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，以了解肌纤维内脂质储存（称为细胞内脂质（IMCL））在脂肪氧化和胰岛素信号传导中的作用。肥胖个体的IMCL升高，已发现与胰岛素抵抗有关；然而，在胰岛素高度敏感的运动员中，IMCL也会升高。IMCL储存的位置及其与线粒体的接近程度在很大程度上尚未得到研究，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是不同的。我之前的研究已经表明，耐力训练导致内膜细胞链从肌鞘下（肌细胞膜下）重新分布到肌纤维的肌间纤维（在肌纤维的收缩装置内）区域，并增加了内膜细胞链与线粒体的接近度。在女性进行一次耐力运动后，IMCL与线粒体的距离增加，而男性则没有，这表明将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与线粒体的距离增加有助于脂肪氧化，这在肥胖和运动个体之间是不同的，也可能对胰岛素信号传导有生理影响。为了确定IMCL储存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)运动和废弃如何影响IMCL储存位置以及这与胰岛素信号和脂肪氧化的关系，以及B)确定IMCL储存位置和与线粒体并置的机制。此外，女性在耐力运动中比男性更依赖脂肪储存，这与观察到的运动后IMCL线粒体共定位的性别差异一致。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储存位置和线粒体的共存位置，以及这如何影响运动期间的脂肪氧化，这将为两性之间固有的内分泌差异提供见解。所提出的研究的强度和新颖性在于对IMCL和线粒体的亚细胞储存库进行了非常详细的表征。这项研究将允许IMCL的细胞生理学变化与胰岛素信号传导的变化相关联，为IMCL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传导提供机制见解。本研究将对了解肌肉血糖调节的基本机制，推动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.