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

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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.**