Role of environmental factors on the alteration of skeletal muscle energy metabolism and insulin sensitivity

环境因素对骨骼肌能量代谢和胰岛素敏感性改变的作用

• 批准号: RGPIN-2015-06263
• 负责人: Aguer, Céline
• 金额: $ 2.4万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684996
• 关键词: Role; environmental; factors; alteration; skeletal

The overarching goal of my lab is to better understand skeletal muscle metabolism defects that results in insulin resistance. Skeletal muscle accounts for ~80% of postprandial glucose disposal and is thus the major organ of glucose uptake. My work over the last 5 years, and that of others, demonstrated that increased inflammation and oxidative stress which results in mitochondrial dysfunction is mechanistically connected with skeletal muscle insulin resistance, however the exact cause of muscle insulin resistance development is not completely understood. Environmental factors, such as inactivity and environmental chemicals, strongly contribute to insulin resistance development. ***The long-term objective of my research program is to significantly advance the understanding of the role of environmental factors on the alteration of skeletal muscle energy metabolism and insulin sensitivity. I will focus my program research for this NSERC discovery grant on two factors known to alter skeletal muscle mitochondrial function and glucose uptake: (1) myokines: cytokines secreted by contracting skeletal muscle that are known to improve muscle fatty acid oxidation and glucose uptake; (2) polychlorinated biphenyls (PCBs), chemical products strongly related to impaired glucose homeostasis. ***The short-term objectives are:***1) To determine the mechanisms by how myokines known to be decreased in insulin resistance conditions (interleukin-15 and Brain Derived Neurotrophic Factor) affect muscle insulin sensitivity. I recently demonstrated that acylcarnitine accumulation due to incomplete fatty acid oxidation results in increased oxidative stress and insulin resistance in muscle cells. I propose to test the hypothesis that these myokines improve complete fatty acid oxidation, resulting in decreased acylcarnitine accumulation, decreased oxidative stress and improved insulin sensitivity.***2) To determine extrinsic mechanisms responsible for PCB-induced energy metabolism defects and insulin resistance in skeletal muscle. I propose to test the hypothesis that PCBs exposure alters adipose tissue cytokine/adipokine release leading to muscle mitochondrial dysfunction, and eventually to muscle insulin resistance.***It is anticipated that the proposed program will substantially advance the understanding of mechanisms by how environmental factors alter muscle insulin sensitivity and mitochondrial function. The ultimate goal of my first research line is to identify myokines that can be targeted in order to improve muscle and whole-body insulin sensitivity. My second research line will advance the understanding of the biological impact of environmental contaminants on muscle metabolism and physiology.**

我实验室的首要目标是更好地了解导致胰岛素抵抗的骨骼肌代谢缺陷。骨骼肌占餐后葡萄糖处置的约80%，因此是葡萄糖摄取的主要器官。在过去的5年里，我和其他人的工作表明，导致线粒体功能障碍的炎症和氧化应激增加与骨骼肌胰岛素抵抗有关，但肌肉胰岛素抵抗发展的确切原因尚未完全了解。环境因素，如不活动和环境化学物质，强烈有助于胰岛素抵抗的发展。*** 我的研究计划的长期目标是显着推进环境因素对骨骼肌能量代谢和胰岛素敏感性改变的作用的理解。我将把我的项目研究的重点放在NSERC发现资助的两个已知改变骨骼肌线粒体功能和葡萄糖摄取的因素上：（1）肌因子：由收缩骨骼肌分泌的细胞因子，已知可改善肌肉脂肪酸氧化和葡萄糖摄取;（2）多氯联苯（PCB），与葡萄糖稳态受损密切相关的化学产品。 * 短期目标是：*1）确定已知在胰岛素抵抗条件下减少的肌因子（白细胞介素-15和脑源性神经营养因子）如何影响肌肉胰岛素敏感性的机制。我最近证明，酰基肉毒碱积累，由于不完全的脂肪酸氧化的结果增加氧化应激和胰岛素抵抗的肌肉细胞。我建议测试这一假设，即这些肌因子改善完全脂肪酸氧化，导致酰基肉毒碱积累减少，氧化应激减少和胰岛素敏感性改善。2)探讨多氯联苯诱导的骨骼肌能量代谢缺陷和胰岛素抵抗的外在机制。我建议测试这一假设，即多氯联苯暴露改变脂肪组织细胞因子/脂肪因子的释放，导致肌肉线粒体功能障碍，并最终导致肌肉胰岛素抵抗。预计拟议的计划将通过环境因素如何改变肌肉胰岛素敏感性和线粒体功能来大大推进对机制的理解。我的第一条研究路线的最终目标是确定可以靶向的肌因子，以改善肌肉和全身胰岛素敏感性。我的第二条研究线将推进对环境污染物对肌肉代谢和生理学的生物影响的理解。