NOVEL MECHANISMS MODULATING SKELETAL MUSCLE FUNCTIONS

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Overall Objective. This research program will elucidate underlying mechanisms by which gut-derived factors and lipid-enriched diets, training and polyphenols (PP) regulate skeletal muscle functions. Justification. This research is prompted by recent findings showing that gut microbiota (GM) and gastrointestinal (GI) peptides influence skeletal muscle mass, contractility and metabolism. Second, high fat (HFD) and Western-type diets (WD) are known to hinder muscle contractility. Thirdly, we recently reported that impaired muscle contractility, lipid metabolism, mitochondrial functions, antioxidant defense and the triggering of inflammation preceded changes in weight gain in young rats fed a HFD. Subsequent transcriptomics and lipidomics analyses have enabled us to identify new genes and lipid moieties that modulate the skeletal muscle. Approach. Collectively, findings have laid the foundation for a NSERC research program that will identify and characterize novel mechanisms by which gut-derived compounds and lipid-enriched diets impact skeletal muscle function and how PPs and exercise may optimize these effects. We are proposing 3 Objectives: (1) Identify new gut regulators of skeletal muscle: This set of experiments that features a library of GI peptides and GM-derivatives in cultured L6 myocytes will provide new insight on how a number of gut-derived factors modulate the skeletal muscle. Thereafter, Wistar rats will be treated with the most bioactive molecules. Absolute force, fatigue resistance and recovery capacity will be measured in muscles. Key pathways regulating muscle mass, fiber typing, metabolism, autophagy, redox state, inflammation and mitochondrial activity will be determined. (2) Define novel lipid mechanisms regulating the gut/skeletal muscle axis: This aim will provide new information on how lipid-enriched diets alter the gut/skeletal muscle axis. Rats will be fed RCD, HFD or WD for 1 to 12 weeks. Dependent variables are identical to Objective 1. Mechanisms by which GI peptides secretion, the production of GM-derived compounds and intestine permeability affect skeletal muscle functions will be elucidated. (3) Design interventions to optimize skeletal muscle functions: These experiments will provide new information on how PP and exercise impact the skeletal muscle. A Library of PPs will be screened in L6 cells (see Objective 1). Rats fed RCD will be supplemented with the most potent form of PP and submitted to endurance, resistance, high intensity interval training or remain sedentary. Dependent variables described in Objectives 1 and 2 will be measured. Significance. This proposed research will have broad implications for NSERC by identifying novel nutritional and physical exercise interventions optimizing muscle functions in a number of apparently unrelated areas such as human and animal health (growth, aging and diseases), sports performance, livestock production and astronauts involved in prolonged space missions.