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.

项目概要 2 型糖尿病 (T2DM) 患者数量仍处于历史最高水平，预计将继续增加 因此，确定其潜在机制具有重要的医学意义。 推动 T2DM 提高治疗效果，这种情况称为胰岛素抵抗效果降低。 尽管几十年来，胰岛素激素仍与葡萄糖稳态改变和肌肉功能障碍有关。 根据调查，关键的知识差距仍然存在于负责这一现象的分子机制中。 骨骼肌在胰岛素抵抗的发生和传播中起着重要作用。 体内平衡并解释了餐后胰岛素信号传导缺陷的大部分。 骨骼肌中的途径已被认为是导致胰岛素抵抗的主要原因 越来越多的证据表明高血糖、蛋白质代谢改变和心血管疾病有关。 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 直接测试 假设通过 AKT 减少胰岛素信号传导会导致胰岛素抵抗并改变肌肉功能，我们 产生的小鼠骨骼肌中特别缺乏 AKT 信号传导，令人惊讶地发现胰岛素可以 在缺乏 AKT 的情况下刺激骨骼肌葡萄糖的摄取和利用 这些数据与此不一致。 胰岛素抵抗的经典分子模型并表明 AKT 不是对照中的必然中间体 骨骼肌葡萄糖代谢在所有条件下的胰岛素依赖性的鉴定。 途径及其作用碳水化合物稳态将是本提案目标 1 的重点，尽管小鼠缺乏。 骨骼肌中的 AKT 具有正常的葡萄糖摄取和胰岛素敏感性，但我们发现它们仍然 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 性能，证实 AKT 是体内肌肉生长和功能所必需的。 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， 该提案将建立在这些重要观察的基础上，并阐明 Akt 的依赖性和独立性 这些实验有可能深刻地揭示控制体内胰岛素代谢作用的途径。 影响我们对胰岛素抵抗途径的机制理解，并将导致 确定 T2DM、心血管和骨骼肌肉疾病的新治疗靶点。