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

项目概要/摘要 2型糖尿病（T2 D）是一种广泛的代谢紊乱，其特征在于胰岛素抵抗 和高血糖症。肥胖，即脂肪量的过度积累，是T2 D的主要风险因素， 与骨骼肌和肝脏中的胰岛素抵抗相关，导致两个器官的葡萄糖摄取减少。 减少的肌肉葡萄糖摄取有助于慢性高血糖症，并且过度的葡萄糖摄取会进一步加剧慢性高血糖症。 肝再生因为骨骼肌是最大的可用于葡萄糖处置的组织库， 肌肉减少症，即骨骼肌质量的损失，也有助于高血糖症。虽然肥胖和 肌肉减少症是导致T2 D发病机制的关键因素，目前的治疗方法针对胰岛素 在没有解决脂肪和肌肉质量之间潜在不平衡的情况下，可用性或敏感性。 骨骼肌线粒体丙酮酸载体（MPC）的破坏增加了胰岛素敏感性， 在从肥胖症恢复的小鼠中加速脂肪损失并保留完整的肌肉质量。因此，调制 骨骼肌丙酮酸代谢可用于治疗作为T2 D根本原因的改变的身体组成。 我们以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破坏如何在脂肪量减少期间维持瘦体重仍然不清楚。 因此，这项建议的总体目标是了解如何破坏骨骼肌线粒体 丙酮酸摄取在从肥胖恢复期间节省肌肉质量。根据我们的初步数据， 该建议的假设是，肌肉MPC中断导致肌肉质量在从 肥胖通过：1）改变肌肉和肝脏之间的底物交换的全身机制， 为肌肉质量提供氮;和2）独特的，MPC破坏依赖的，肌肉自主的 氮素滞留机理具体目标1的实验将检验肌肉MPC 破坏增加了科里循环，肌肉和肝脏之间的乳酸和葡萄糖交换， 在体重减轻和从肥胖恢复期间骨骼肌蛋白质和氨基酸合成的氮。 具体目标2的实验将检验骨骼肌MPC破坏增加天冬氨酸 和支链氨基酸（BCAA）的可用性，导致维持肌细胞蛋白质含量。 这项研究是重要的，因为完成将提供一种改变骨骼的方式的机械信息， 肌肉代谢，可能为治疗肥胖症和导致T2 D的肌肉减少症提供信息。本研究是 新颖，因为它提出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.