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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：
10618365
负责人：
Jane Buchanan
金额：
$ 3.61万
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 2024-05-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618365
关键词：
Acceleration 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 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 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.

项目总结/文摘