Understanding the role of intramyocellular lipid droplet localization in human skeletal muscle and its influence on insulin signalling

了解肌细胞内脂滴定位在人类骨骼肌中的作用及其对胰岛素信号传导的影响

• 批准号: RGPIN-2017-03989
• 负责人: DevriesAboud, Michaela
• 金额: $ 4.37万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757734
• 关键词: Understanding; role; intramyocellular; lipid; droplet

My research program combines exercise physiology, nutrition and skeletal muscle metabolism to understand the role that lipid stores within muscle fibres (known as intramyocellular lipid (IMCL)) have in fat oxidation and insulin signalling. IMCL are elevated in obese individuals and have been found to be related to insulin resistance; however, IMCL are also elevated in athletes who are highly insulin sensitive. The location of IMCL stores and their proximity to mitochondria are largely unexamined and may be related to insulin signalling and fat oxidation, which would be different in obese and athletic individuals. My previous research has shown that endurance training results in a redistribution of IMCL from the subsarcolemmal (just under the muscle cell membrane) to the intermyofibrillar (within the contractile apparatus of the muscle fibre) region of the muscle fibre as well as an increase in the proximity of IMCL to mitochondria. The increased proximity of IMCL to mitochondria is also seen following a single bout of endurance exercise in women, but not men, suggesting that the process of re-locating IMCL to mitochondria is different between sexes. Location of IMCL is important as it is thought that the increased proximity of IMCL to mitochondria facilitates fat oxidation, which differs between obese and athletic individuals and may also have physiological implications on insulin signalling. In order to determine the physiological importance of IMCL storage location and proximity with mitochondria, the first two themes of my NSERC Discovery research program will examine: A) how exercise and disuse influence IMCL storage location and how this relates to insulin signalling and fat oxidation, and B) the mechanisms by which IMCL storage location and juxtaposition with mitochondria are determined. In addition, women rely to a greater extent on fat stores during endurance exercise than men, which is line with the observed sex difference in IMCL mitochondria co-location post exercise. Thus, the third theme (C) of my NSERC Discovery research program will examine how sex influences IMCL storage location and co-location with mitochondria and how this impacts fat oxidation during exercise, which will provide insight on inherent endocrinological differences between the sexes. The strength and novelty of the proposed research lies in the highly detailed characterization of subcellular storage depots of IMCL and mitochondria. This examination will allow changes in the cellular physiology of IMCL to be associated with changes in insulin signalling, providing mechanistic insight into how IMCL localization, and regulation of IMCL localization by exercise and nutrition, impacts insulin signalling. This research will have significant implications for understanding the basic mechanisms of muscle glycemic regulation to advance the fields of exercise physiology and muscle metabolism.

我的研究计划结合了运动生理学，营养和骨骼肌代谢，以了解脂质在肌肉纤维中的作用（称为脂肪内脂质（IMCL））在脂肪氧化和胰岛素信号中具有。 IMCL在肥胖个体中升高，并被发现与胰岛素抵抗有关。但是，在高度胰岛素敏感的运动员中，IMCL也升高。 IMCL存储的位置及其与线粒体的邻近性在很大程度上没有审查，并且可能与胰岛素信号传导和脂肪氧化有关，这在肥胖和运动个体中会有所不同。我先前的研究表明，耐力训练会导致IMCL从肌肉纤维的肌肉纤维区域（在肌肉纤维的收缩仪中）重新分布，并在肌肉纤维区域的收缩仪中重新分布。在女性中进行了一次耐力运动后，还可以看到IMCL与线粒体的邻近性增加，但表明将IMCL重新定位到线粒体的过程之间是不同的。 IMCL的位置很重要，因为认为IMCL与线粒体的接近性增加促进了脂肪氧化，这在肥胖和运动个体之间有所不同，并且可能对胰岛素信号传导具有生理意义。为了确定IMCL存储位置和与线粒体接近的生理重要性，我的NSERC发现研究计划的前两个主题将研究：a）锻炼方式如何影响IMCL存储位置，以及这与胰岛素信号和脂肪氧化的关系以及与IMCL存储位置和yxtapostria的机制有关。此外，女性在耐力运动过程中比男性更依赖于脂肪储存，这与运动后IMCL线粒体共处的性别差异保持一致。因此，我的NSERC发现研究计划的第三个主题（c）将研究性别如何影响IMCL的存储位置和与线粒体共同设置，以及这如何影响运动过程中的脂肪氧化，这将洞悉性别之间固有的内分泌差异。拟议研究的强度和新颖性在于IMCL和线粒体的亚细胞存储库的高度详细表征。这项检查将使IMCL细胞生理的变化与胰岛素信号传导的变化有关，从而提供有关IMCL定位以及通过运动和营养对IMCL定位的调节的机械洞察力，从而影响胰岛素信号传导。这项研究将对理解肌肉血糖调节的基本机制具有重要意义，以推进运动生理和肌肉代谢领域。