SIRT1 in Skeletal Muscle Development, Regeneration, and Atrophy

肌肉发育与再生 依赖于烟酰胺腺嘌呤二核苷酸(NAD)的脱乙酰酶SIRT1被证明在细胞培养系统中控制骨骼肌的分化。SIRT1与乙酰基转移酶PCAF和p300以及发育调节因子MyoD形成复合体，当SIRT1过表达时，会抑制肌肉分化。相反，SIRT1蛋白水平降低或具有SIRT1酶活性的细胞会被药物特异性地抑制，过早分化。我们建议研究SIRT1是否控制动物的肌肉分化。肌肉在体内的分化发生在发育过程中，在新肌肉的形成过程中，在成年肌肉中，在肌肉损伤后的再生过程中。了解SIRT1在肌肉发育和肌肉再生中的作用可能对治疗肌肉萎缩(即肌肉营养不良、创伤后的肌肉愈合和老年人的骨骼减少)具有重要意义。 肌肉萎缩 骨骼肌萎缩和虚弱(萎缩)与许多情况有关，包括肌肉营养不良、废用、烧伤、失神经和癌症。从生理学角度来看，老年人肌肉质量和功能下降(骨质疏松症)。由于骨骼肌群是通过蛋白质合成和降解的平衡来维持的，对这些途径的更清楚的理解可能会导致针对肌肉萎缩和虚弱的情况制定新的治疗策略。 此前，SIRT1蛋白水平的增加曾被认为与小鼠寿命的延长有关。此外，SIRT1还被发现可以减少一些被认为与骨骼肌萎缩有关的蛋白质的表达。然而，到目前为止，还没有研究检验SIRT1在肌肉萎缩动物模型中的作用。这些实验的结果将为SIRT1激活的潜在治疗应用提供新的和重要的结果。此外，这些结果将对许多表明肌肉萎缩和虚弱的情况产生影响。

Muscle Development and Regeneration The nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1 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 is 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 has 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.