Effect of n-3 fatty acid supplementation on atrophy induced by hindlimb suspension and hypertrophy induced by reweighting in C57BL/6 mice fed a high-fat diet

Abstract

Insulin resistance (IR) is observed in several conditions, including obesity, type 2 diabetes mellitus and metabolic syndrome. Under these conditions an increase in pro-inflammatory factors and oxidative stress has been observed, which may play an important role in activation of pathways related to skeletal muscle (ME) wasting (atrophy) and a shift toward fast twitch, glycolytic fibers, which may contribute to exercise intolerance, decreased quality of life and increase of mortality. Among the pathways of protein degradation, ubiquitin proteasome system (UPS) has an important role in skeletal muscle atrophy, being responsible for the degradation of sarcomeric proteins in several conditions such as IR, cancer, diabetes mellitus and obesity. Muscle atrophy is regulated by two E3 ubiquitin-ligases, known as MAFbx/Atrogin1 and MuRF1. Up-regulation of these genes is associated with increased proteolysis. Polyunsaturated fatty acids (n-3 PUFA) have been suggested as an important adjuvant therapy for several diseases, and recent studies have demonstrated beneficial effects of n-3 PUFA on skeletal muscle following sepsis, cachexia, and starvation. It has been demonstrated that obesity-induced diet (HFD) can interfere with the process of muscle protein synthesis in a model of load-induced hypertrophy. However, it is not established yet if n-3 PUFA supplementation can prevent or attenuate this impairment. Thus, this project aims to investigate whether IR induced by a high-fat diet modulate the activation of pathways involved in protein synthesis and degradation during atrophy and the recovery of mass following atrophy, and to verify the possible preventive or attenuating role of supplementation with n-3 PUFA. C57BL/6 mice will be supplemented or not with n-3 PUFA and will be submitted to a balanced or high-fat diet for 15 weeks. We hypothesized that obesity-induced insulin resistance would increase UPS and calpains activation resulting in increased protein degradation and impair signaling pathways involving protein synthesis in skeletal muscle, ultimately leading to increased muscle loss during disuse and inhibition of recovery of mass following reloading. Further, we hypothesize that supplementation with n-3 PUFA would prevent these effects. Thus, supplementation of n-3 PUFA can be a good strategy for treating or preventing disorders associated with unbalanced protein metabolism. (AU)