Combinatorial and independent effects of exercise and myostatin/activin blocking on muscle gene expression profiling

Abstract

The administration of soluble ligand binding domain of type IIb activin receptor fused to the Fc domain (sActRIIB-Fc) has been recently shown to attenuate dystrophic pathology and to increase muscle mass, but also to supress aerobic metabolism. In contrast, aerobic exercise is known for promoting aerobic capacity. The aim of the present thesis was to investigate the effects of the combination of myostatin/activin blocking and aerobic exercise on muscle gene expression profile of a in Duchenne Muscular Dystrophy (DMD) model, the mdx mouse. Microarray analysis was conducted from the gastrocnemius muscle and Gene Set Enrichement Analysis (GSEA) was performed to examine the effects of the treatments and muscle dystrophy on gene sets and pathways. The level of significance was set at False Discovery Rate (FDR) < 0.05. The results indicate that the beneficial effects of exercise in dystrophic muscle induce transcription responses towards the gene expression profile of the healthy muscle. Furthermore, the combination of exercise with myostatin/activin inhibition combines the benefits of each intervention alone, without any obvious side effect. The most profound changes were observed in aerobic metabolism pathways, where the shift in gene expression is presented in many different pathways. Moreover, the elevated expressions in glutathione and drug metabolism by cytochrome P450 pathways suggest a possible role for oxidative damage in DMD pathology and increases in BCAAs degradation and lipid metabolism indicate a possible connection between these two processes, but further research is needed to explore the role of oxidative damage in DMD pathology and their possible connections.