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: 10502819
• 负责人: Paul Michael Titchenell
• 金额: $ 11.58万
• 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/10502819
• 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 2型糖尿病（T2DM）的个体数量保持在历史最高水平，预测为 因此，在接下来的十年中，定义基本机制具有重大的医疗兴趣 驱动T2DM提高治疗效率。 激素胰岛素与葡萄糖稳态和肌肉功能障碍有关 在调查中，关键知识差距仍然存在于负责该的分子机制中。 胰岛素抵抗的起始和传播。 在胰岛素信号中，稳态和大部分葡萄糖处置。 骨骼肌中的途径也假设是胰岛素抵抗的主要原因 高血糖，蛋白质的代谢改变和心血管疾病。 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。 假设通过AKT减少胰岛素信号传导会引起胰岛素抵抗和改变肌肉功能，我们 在骨骼肌中缺乏AKT信号的小鼠，令人惊讶地发现胰岛素可以可以 在没有AKT的情况下，刺激骨骼肌葡萄糖的吸收和利用。 对照中中间的规范分子模型 胰岛素在所有条件下都可以识别胰岛素的骨骼肌肉代谢。 途径和角色碳水化合物稳态将成为目标1的重点。 AKT骨骼肌的葡萄糖吸收和胰岛素敏感性正常，我们发现它们仍然 表现出显着的萎缩萎缩和线粒体功能障碍，肌肉中的相应缺陷 性能，证实我需要在下游的肌肉生长和功能 AIM 2将定义负责AKT控制肌肉和功能的机制。 该提议将基于重要的观察，并阐明Akt偏见和独立 控制体内胰岛素的化学作用的途径。 影响我们对胰岛素抵抗潜在途径的机械理解，并将导致您 鉴定T2DM，心血管和骨骼肌肉疾病的新治疗靶标。