SIRT1 in Skeletal Muscle Development, Regeneration, and Atrophy

SIRT1 在骨骼肌发育、再生和萎缩中的作用

• 批准号: 8746509
• 负责人: Vittorio Sartorelli
• 金额: $ 93.4万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 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/8746509
• 关键词: Acetyltransferase; Actins; Adult; Animal Model; Animals; Atrophic; Biochemical; Burn injury; Cell Culture System; Cells; Complex; Conceptions; Deacetylase; Denervation; Development; Dexamethasone; Differentiation Inducer; EP300 gene; Elderly; Equilibrium; Female; Fetus; Goals; Harvest; Healed; Heart; Hormones; Inbred ICR Mice; Infusion procedures; Injury; Kidney; Knock-out; Knowledge; Lead; Limb structure; Link; Liver; Longevity; Malignant Neoplasms; Measures; Modeling; Molecular; Molecular Analysis; Mus; Muscle; Muscle Development; Muscle Fibers; Muscle function; Muscular Atrophy; Muscular Dystrophies; Myoblasts; Natural regeneration; Nicotinamide adenine dinucleotide; PCAF gene; Pancreas; Pathway interactions; Process; Protein Biosynthesis; Proteins; Role; Saline; Sampling; Skeletal Muscle; Skeletal Muscle Satellite Cells; Spleen; Staging; Techniques; Therapeutic; Therapeutic Uses; Time; Tissues; Transgenic Animals; Transgenic Mice; healing; in vivo; injured; muscle form; muscle regeneration; muscular structure; novel; overexpression; pre-clinical; pregnant; promoter; protein degradation; recombinase; regenerative; research study; sarcopenia; sciatic nerve; skeletal; skeletal muscle differentiation; skeletal muscle wasting; treatment strategy; wasting

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.

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SIRT 1已被证明在细胞培养系统中控制骨骼肌分化。SIRT1与乙酰基转移酶PCAF和p300以及发育调节因子MyoD形成复合物，并且当过表达时，延缓肌肉分化。相反，SIRT1蛋白水平降低或SIRT1酶活性被药理学试剂特异性抑制的细胞过早分化。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期间，在新肌肉的形成中，以及在成人中，在肌肉损伤后的再生期间。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的治疗有意义（即，肌肉营养不良、创伤性损伤后的肌肉愈合和老年人的少肌症）。 肌肉萎缩 骨骼肌萎缩和无力（萎缩）与许多疾病有关，包括肌肉营养不良、废用、烧伤、去神经支配和癌症。在老年人中生理学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理解可能会导致针对肌肉萎缩和虚弱的疾病的新治疗策略。 SIRT1蛋白水平的增加以前曾被认为与小鼠寿命的延长有关。此外，SIRT1已被发现减少了许多蛋白质的表达，这些蛋白质被认为与骨骼肌萎缩有关。然而，迄今为止还没有研究检查SIRT1在肌肉萎缩动物模型中的作用。这些实验的结果将为SIRT1激活的潜在治疗应用提供新的重要结果。此外，这些结果将对许多肌肉萎缩和无力的情况产生影响。