Protective effects of omega-3 fatty acids against skeletal muscle cell lipotoxicity

Abstract

Skeletal muscle is a highly malleable tissue with the capacity to alter its phenotype in response to exercise and nutrient availability. Adult skeletal muscle is primarily composed of terminally differentiated post-mitotic cells and relies on specialised muscle stem cells (satellite cells) to facilitate repair and regeneration. Satellite cell regenerative capacity is impaired by diets enriched with high concentrations of saturated fat as well as other environmental lifestyle factors such as obesity and physical inactivity. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), commonly found in fish oil supplements, possess anti-inflammatory properties and have been shown to improve aspects of skeletal muscle function and metabolism. These protective properties have established n-3 PUFAs as a potential dietary supplement strategy to help combat muscle wasting and promote muscle growth and repair. However, the cell signalling pathways underlying their efficacy in skeletal muscle cells are not completely understood. This Master’s thesis comprises a published review of the literature pertaining to the potential roles of n-3 PUFAs during muscle growth and regeneration, and an original research study investigating and comparing the purported beneficial protective effects of n-3 PUFAs in skeletal muscle cells against lipotoxicity induced by the saturated fatty acid palmitate (PAL). The experimental data collected for this thesis demonstrate that the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish oil supplements, protect skeletal muscle cells against the deleterious effects of PAL. Furthermore, the work in this thesis provide novel data regarding the beneficial effects and potential mechanisms of Docosapentaenoic acid (DPA), a lesser studied intermediary n-3 PUFA, on maintaining skeletal muscle cell viability in an environment of high fat availability. The results obtained demonstrate that all n-3 PUFAs induce protective effects against the deleterious effects of PAL on skeletal muscle cell viability and subsequent differentiation capacity. However, DPA confers the greatest protection against the induction of PAL-induced ER stress. Mechanistically, DPA protects against PAL-induced cytotoxicity via maintaining muscle cell mitochondrial membrane integrity. In the context of the previous literature overviewed in the published review article, these data contribute important novel findings demonstrating that all n-3 PUFAs including DPA protect skeletal muscle cells in vitro against stimuli known to be deleterious to skeletal muscle growth and repair in vivo. These data also reveal that DPA has the potential to elicit superior protective effects against lipotoxicity compared to EPA and DHA, setting the stage for further research into the mechanisms underlying DPA’s beneficial effects and potential future therapeutic applications in fish oil supplements to help promote muscle growth, maintenance and repair.