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

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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.