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. .

我们感兴趣的是表征分子和机制，这些分子和机制主持热量限制，运动和小分子对骨骼肌代谢的有益影响，特别强调SIRT 1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型糖尿病的发病机制中起重要作用。总的来说，II型糖尿病患者的骨骼肌具有降低的氧化能力和代谢能力（即，不能从禁食条件下的脂肪氧化转换为响应胰岛素刺激的碳水化合物氧化）。体育锻炼触发骨骼肌的重塑程序，涉及肌纤维内代谢程序和结构蛋白的变化。这种适应与抗疲劳的收缩蛋白（I型慢收缩氧化纤维）基因表达的增加有关，这些基因参与线粒体呼吸和脂肪酸氧化。这些改善表现的基因表达修饰也可以防止肥胖和相关的代谢紊乱（即，II型糖尿病和代谢综合征）。此外，富含I型慢收缩氧化纤维的骨骼肌对肌肉萎缩有抵抗力。 除了运动，旨在减少卡路里摄入的饮食干预也可以改善骨骼肌性能（即，改善的线粒体呼吸和改善的运动功能）。将热量摄入减少到自由采食水平以下30%-50%，或每隔一天喂食一次自由采食饮食，可以延迟年龄相关疾病的发作，提高抗应激能力，并延缓机体功能衰退。 NAD+依赖性脱乙酰基酶SIRT 1的小分子激动剂已显示以良好的近似性概括了热量限制在延迟年龄相关的器官退化、防止饮食诱导的肥胖和胰岛素抵抗以及改善骨骼肌代谢和性能方面的作用。为了支持所提出的SIRT 1在体内调节肌肉代谢中的作用，用SIRT 1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，并且对通常由高脂肪饮食（HFD）引起的体重增加和胰岛素抵抗具有抗性。RSV通过激活SIRT 1和PGC 1-及其下游蛋白质（包括MCAD、细胞色素C、雌激素相关受体α（ERR-）和PGC 1本身），至少部分抵消这些有害变化。虽然这些证据令人信服，但应谨慎解释，因为RSV不是SIRT 1的特异性激活剂，并且已发现可调节其他几种途径。.