Age-related insulin resistance, muscle, and exercise

年龄相关的胰岛素抵抗、肌肉和运动

• 批准号: 7214521
• 负责人: Joseph A Houmard
• 金额: $ 0.26万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214521
• 关键词: Age; related; insulin; resistance; muscle

DESCRIPTION (provided by applicant): Advancing age is typically accompanied by insulin resistance. Relatively little, however, is known concerning the cellular mechanism(s) responsible for age-related insulin resistance, particularly in the primary target tissue for insulin action, skeletal muscle. In the current proposal, the hypothesis to be tested is that the insulin signal leading to glucose transport is impaired with the aging process in human skeletal muscle, which subsequently contributes to insulin resistance. Our working hypothesis is that insulin signal transduction is reduced in aged skeletal muscle due to inhibition from increased muscle lipid content and/or reduced oxidative capacity. As decrements during the aging process can be a consequence of physical inactivity, our secondary hypothesis is that age-related insulin resistance is compensated for with exercise training by enhanced insulin signaling. The following aims will test these hypotheses. Specific Aim 1: Determine if insulin signal transduction is impaired with aging in human skeletal muscle. We will examine if insulin signal transduction in skeletal muscle is impaired with the aging process in humans and if muscle lipid accumulation and/or impaired oxidative capacity contribute to the decrement. Specific Aim 2: Determine if lipid accumulation and or reduced muscle oxidative capacity impairs insulin signal transduction in human skeletal muscle. Using a primary human skeletal muscle cell culture system we will determine if lipid exposure impairs insulin signaling and if decrements in lipid oxidation (akin to aging) induce insulin resistance. With PPARa agonist treatment we will conversely increase muscle oxidative capacity in muscle cells and in aged individuals and determine if this increase reverses lipid-induced insulin resistance. Specific Aim 3: Determine the cellular mechanism(s) by which insulin action is enhanced with physical activity in aged skeletal muscle. We will determine if enhanced insulin signal transduction contributes to the improvement in insulin action seen with endurance- and resistance-oriented exercise training in aged individuals and if changes in muscle lipid content and/or oxidative capacity are mechanisms that can explain such changes.

描述（由申请人提供）：前进的年龄通常伴有胰岛素抵抗。然而，相对较少，关于导致年龄相关胰岛素抵抗的细胞机制，尤其是在用于胰岛素作用的主要目标组织中，已知的知之甚少。在当前的建议中，要检验的假设是导致葡萄糖转运的胰岛素信号受到人骨骼肌的衰老过程的损害，这随后导致胰岛素抵抗。我们的工作假设是，由于肌肉脂质含量增加和/或氧化能力降低，老年骨骼肌的胰岛素信号转导减少。由于衰老过程中的减少可能是身体不活跃的结果，因此我们的次要假设是，与年龄相关的胰岛素抵抗通过增强的胰岛素信号传导来补偿与年龄相关的胰岛素抵抗。以下目标将检验这些假设。特定目标1：确定人骨骼肌衰老是否会损害胰岛素信号转导。我们将检查骨骼肌中的胰岛素信号转导对人的衰老过程是否受损，以及肌肉脂质积累和/或氧化能力受损是否有助于减少。具体目标2：确定脂质积累和 / / / / / /肌肉氧化能力是否会损害人骨骼肌中的胰岛素信号转导。使用原发性人类骨骼肌细胞培养系统，我们将确定脂质暴露是否会损害胰岛素信号传导以及脂质氧化（类似于衰老）的减少会诱导胰岛素抵抗。通过PPARA激动剂治疗，我们将相反会增加肌肉细胞和老年个体的肌肉氧化能力，并确定这种增加是否会逆转脂质诱导的胰岛素抵抗。特定目标3：确定胰岛素作用随着老年骨骼肌的体育锻炼增强的细胞机制。我们将确定增强的胰岛素信号转导能否有助于改善老年人的耐力和耐药性运动训练，以及肌肉脂质含量和/或氧化能力的变化是否是可以解释这种变化的机制。