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:
    10468660
  • 负责人:
  • 金额:
    $ 3.74万
  • 依托单位:
  • 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

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.
项目摘要/摘要 2型糖尿病(T2D)是一种广泛的代谢性疾病,其特征是胰岛素抵抗 和高血糖。肥胖,脂肪质量的过量积累,是主要的T2D风险因素,强烈 与骨骼肌和肝脏中的胰岛素耐药性相关,导致两种器官的葡萄糖摄取较少。 减少肌肉葡萄糖的摄取有助于慢性高血糖,并因过度加剧 肝糖异生。因为骨骼肌是可用于葡萄糖处置的最大的组织仓库,所以 肌肉减少症,骨骼肌质量的丧失也导致高血糖。虽然肥胖和 肌肉减少症是导致T2D发病机理的关键因素,当前疗法解决胰岛素 可用性或灵敏度,而无需解决脂肪和肌肉质量之间的潜在失衡。 骨骼肌线粒体丙酮酸载体(MPC)的破坏会增加胰岛素敏感性和 从肥胖症中恢复的小鼠中,通过完全肌肉质量降低了脂肪的损失。因此,调制 骨骼肌丙酮酸代谢可能有助于将改变的身体组成作为T2D根本原因。 我们以前的工作重点是了解肌肉特异性MPC如何增加脂肪氧化。 然而,在脂肪质量损失期间骨骼肌MPC如何保持瘦质量仍然尚不清楚。 因此,该提议的总体目标是了解骨骼肌肉线粒体的破坏程度 丙酮酸摄取在从肥胖症中恢复过程中挽救了肌肉质量。基于我们的初步数据,中央 该提议的假设是肌肉MPC的破坏会导致肌肉质量在从 肥胖至:1)肌肉和肝脏之间底物交换改变的全身机制 用于肌肉质量的辅助氮; 2)独特的MPC破坏依赖性,肌肉自治 氮保留机制。特定目标1的实验将检验肌肉MPC的假设 破坏增加了cori骑自行车,肌肉和肝脏之间的乳酸和葡萄糖的交换 体重减轻和从肥胖症中恢复期间,用于骨骼肌蛋白和氨基酸合成的氮。 特定目标2的实验将检验以下假设:骨骼肌MPC破坏会增加天冬氨酸 和分支链氨基酸(BCAA)的可用性,可维持心肌细胞蛋白含量。 这项研究很重要,因为完成将提供有关改变骨骼的方法的机械信息 肌肉代谢可能会导致肥胖和肌肉减少症的治疗。这项研究是 小说是因为它解决了细胞和全身氮处理中的新概念。

项目成果

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Jane Buchanan其他文献

Jane Buchanan的其他文献

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{{ truncateString('Jane Buchanan', 18)}}的其他基金

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
  • 批准号:
    10618365
  • 财政年份:
    2021
  • 资助金额:
    $ 3.74万
  • 项目类别:
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
  • 批准号:
    10314711
  • 财政年份:
    2021
  • 资助金额:
    $ 3.74万
  • 项目类别:

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