SIRT1 in Skeletal Muscle Development, Regeneration, and Atrophy

SIRT1 在骨骼肌发育、再生和萎缩中的作用

基本信息

批准号：
10265852
负责人：
Vittorio Sartorelli
金额：
$ 87.45万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265852
关键词：
Acetyltransferase Actins Adult Animal Model Animals Atrophic Biochemical Burn injury Cell Culture System Cells Complex Conceptions Deacetylase Denervation Development Dexamethasone EP300 gene Elderly Enterobacteria phage P1 Cre recombinase Equilibrium Exposure to Female Fetus Goals Harvest Heart Histologic Hormones Inbred ICR Mice Infusion procedures Injury Kidney Knock-out Lead Limb structure Link Liver Longevity LoxP-flanked allele Malignant Neoplasms Measures Modeling Molecular Molecular Analysis Morphology Mus Muscle Muscle Development Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Muscular Dystrophies Myoblasts Natural regeneration Nicotinamide adenine dinucleotide PCAF gene Pancreas Pathway interactions Pharmacology Physiological Process Protein Biosynthesis Proteins Role SIRT1 gene Saline Sampling Skeletal Muscle Spleen Techniques Therapeutic Therapeutic Uses Time Tissues Transgenic Animals Transgenic Mice Traumatic injury experimental study healing in vivo injured knockout animal muscle form muscle regeneration muscular structure novel overexpression pregnant premature promoter protein degradation regenerative sarcopenia satellite cell sciatic nerve skeletal skeletal muscle differentiation skeletal muscle wasting treatment strategy

项目摘要

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.

肌肉发育和再生烟酰胺腺嘌呤二核苷酸 (NAD+) 依赖性脱乙酰酶 SIRT1 已被证明可以控制细胞培养系统中的骨骼肌分化。 SIRT1 与乙酰转移酶 PCAF 和 p300 以及发育调节因子 MyoD 形成复合物，当过度表达时，会阻碍肌肉分化。相反，SIRT1 蛋白水平降低或 SIRT1 酶活性被药物特异性抑制的细胞会过早分化。我们建议研究 SIRT1 是否控制动物的肌肉分化。体内肌肉分化发生在发育过程中、新肌肉的形成过程中，以及成人中发生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过程中的作用可能对肌肉萎缩（即肌肉营养不良、创伤后肌肉愈合和老年人肌少症）的治疗具有影响。肌肉萎缩骨骼肌消耗和无力（萎缩）与许多疾病有关，包括肌营养不良、废用、烧伤、去神经支配和癌症。在老年人中生理上观察到肌肉质量和功能的减少（肌肉减少症）。由于骨骼肌质量是通过蛋白质合成和降解的平衡来维持的，因此对这些途径的更清晰的了解可能会导致针对肌肉萎缩和无力的情况制定新的治疗策略。此前研究表明，SIRT1 蛋白水平的增加与小鼠寿命的延长有关。此外，还发现 SIRT1 可以降低许多被认为与骨骼肌萎缩有关的蛋白质的表达。然而，迄今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颖且重要的结果。此外，这些结果将对许多表明肌肉萎缩和无力的情况产生影响。