Age-related insulin resistance, muscle, and exercise

描述（由申请人提供）：年龄的增长通常伴随着胰岛素抵抗。然而，关于年龄相关胰岛素抵抗的细胞机制，特别是胰岛素作用的主要靶组织骨骼肌，所知相对较少。在目前的提案中，需要验证的假设是，导致葡萄糖运输的胰岛素信号随着人类骨骼肌的衰老过程而受损，从而导致胰岛素抵抗。我们的工作假设是，由于肌肉脂质含量增加和/或氧化能力降低的抑制，胰岛素信号转导在老年骨骼肌中减少。由于衰老过程中的胰岛素减少可能是缺乏身体活动的结果，我们的第二个假设是，与年龄相关的胰岛素抵抗可以通过锻炼来增强胰岛素信号来补偿。下面的目标将检验这些假设。具体目的1：确定胰岛素信号转导是否随着人类骨骼肌的衰老而受损。我们将研究骨骼肌中的胰岛素信号转导是否随着人类衰老过程而受损，以及肌肉脂质积累和/或氧化能力受损是否会导致这种衰退。特定目的2：确定脂质积累和或肌肉氧化能力降低是否会损害人类骨骼肌的胰岛素信号转导。使用原代人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，以及脂质氧化的减少（类似于衰老）是否会诱导胰岛素抵抗。使用PPARa激动剂治疗，我们将反过来增加肌肉细胞和老年人的肌肉氧化能力，并确定这种增加是否逆转脂质诱导的胰岛素抵抗。特定目的3：确定胰岛素作用随老年骨骼肌运动增强的细胞机制。我们将确定增强的胰岛素信号转导是否有助于老年人耐力和阻力导向运动训练中胰岛素作用的改善，以及肌肉脂质含量和/或氧化能力的变化是否可以解释这种变化的机制。

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.