SIRT1 in Skeletal Muscle Development, Regeneration, and Atrophy

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Muscle Development and Regeneration The nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1 has been shown to control skeletal muscle differentiation in a cell culture system. SIRT1 forms a complex with the acetyltransferases PCAF and p300 and the developmental regulator MyoD and, when overexpressed, retards muscle differentiation. Conversely, cells with decreased SIRT1 protein levels, or with enzymatic activity of SIRT1 specifically inhibited by pharmacological agents, differentiate prematurely. We propose to investigate whether SIRT1 controls muscle differentiation in the animal. Muscle differentiation in vivo occurs during development, in the formation of new muscles, and in the adult, during regeneration following muscle injury. Understanding the role of SIRT1 during muscle development and muscle regeneration might have implications for the therapy of muscle wasting (i.e., muscle dystrophies, muscle healing following traumatic injuries, and sarcopenia of the elderly). Muscle Atrophy Skeletal muscle wasting and weakness (atrophy) is associated with numerous conditions, including the muscular dystrophies, disuse, burns, denervation, and cancer. A reduction of muscle mass and function is physiologically observed in the elderly (sarcopenia). As skeletal muscle mass is maintained through a balance of protein synthesis and degradation, a clearer understanding of these pathways may lead to novel treatment strategies for conditions where muscle wasting and weakness are described. Increased levels of the protein SIRT1 have previously been linked to increased lifespan in mice. In addition, SIRT1 has been found to decrease the expression of a number of proteins believed to be associated with skeletal muscle atrophy. However, no study to date has examined the role of SIRT1 in an animal model of muscle atrophy. The results from these experiments will provide novel and important results relating to the potential therapeutic applications of SIRT1 activation. Furthermore, these results will have implications for numerous conditions where muscle wasting and weakness are indicated.