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

我的研究项目结合了运动生理学、营养学和骨骼肌代谢，以了解肌肉纤维中储存的脂肪(称为肌内脂质(IMCL))在脂肪氧化和胰岛素信号传递中所起的作用。IMCL在肥胖者中升高，并被发现与胰岛素抵抗有关；然而，IMCL在高度胰岛素敏感的运动员中也会升高。IMCL储存库的位置及其与线粒体的接近程度在很大程度上没有得到研究，可能与胰岛素信号和脂肪氧化有关，这在肥胖者和运动者中是不同的。我以前的研究表明，耐力训练导致IMCL从肌膜下(就在肌肉细胞膜下)重新分布到肌纤维的肌纤维间(在肌肉纤维的收缩装置内)，并增加IMCL与线粒体的接近程度。在单次耐力运动后，女性的IMCL与线粒体的亲和力增加，而男性则不同，这表明IMCL重新定位到线粒体的过程在性别之间是不同的。IMCL的位置很重要，因为人们认为IMCL与线粒体的接近程度增加促进了脂肪氧化，这在肥胖和运动者中是不同的，也可能对胰岛素信号传递有生理意义。为了确定IMCL存储位置和与线粒体的接近程度的生理重要性，我的NSERC Discovery研究计划的前两个主题将检查：A)锻炼和停用如何影响IMCL存储位置，以及这与胰岛素信号和脂肪氧化如何相关；以及B)IMCL存储位置和与线粒体并列的机制。此外，女性在耐力运动中对脂肪储备的依赖程度高于男性，这与运动后观察到的IMCL线粒体位置的性别差异是一致的。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的共处，以及这如何影响运动中的脂肪氧化，这将提供对性别之间固有内分泌差异的洞察。这项研究的优势和新颖性在于对IMCL和线粒体亚细胞储存库的高度详细的描述。这项检查将使IMCL细胞生理学的变化与胰岛素信号的变化联系在一起，为IMCL的定位以及运动和营养对IMCL定位的调节如何影响胰岛素信号提供机械性的洞察。本研究对于了解肌肉血糖调节的基本机制，促进运动生理学和肌肉代谢领域的发展具有重要意义。

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.