Research Projects

Skeletal muscle immunometabolic responses to exercise and diabetes

Skeletal muscle inflammation is emerging as a potential contributor to T2D. Inflammation occurs during exercise and repair and is a hallmark of myopathies, suggesting that it plays crucial roles in skeletal muscle homeostasis. Despite the fact that exercise is associated with inflammation, physical activity has beneficial effects on T2D, which highlights the ambivalent role of muscle inflammation in controlling glucose homeostasis. Surprisingly, it is unknown whether there is any parallel between local inflammation of muscle and T2D and no therapeutic strategies currently target skeletal muscle for T2D treatment. The overall aim of our studies is to determine the interaction between inflammation and the metabolic response to exercise and T2D to define novel strategies that can improve insulin sensitivity. Our aime is to identify what type of inflammatory response induces the greatest metabolic effect on signal transduction and expression of genes. We use human muscle biopsies as well as primary cell cultures of skeletal muscle cells to study whether the beneficial effect of exercise on metabolism are dependent on inflammation, and translate these discoveries into innovative exercise and anti-inflammatory intervention strategies to improve insulin sensitivity. Read our publications on the topic:


 

Metabolic regulation of skeletal muscle internal clock

Circadian rhythms occur in all species and modulate fundamental physiological processes. Day-night cycles align the phase of circadian rhythms to earth rotation, but most cells of the body follow an endogenous circadian clock independent of light exposure. Disruption of circadian cycles is associated with metabolic imbalance, and leads to increased risk of type 2 diabetes in individuals working night shifts. This suggests that alterations in circadian rhythms could contribute to the worldwide epidemic of metabolic syndrome, but the pathophysiological mechanisms are poorly understood. Skeletal muscle is engaged in locomotor activity, and glucose uptake and metabolism in this tissue are exquisitely regulated by insulin-independent contractile activity. Skeletal muscle is indeed the major determinant of post-prandial glycaemia and whole-body insulin sensitivity. But surprisingly little is known about the cross-talk between glucose/lipid metabolism and the internal clock in skeletal muscle and subsequent impact on whole body insulin sensitivity. The aim of this study is to determine if and how metabolic challenges impair the skeletal muscle internal clock leading to disturbances in glucose and fatty acid metabolism. It will identify if and how fatty acids discretely affect elements of the core clock in skeletal muscle and the interactions between insulin resistance and clock impairments to decipher the cause-consequence relationship between these two events. Identification of pathways linking metabolic and clock disturbances could lead to new pharmacological targets to target fatty acid-induced insulin resistance.


 

Insulin resistance induced by lipid peroxidation by-products

Oxidative stress is involved in the pathophysiology of type 2 diabetes (T2D) and associated complications. In particular, the oxidation of polyunsaturated fatty acids produces deleterious lipid aldehydes able to interfere with many pathophysiological processes. 4-hydroxy-2-hexenal (4-HHE) is specifically derived from the peroxidation of omega-3 fatty acids, while 4-hydroxy-2-nonenal (4-HNE) is produced from omega-6 fatty acids. The aim of our studies is to investigate the involvement of 4-HHE and 4-HNE in the development of insulin resistance. We measure the concentration of aldehydes in the plasma from T2D humans and rats. We then use muscle cells and adipocytes exposed to aldehydes in vitro to measure their effects on insulin sensitivity by measuring glucose uptake and signalling pathways. Finally, we develop strategies to prevent the deleterious effects of aldehydes using antioxidants and pharmacological modulation of cellular detoxification mechanisms. This project will characterize the role of lipid aldehydes in T2D and its antagonism as a potential therapeutic mean to taper oxidative stress-induced insulin resistance. Read our publications on the topic: