Age-related insulin resistance, muscle, and exercise

描述（由申请人提供）：年龄的增长往往伴随着胰岛素抵抗。然而，对于胰岛素作用的主要靶组织骨骼肌中与年龄相关的胰岛素抵抗有关的细胞机制，我们所知相对较少。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，从而诱发胰岛素抵抗。我们的工作假设是，由于肌肉脂质含量增加和氧化能力降低的抑制，胰岛素信号转导在老年骨骼肌中受损。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运动训练来增强胰岛素信号来补偿。下面的目标将检验这些假设。

DESCRIPTION (provided by applicant): Advancing age is often accompanied by insulin resistance. Relatively little, however, is known concerning the cellular mechanism(s) responsible for age-related insulin resistance 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 induces insulin resistance. Our working hypothesis is that insulin signal transduction is impaired in aged skeletal muscle due to inhibition from increased muscle lipid content and 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 enhancing 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 reduced oxidative capacity contribute to the decrement. Specific Aim 2. 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 a reduction in bioactive muscle lipid content is the unifying mechanism by which physical activity enhances insulin action in the aged, regardless of exercise mode. Specific Aim 3. Determine if muscle oxidative capacity specifically influences insulin signal transduction in human skeletal muscle. With aging there is a decline in muscle oxidative capacity, which can be at least partially compensated for by endurance-oriented physical activity. By using a primary human cell culture system we intend to determine if oxidative capacity directly influences insulin signaling/insulin action.