Muscle Mitochondrial Pyruvate Carrier Disruption Alters Amino Acid Metabolism to Maintain Muscle Mass During Recovery from Obesity

项目摘要/摘要 2型糖尿病(T2D)是一种以胰岛素抵抗为特征的广泛的代谢紊乱 和高血糖。肥胖，即过多的脂肪堆积，是T2D的主要危险因素，并且强烈 与骨骼肌和肝脏的胰岛素抵抗有关，导致这两个器官对葡萄糖的摄取减少。 肌肉葡萄糖摄取减少导致慢性高血糖，过量的葡萄糖摄取会进一步加重 肝脏糖异生。因为骨骼肌是可用于葡萄糖处理的最大组织仓库， 骨质疏松症，即骨骼肌质量的丧失，也会导致高血糖。虽然肥胖和 骨质疏松症是T2D发病的关键因素，目前的治疗方法针对的是胰岛素 可获得性或敏感性，但没有解决脂肪和肌肉质量之间的潜在失衡问题。 破坏骨骼肌线粒体丙酮酸载体(MPC)可增加胰岛素敏感性和 在从肥胖中恢复的小鼠中，通过完全节省肌肉来加速脂肪的流失。因此，调制 骨骼肌丙酮酸代谢可能有助于治疗作为T2D根本原因的身体成分改变。 我们之前的工作集中在了解肌肉特异性MPC破坏如何增加脂肪氧化。 然而，骨骼肌MPC的破坏如何在脂肪质量减少的过程中维持瘦质量仍然不清楚。 因此，这项提议的总体目标是了解骨骼肌线粒体是如何被破坏的 在从肥胖中恢复的过程中，摄取丙酮酸可以节省肌肉质量。根据我们的初步数据，中央 这一建议的假设是，在恢复过程中，肌肉MPC的破坏导致肌肉质量的保留 肥胖通过：1)肌肉和肝脏之间改变底物交换的全身机制，即 为肌肉质量节省氮气；以及2)独特的、依赖于MPC中断的肌肉自主 氮素滞留的机理。针对特定目标1的实验将检验肌肉MPC的假设 中断增加了Cori循环，肌肉和肝脏之间的乳酸和葡萄糖交换，这使 减肥和肥胖恢复过程中骨骼肌蛋白质和氨基酸合成所需的氮。 针对特定目标2的实验将验证骨骼肌MPC中断增加天冬氨酸的假设 和支链氨基酸(BCAA)的可用性，导致维持心肌细胞蛋白质含量。 这项研究意义重大，因为这项研究的完成将为改变骨骼的方式提供机械信息 肌肉代谢可能为肥胖症和骨质疏松症的治疗提供信息。这项研究是 新颖，因为它解决了细胞和系统氮处理的新概念。

Project Summary/Abstract Type 2 diabetes (T2D) is a widespread metabolic disorder that is characterized by insulin resistance and hyperglycemia. Obesity, the excess accumulation of fat mass, is a major T2D risk factor and is strongly associated with insulin resistance in skeletal muscle and liver, resulting in less glucose uptake by both organs. Reduced muscle glucose uptake contributes to chronic hyperglycemia and is further exacerbated by excessive hepatic gluconeogenesis. Because skeletal muscle is the largest tissue depot available for glucose disposal, sarcopenia, the loss of skeletal muscle mass, also contributes to hyperglycemia. Though obesity and sarcopenia are key factors that contribute to the pathogenesis of T2D, current therapies address insulin availability or sensitivity without addressing the underlying imbalance between fat and muscle mass. Disruption of the skeletal muscle mitochondrial pyruvate carrier (MPC) increases insulin sensitivity and accelerates fat loss with complete muscle mass sparing in mice recovering from obesity. Thus, modulating skeletal muscle pyruvate metabolism may be useful for treating altered body composition as a T2D root cause. Our previous work has focused on understanding how muscle-specific MPC disruption increases fat oxidation. However, how skeletal muscle MPC disruption maintains lean mass during fat mass loss is still not understood. Therefore, the overall goal of this proposal is to understand how disrupting skeletal muscle mitochondrial pyruvate uptake spares muscle mass during recovery from obesity. Based on our preliminary data, the central hypothesis of this proposal is that muscle MPC disruption leads to muscle mass sparing during recovery from obesity through: 1) a whole-body mechanism of altered substrate exchange between muscle and liver that spares nitrogen for muscle mass; and 2) a unique, MPC disruption-dependent, muscle-autonomous mechanism of nitrogen retention. Experiments for specific aim 1 will test the hypothesis that muscle MPC disruption increases Cori Cycling, the exchange of lactate and glucose between muscle and liver, which spares nitrogen for skeletal muscle protein and amino acid synthesis during weight loss and recovery from obesity. Experiments for specific aim 2 will test the hypothesis that skeletal muscle MPC disruption increases aspartate and branched-chain amino acid (BCAA) availability that leads to maintenance of myocellular protein content. This research is significant because completion will provide mechanistic information on a way to alter skeletal muscle metabolism that may inform treatment of obesity and sarcopenia contributing to T2D. This research is novel because it addresses new concepts in cellular and systemic nitrogen handling.