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苷二核苷酸（NAD+） - 依赖性脱乙酰基酶SIRT1已显示可控制细胞培养系统中的骨骼肌分化。 SIRT1与乙酰基转移酶PCAF和P300以及发育调节器Myod形成复合物，并且在过表达时会阻碍肌肉分化。相反，药理学剂特异性抑制的SIRT1蛋白水平降低或具有SIRT1的酶活性的细胞会过早区分。我们建议研究SIRT1是否控制动物中的肌肉分化。体内肌肉分化在发育过程中发生，在新肌肉的形成和成年后，在肌肉损伤后再生。了解SIRT1在肌肉发育和肌肉再生中的作用可能对肌肉浪费的治疗有影响（即，肌肉营养不良，创伤性损伤后的肌肉愈合以及老年人的肌肉减少症）。肌肉萎缩骨骼肌浪费和无力（萎缩）与多种疾病有关，包括肌肉营养不良，废除，烧伤，烧伤，神经保护和癌症。在老年人（肌肉减少症）中观察到肌肉质量和功能的降低。由于通过蛋白质的合成和降解来保持骨骼肌质量，因此对这些途径的更清晰的了解可能会导致对肌肉浪费和无力的疾病的新型治疗策略。蛋白质SIRT1的水平升高与小鼠的寿命增加有关。此外，已经发现SIRT1降低了许多被认为与骨骼肌萎缩有关的蛋白质的表达。但是，迄今为止尚无研究检查SIRT1在肌肉萎缩动物模型中的作用。这些实验的结果将提供与SIRT1激活的潜在治疗应用有关的新颖重要结果。此外，这些结果将对肌肉浪费和无力的许多条件有影响。