Role of Skeletal Muscle SIRT1 in the Pathogenesis of Metabolic Disorders

我们感兴趣的是描述限制卡路里、运动和小分子对骨骼肌代谢产生有益影响的分子和机制，特别是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，在胰岛素抵抗和II型糖尿病的发病机制中发挥着重要作用。总体而言，II型糖尿病患者的骨骼肌氧化能力减弱，代谢缺乏灵活性(即无法从禁食条件下的脂肪氧化转换为对胰岛素刺激的碳水化合物氧化)。体育锻炼触发了骨骼肌的重塑程序，包括代谢程序和肌纤维内结构蛋白的变化。这种适应与抗疲劳的收缩蛋白(I型慢抽动氧化纤维)基因的表达增加有关，与线粒体呼吸和脂肪酸氧化有关的基因。这些基因表达的改变可以提高运动能力，还可以预防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型慢抽动氧化纤维的骨骼肌可以抵抗肌肉萎缩。 除了锻炼，旨在减少卡路里摄入量的饮食干预也可以改善骨骼肌的表现(即改善线粒体呼吸和改善运动功能)。将卡路里摄入量减少到30%-50%以下，或每隔一天喂食一次随意饮食，可以延缓与年龄相关的疾病的发生，提高抗应激能力，并延缓机体功能下降。 依赖NAD+的脱乙酰酶SIRT1的小分子激动剂已被证明能够很好地概括限制卡路里在延缓与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运动能力方面的作用。为了支持SIRT1在体内调节肌肉代谢的拟议作用，SIRT1激动剂白藜芦醇(RSV)治疗的小鼠显示出骨骼肌线粒体功能增强，并能抵抗通常由高脂饮食(HFD)引起的体重增加和胰岛素抵抗。RSV至少部分地通过激活SIRT1和PGC1以及下游蛋白，包括MCAD、细胞质C、雌激素相关受体α(ERR)和PGC1本身来抵消这些有害的变化。尽管这些证据令人信服，但应谨慎解释，因为RSV不是SIRT1的特定激活剂，已被发现调节其他几种途径。。

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. .