Training Effects on Skeletal Muscle Lipid Dynamics

描述(由申请人提供)：骨骼肌脂代谢的改变被认为是骨骼肌胰岛素抵抗的重要因素，这是2型糖尿病(T2 DM)的先兆和预测。有氧训练被认为可以预防脂质诱导的胰岛素抵抗，即使在休息状态下也是如此。然而，我们的初步数据发现，在有氧训练的参与者中，胰岛素敏感性下降得比久坐不动的参与者更早 FFA的适度升高，表明有氧训练可能在葡萄糖和脂肪都可用的情况下促进脂肪的利用。大量研究已经解释了耐力训练人类肌肉高脂肪含量和高肌肉胰岛素敏感性的明显悖论，这是肌肉脂肪代谢产物减少的结果，肌肉脂肪代谢产物被认为是脂质诱导的胰岛素抵抗的中介。然而，这些研究只涉及静态测量，目前尚不清楚有氧训练如何改变肌肉脂肪代谢的动态。这项建议将研究有氧训练对久坐、超重/肥胖、胰岛素抵抗的人脂代谢动力学的影响，这些人可能特别容易受到IMCL和有毒脂代谢产物积累的影响。我们将验证有氧训练增加静息肌肉脂肪代谢的假设，通过IMCL脂解、脂质代谢物积累和线粒体对脂肪酸的利用的标记物来衡量。在目标1中，我们计划确定有氧训练对骨骼肌IMCL脂解标志物的影响。在目标2中，我们计划确定有氧训练对骨骼肌脂代谢产物动力学的影响。在目标3中，我们计划确定有氧训练对骨骼肌中线粒体利用脂肪酸的影响。这项研究的创新之处在于，它关注有氧训练对骨骼肌脂类动力学的影响，特别是使用一种尖端的、稳定的同位素、脉冲追逐设计来动态检查IMCL的积累和脂质代谢产物。通过专注于久坐不动、超重/肥胖、胰岛素抵抗的受试者，我们正在研究一群特别容易受到骨骼肌脂代谢失调影响的人群，这可能会从有氧训练中显著受益。本研究的意义在于为揭示有氧训练对骨骼肌脂代谢的作用机制提供重要的认识，为治疗2型糖尿病胰岛素抵抗及其并发症开辟新的方向。

DESCRIPTION (provided by applicant): Alteration in skeletal muscle lipid metabolism is thought to significantly contribute to skeletal muscle insulin resistance, which precedes and predicts type 2 diabetes (T2DM). Aerobic training is believed to protect against lipid induced insulin resistance, even in the resting state. Yet, our preliminary data found that insulin sensitivity declines earlier in aerobically trained participants than sedentary participants during modest FFA elevation, suggesting that aerobic training may promote lipid utilization when both glucose and lipid are available. Numerous studies have explained the apparent paradox of high muscle lipid content and high muscle insulin sensitivity in endurance trained humans as a consequence of reduced muscle lipid metabolites, the presumed mediator of lipid induced insulin resistance. However, these studies have only involved static measures and it remains unknown how aerobic training may alter the dynamics of muscle lipid metabolism. This proposal will study the aerobic training effect on lipid metabolism dynamics in sedentary, overweight/obese, insulin resistant humans, who may be particularly susceptible to the effects of IMCL and toxic lipid metabolites accumulation. We will test the hypothesis that aerobic training increases resting muscle lipid metabolism, as measured by markers of IMCL lipolysis, accumulation of lipid metabolites and mitochondrial utilization of fatty acids. In Aim 1, we plan t identify aerobic training effects on markers of skeletal muscle IMCL lipolysis. In Aim 2, we plan to identify aerobic training effects on the dynamics of skeletal muscle lipid metabolites. In Aim 3 we plan to identify aerobic training effects on mitochondrial utilization of fatty acids in skeleta muscle. This study is innovative in its focus on aerobic training associated alterations in skeleta muscle lipid kinetics, particularly in the use of a cutting-edge, stable isotope, pulse-chase desig to dynamically examine IMCL accumulation and lipid metabolites. By focusing on sedentary, overweight/obese, insulin resistant subjects, we are studying a population particularly susceptible to dysfunctional skeletal muscle lipid metabolism that may significantly benefit from aerobic training. The significance of this study will be to provide important insights into the mechanistic benefit of aerobic training on skeletal muscle lipid metabolism, opening new directions for treatment of insulin resistance and its consequent complications of T2DM.