Role of Skeletal Muscle SIRT1 in the Pathogenesis of Metabolic Disorders

骨骼肌 SIRT1 在代谢紊乱发病机制中的作用

• 批准号: 8344725
• 负责人: Vittorio Sartorelli
• 金额: $ 118.86万
• 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/8344725
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Accounting; Actins; Adult; Agonist; Animals; Antidiabetic Drugs; Caloric Restriction; Carbohydrates; Contractile Proteins; Deacetylase; Deterioration; Diabetes Mellitus; Diet; Dietary Intervention; Disease; ERR1 protein; Energy Intake; Enzymes; Exercise; Exhibits; Experimental Diabetes Mellitus; Fasting; Fatigue; Fatty acid glycerol esters; Fiber; Gene Expression; Genes; Glucose; Glucose tolerance test; Hyperglycemia; Insulin; Insulin Resistance; Intake; Learning; Link; Measures; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metformin; Mitochondria; Modification; Molecular Target; Monitor; Mus; Muscle; Muscle Development; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organ; Oxygen Consumption; Pathogenesis; Pathway interactions; Patients; Performance; Play; Process; Proteins; Reporting; Resistance; Respiration; Resveratrol; Role; Running; Skeletal Muscle; Specificity; Stress; Structural Protein; Tamoxifen; Testing; Tissues; Transgenic Mice; age related; blood glucose regulation; effective therapy; fatty acid oxidation; feeding; functional decline; functional outcomes; glucose uptake; improved; in vivo; insulin tolerance; interest; intraperitoneal; muscle metabolism; oxidation; programs; promoter; recombinase; research study; response; small molecule; wasting

We are interested in characterizing the molecules and the mechanisms that preside to the beneficial effects exerted by calorie restriction, exercise, and small molecules on skeletal muscle metabolism, with a special emphasis on the role of SIRT1 in these processes. Skeletal muscle account for more than 80% of insulin-stimulated whole body glucose uptake, thus playing an important role in the pathogenesis of insulin resistance and type II diabetes. Overall, skeletal muscle of patients with type II diabetes has a diminished oxidative capacity and metabolic inflexibility (i.e., the inability of switching from fat oxidation under fasting conditions to carbohydrate oxidation in response to insulin stimulation). Physical exercise triggers a remodeling program in skeletal muscle that involves changes in metabolic programs and structural proteins within the myofibers. Such adaptations are linked to increase in the expression of genes for contractile proteins that are resistant to fatigue (type I slow-twitch oxidative fibers), genes involved in mitochondrial respiration, and fatty acid oxidation. These modifications in gene expression that improve performance can also protect against obesity and related metabolic disorders (i.e., type II diabetes and metabolic syndrome). Moreover, skeletal muscles rich in type I slow-twitch oxidative fibers are resistant to muscle wasting. In addition to exercise, dietary interventions aimed at reducing calorie intake can also improve skeletal muscle performance (i.e., improved mitochondrial respiration and improved locomotor function). Reduction of caloric intake to 30%-50% below ad libitum levels, or every-other-day feeding of an ad libitum diet can delay the onset of age- related diseases, improve stress resistance, and retard organismal functional decline. Small molecule agonists of the NAD+-dependent deacetylase SIRT1 have been shown to recapitulate, with a good approximation, the effects of calorie restriction in delaying age-related organ deterioration, protecting against diet-induced obesity and insulin resistance, and ameliorating skeletal muscle metabolism and performance. In support of the proposed role of SIRT1 in regulating muscle metabolism in vivo, mice treated with the SIRT1 agonist resveratrol (RSV) exhibit increased skeletal muscle mitochondrial function and are resistant to the increase in body mass and insulin resistance normally caused by a high fat diet (HFD). RSV counteracts these detrimental changes, at least in part, through the activation of SIRT1 and PGC1-α and downstream proteins including MCAD, cytocrome C, estrogen-related receptor alpha (ERR-α) and PGC1−α itself. While compelling, these evidences should be interpreted with caution as RSV is not a specific activator of SIRT1 and has been found to modulate several other pathways. .

我们有兴趣表征分子和主持卡路里限制，运动和小分子对骨骼肌代谢产生的有益作用的机制，并特别强调了SIRT1在这些过程中的作用。 骨骼肌占胰岛素刺激的全身葡萄糖摄取的80％以上，因此在胰岛素抵抗和II型糖尿病的发病机理中起着重要作用。总体而言，II型糖尿病患者的骨骼肌的氧化能力和代谢不灵活性降低（即，从禁食条件下从脂肪氧化转变为响应胰岛素刺激的碳水化合物氧化）。体育锻炼会触发骨骼肌中的重塑程序，涉及肌纤维内代谢程序和结构蛋白的变化。这种适应与对疲劳具有抗药性（I型慢晶芯氧化纤维）的收缩蛋白表达的增加有关，与线粒体呼吸和脂肪酸氧化有关。这些改善性能的基因表达中的这些修饰也可以预防肥胖和相关代谢疾病（即II型糖尿病和代谢综合征）。此外，富含I型慢速氧化纤维的骨骼肌对肌肉浪费具有抵抗力。 除运动外，旨在减少卡路里摄入量的饮食干预措施还可以改善骨骼肌性能（即改善了线粒体呼吸和改善的运动功能）。将热量摄入量的降低至多数次的30％-50％，或者每天喂食的饮食饮食每天喂食可以延迟与年龄相关疾病的发作，提高压力抗性和延缓生物体功能下降。 NAD+依赖性脱乙酰基酶SIRT1的小分子激动剂已被证明可以概括地概括了卡路里限制在延迟年龄相关的器官降低中的影响，从而防止饮食诱导的肥胖症和胰岛素耐药性，并降低骨骼肌肉肌肉肌肉代理和表现。为了支持SIRT1在体内调节肌肉代谢中的拟议作用，用SIRT1激动剂白藜芦醇（RSV）处理的小鼠表现出增加的骨骼肌线粒体功能增加，并且对体重增加和胰岛素耐药性的耐药性（HFD）通常引起（HFD）。 RSV至少部分通过SIRT1和PGC1-α和下游蛋白（包括MCAD，Cytocrome C，雌激素相关受体α（ERR-α）和PGC1-α本身的激活来抵消这些有害的变化。尽管引人注目，但应谨慎解释这些证据，因为RSV不是SIRT1的特定激活剂，并且已发现可以调节其他几种途径。 。