PGC-1α and PGC-1β Increase Protein Synthesis via ERRα in C2C12 Myotubes.

Erin L Brown,Aaron P Russell,Victoria C Foletta,Anastasia Kralli,Andrew Sanigorski,Nicky Konstantopoulos,Patricio V Sepulveda,David Cameron-Smith,Craig R Wright,Paul Della Gatta

doi:10.3389/fphys.2018.01336

Abstract

The transcriptional coactivators peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and PGC-1β are positive regulators of skeletal muscle mass and energy metabolism; however, whether they influence muscle growth and metabolic adaptations via increased protein synthesis is not clear. This study revealed PGC-1α or PGC-1β overexpression in C2C12 myotubes increased protein synthesis and myotube diameter under basal conditions and attenuated the loss in protein synthesis following the treatment with the catabolic agent, dexamethasone. To investigate whether PGC-1α or PGC-1β signal through the Akt/mTOR pathway to increase protein synthesis, treatment with the PI3K and mTOR inhibitors, LY294002 and rapamycin, respectively, was undertaken but found unable to block PGC-1α or PGC-1β’s promotion of protein synthesis. Furthermore, PGC-1α and PGC-1β decreased phosphorylation of Akt and the Akt/mTOR substrate, p70S6K. In contrast to Akt/mTOR inhibition, the suppression of ERRα, a major effector of PGC-1α and PGC-1β activity, attenuated the increase in protein synthesis and myotube diameter in the presence of PGC-1α or PGC-1β overexpression. To characterize further the biological processes occurring, gene set enrichment analysis of genes commonly regulated by both PGC-1α and PGC-1β was performed following a microarray screen. Genes were found enriched in metabolic and mitochondrial oxidative processes, in addition to protein translation and muscle development categories. This suggests concurrent responses involving both increased metabolism and myotube protein synthesis. Finally, based on their known function or unbiased identification through statistical selection, two sets of genes were investigated in a human exercise model of stimulated protein synthesis to characterize further the genes influenced by PGC-1α and PGC-1β during physiological adaptive changes in skeletal muscle.

Highlights

IntroductionThe significant reduction in skeletal muscle mass known as atrophy occurs as a consequence of protein catabolism outweighing protein synthesis rates (reviewed in Favier et al, 2008; Huang and Zhu, 2016) with mitochondrial dysfunction potentially contributing to muscle atrophy (Romanello et al, 2010; Russell et al, 2014)
The significant reduction in skeletal muscle mass known as atrophy occurs as a consequence of protein catabolism outweighing protein synthesis rates with mitochondrial dysfunction potentially contributing to muscle atrophy (Romanello et al, 2010; Russell et al, 2014)
To overexpress PGC-1α and PGC-1β, C2C12 myotubes were infected with adenoviruses expressing green fluorescent protein (GFP), PGC-1α, or PGC-1β

Summary

Introduction

The significant reduction in skeletal muscle mass known as atrophy occurs as a consequence of protein catabolism outweighing protein synthesis rates (reviewed in Favier et al, 2008; Huang and Zhu, 2016) with mitochondrial dysfunction potentially contributing to muscle atrophy (Romanello et al, 2010; Russell et al, 2014). The expression of PGC-1α and/or PGC-1β is reduced in conditions associated with skeletal muscle atrophy and perturbed metabolic function, such as aging (Ling et al, 2004; Rodriguez-Calvo et al, 2006; Joseph et al, 2012), denervation (Sandri et al, 2006; Sacheck et al, 2007), heart failure (Garnier et al, 2003; Vescovo et al, 2005), sepsis (Menconi et al, 2010), cancer cachexia and renal failure (Sandri et al, 2006), amyotrophic lateral sclerosis (ALS; Russell et al, 2013), insulin-resistance, and diabetes (Mootha et al, 2003; Patti et al, 2003) To extend these findings, the overexpression of PGC-1α or PGC-1β in mouse skeletal muscle was found protective against muscle mass loss following denervation, fasting, and hindlimb unloading (Sandri et al, 2006; Brault et al, 2010; Cannavino et al, 2014, 2015) and in a model of Duchenne muscular dystrophy (DMD; Handschin et al, 2007; Selsby et al, 2012). A clear role for PGC-1α and PGC-1β in regulating skeletal muscle protein synthesis requires further investigation to understand their contribution to muscle fiber hypertrophy and metabolic adaptations

Methods

Results

Discussion

Conclusion