Regulation of Skeletal Muscle Metabolism by Insulin Signaling

胰岛素信号对骨骼肌代谢的调节

• 批准号: 10349576
• 负责人: Paul Michael Titchenell
• 金额: $ 39.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-23 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349576
• 关键词: Address; Affect; Aging; Anabolism; Automobile Driving; Biochemical; Carbohydrates; Cardiovascular Diseases; Cardiovascular system; Clinical; Data; Defect; Development; Diabetes Mellitus; Disease; Disuse Atrophy; Effectiveness; Event; Exhibits; FOXO1A gene; Functional disorder; Genetic; Glucose; Glucose Intolerance; Goals; Growth; Homeostasis; Hormones; Human; Hyperglycemia; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; Investigation; Isotope Labeling; Knowledge; Measures; Mediating; Medical; Metabolic; Metabolic Control; Metabolic Diseases; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Muscle; Muscle Mitochondria; Muscle Proteins; Muscle function; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathway interactions; Performance; Pharmacology; Phosphotransferases; Pilot Projects; Play; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Regulation; Research; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Techniques; Testing; Therapeutic Intervention; Time; Treatment Efficacy; adenylate kinase; blood glucose regulation; carbohydrate metabolism; diabetic; experimental study; genetic manipulation; glucose disposal; glucose metabolism; glucose uptake; improved; in vivo; insulin mediators; insulin sensitivity; insulin signaling; interest; metabolomics; mitochondrial dysfunction; molecular modeling; muscle form; new therapeutic target; novel therapeutics; phosphoproteomics; preservation; protein degradation; protein metabolism; restoration; skeletal muscle growth; skeletal muscle metabolism; skeletal muscle wasting; stem; uptake; wasting

Project Summary The number of individuals with type 2 diabetes mellitus (T2DM) remains at an all-time high and is predicted to increase over the next decade. Therefore, it is of significant medical interest to define the underlying mechanisms driving T2DM to improve therapeutic efficacy. Insulin resistance, a condition known as reduced effectiveness to the hormone insulin, is associated with altered glucose homeostasis and muscle dysfunction. Despite decades of investigation, critical knowledge gaps remain in the molecular mechanisms that are responsible for the initiation and propagation of insulin resistance. The skeletal muscle plays a significant role in glucose homeostasis and accounts for a majority of glucose disposal following a meal. Defects in the insulin signaling pathway in the skeletal muscle have been hypothesized to be the primary cause of insulin resistance leading to hyperglycemia, altered protein metabolism and cardiovascular disease. Accumulating evidence has implicated the serine/threonine kinase Akt (protein kinase B) as a critical regulator of insulin action. To directly test the hypothesis that reduced insulin signaling via AKT causes insulin resistance and alters muscle function, we generated mice that lack AKT signaling specifically in skeletal muscle and surprisingly found that insulin can stimulate skeletal muscle glucose uptake and utilization in the absence of AKT. These data are inconsistent with the canonical molecular model of insulin resistance and suggest AKT is not an obligate intermediate in the control of skeletal muscle glucose metabolism by insulin in all conditions. The identification of this AKT-independent pathway and its role carbohydrate homeostasis will be the focus of Aim 1 of this proposal. Although mice lacking AKT in skeletal muscle have normal glucose uptake and insulin sensitivity, we found that they nevertheless exhibit significant muscle atrophy and mitochondrial dysfunction with a corresponding defect in muscle performance, confirming that AKT is required for muscle growth and function in vivo. The downstream mechanisms responsible for AKT’s control of muscle growth and function will be defined in Aim 2. Collectively, this proposal will build upon these important observations and elucidate the Akt-dependent and independent pathways that control the metabolic actions of insulin in vivo. These experiments have the potential to profoundly affect our mechanistic understanding of the pathways underlying insulin resistance and will lead to the identification of new therapeutic targets for T2DM, cardiovascular and skeletomuscular diseases.

项目摘要 患有2型糖尿病（T2 DM）的个体数量仍然处于历史最高水平，预计 在未来十年内增加。因此，确定潜在的机制具有重要的医学意义 推动T2 DM改善治疗效果。胰岛素抵抗，一种被称为有效性降低的疾病， 激素胰岛素与改变的葡萄糖稳态和肌肉功能障碍有关。尽管几十年 调查，关键的知识差距仍然存在于负责的分子机制， 胰岛素抵抗的起始和传播。骨骼肌在葡萄糖代谢中起着重要作用 体内平衡，并占餐后葡萄糖处置的大部分。胰岛素信号传导的缺陷 已经假设骨骼肌中的胰岛素途径是导致胰岛素抵抗的主要原因， 高血糖、蛋白质代谢改变和心血管疾病。越来越多的证据表明 丝氨酸/苏氨酸激酶Akt（蛋白激酶B）作为胰岛素作用的关键调节剂。要直接测试 假设通过AKT减少胰岛素信号传导导致胰岛素抵抗并改变肌肉功能， 制造了缺乏骨骼肌特异性AKT信号传导的小鼠，令人惊讶地发现胰岛素可以 在不存在AKT的情况下刺激骨骼肌葡萄糖摄取和利用。这些数据与 胰岛素抵抗的典型分子模型，并表明AKT不是对照中的专性中间体 在所有条件下胰岛素对骨骼肌葡萄糖代谢的影响。这种不依赖AKT的 途径和它的作用碳水化合物的稳态将是本提案的目标1的重点。虽然老鼠缺乏 骨骼肌中的AKT具有正常的葡萄糖摄取和胰岛素敏感性，但我们发现， 表现出明显的肌肉萎缩和线粒体功能障碍，并伴有相应的肌肉缺陷 AKT是肌肉生长和体内功能所必需的。下游 负责AKT控制肌肉生长和功能的机制将在目标2中定义。总的来说， 本建议将建立在这些重要的观察和阐明Akt依赖和独立 控制胰岛素在体内代谢作用的途径。这些实验有可能深刻地 影响我们对胰岛素抵抗潜在途径的机械理解，并将导致 确定T2 DM、心血管和骨骼肌疾病的新治疗靶点。