Age-related insulin resistance, muscle, and exercise

描述(申请人提供)：高龄通常伴随着胰岛素抵抗。然而，对于胰岛素作用的主要目标组织--骨骼肌中与年龄相关的胰岛素抵抗的细胞机制(S)，人们知之甚少。在目前的方案中，需要检验的假设是，随着人体骨骼肌衰老过程，导致葡萄糖运输的胰岛素信号受损，从而导致胰岛素抵抗。我们的工作假设是，由于肌肉脂肪含量的增加和氧化能力的降低，老年骨骼肌的胰岛素信号转导受到了抑制。由于衰老过程中的减少可能是缺乏运动的结果，我们的第二个假设是，运动训练通过增强胰岛素信号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。 具体目的1.确定人骨骼肌中胰岛素信号转导是否随年龄增长而受损。我们将研究骨骼肌中的胰岛素信号转导是否随着人类的衰老过程而受损，以及肌肉脂肪堆积和氧化能力降低是否导致这种减少。 具体目的2.确定老年骨骼肌胰岛素作用随体力活动增强的细胞机制(S)。我们将确定增强的胰岛素信号转导是否有助于老年人以耐力和阻力为导向的运动训练的胰岛素作用的改善，以及无论运动方式如何，生物活性肌脂含量的减少是否是体力活动增强老年人胰岛素作用的统一机制。 特定目标3.确定肌肉氧化能力是否特别影响人体骨骼肌中的胰岛素信号转导。随着年龄的增长，肌肉氧化能力会下降，这至少可以通过以耐力为导向的体力活动来部分弥补。通过使用原代人类细胞培养系统，我们打算确定氧化能力是否直接影响胰岛素信号/胰岛素作用。

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.