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

肌肉线粒体丙酮酸载体破坏改变氨基酸代谢，以在肥胖恢复过程中维持肌肉质量

基本信息

批准号：
10314711
负责人：
Jane Buchanan
金额：
$ 3.67万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-08 至 2024-06-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10314711
关键词：
Acids Acute Address Affect Age Alanine Amino Acids Anabolism Aspartate Body Composition Body Weight Body Weight decreased Branched-Chain Amino Acids Cell Culture Techniques Chronic Citric Acid Cycle Data Diabetes Mellitus Diet Disease Outcome Excretory function Fatty acid glycerol esters Fellowship Generations Genetic Glucose Glycolysis Goals Health Hyperglycemia Insulin Insulin Resistance Intervention Knock-out Knowledge Label Link Liver Maintenance Measurement Metabolic Metabolic Diseases Metabolism Mission Mitochondria Modeling Mus Muscle Muscle Fibers Muscle Mitochondria Muscle Proteins Muscular Atrophy Nitrogen Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Pathogenesis Patients Physicians Plant Roots Production Protein Biosynthesis Proteins Public Health Publishing Puromycin Pyruvate Pyruvate Metabolism Pathway Recovery Research Risk Factors Scientist Skeletal Muscle Testing Thinness Tissues Training Transfer RNA Aminoacylation United States National Institutes of Health Weight Wild Type Mouse Work amino acid metabolism base career diabetes pathogenesis experimental study glucose disposal glucose uptake hepatic gluconeogenesis improved insulin sensitivity muscle form nitrogen balance novel obesity treatment oxidation polypeptide preservation prevent pyruvate carrier sarcopenia skeletal muscle metabolism skeletal muscle wasting stable isotope uptake

项目摘要

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.

项目概要/摘要 2 型糖尿病 (T2D) 是一种广泛存在的代谢性疾病，其特征是胰岛素抵抗和高血糖。肥胖，即脂肪量的过度积累，是 T2D 的主要危险因素，并且与与骨骼肌和肝脏的胰岛素抵抗有关，导致两个器官吸收的葡萄糖减少。肌肉葡萄糖摄取减少会导致慢性高血糖，并且过量摄入会进一步加剧肝脏糖异生。因为骨骼肌是可用于葡萄糖处理的最大组织库，肌肉减少症（骨骼肌质量减少）也会导致高血糖。虽然肥胖和肌肉减少症是导致 T2D 发病机制的关键因素，目前的治疗方法主要针对胰岛素可用性或敏感性，而不解决脂肪和肌肉质量之间的潜在不平衡。骨骼肌线粒体丙酮酸载体 (MPC) 的破坏会增加胰岛素敏感性在从肥胖中恢复的小鼠中加速脂肪减少并保留完整的肌肉质量。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。我们之前的工作重点是了解肌肉特异性 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保持瘦体重仍不清楚。因此，该提案的总体目标是了解如何破坏骨骼肌线粒体在肥胖恢复过程中，丙酮酸的摄取可以减少肌肉质量。根据我们的初步数据，中央该提议的假设是，肌肉 MPC 破坏会导致肌肉质量在恢复过程中得到保留。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节省氮； 2) 独特的、MPC 中断依赖性、肌肉自主性氮保留机制。针对特定目标 1 的实验将检验肌肉 MPC 的假设破坏增加了 Cori Cycling，即肌肉和肝脏之间乳酸和葡萄糖的交换，从而避免了氮用于减肥和肥胖恢复期间骨骼肌蛋白质和氨基酸的合成。具体目标 2 的实验将检验骨骼肌 MPC 破坏增加天冬氨酸的假设支链氨基酸 (BCAA) 的可用性可维持肌细胞蛋白质含量。这项研究意义重大，因为完成后将提供改变骨骼的机制信息肌肉代谢可能有助于治疗导致 T2D 的肥胖和肌肉减少症。这项研究是之所以新颖，是因为它解决了细胞和系统氮处理的新概念。