 activity in skeletal muscle. Our model predicts that reducing SIRT1 activity will lead to an enhanced adaptive growth response, in concert with increased acetylation of targets of SIRT1. Specifically, Aim #1 will elucidate the contribution of SIRT1 to the adaptive growth response in skeletal muscle, whilst Aim #2 will determine whether acetylation of SIRT1 targets underlies differences in the growth response. Altogether, these studies will broaden our understanding of the contribution of SIRT1 and acetylation to skeletal muscle growth in response to loading. Ultimately, we expect this will have wide-reaching impact on the development of therapies to treat not only muscle atrophy, but also other diseases of skeletal muscle.! !