SREBP-1 Transcription Factors Regulate Skeletal Muscle Cell Size by Controlling Protein Synthesis through Myogenic Regulatory Factors

Kevin Dessalle,Joffrey Delarichaudy,Hubert Vidal,Etienne Lefai,Stéphanie Chanon,Georges Nemoz,Sophie Rome,Vanessa Euthine,Chantal Simon,Isao Fujii

doi:10.1371/journal.pone.0050878

Abstract

SREBP-1 are ubiquitously expressed transcription factors, strongly expressed in lipogenic tissues where they regulate several metabolic processes like fatty acid synthesis. In skeletal muscle, SREBP-1 proteins regulate the expression of hundreds of genes, and we previously showed that their overexpression induced muscle atrophy together with a combined lack of expression of myogenic regulatory factors. Here we present evidences that SREBP-1 regulate muscle protein synthesis through the downregulation of the expression of MYOD1, MYOG and MEF2C factors. In myotubes overexpressing SREBP-1, restoring the expression of myogenic factors prevented atrophy and rescued protein synthesis, without affecting SREBP-1 action on atrogenes and proteolysis. Our results point out the roles of MRFs in the maintenance of the protein content and cell size in adult muscle fibre, and contribute to decipher the mechanisms by which SREBP-1 regulate muscle mass.

Highlights

Loss of skeletal muscle mass occurs during aging, disease, or inactivity and results from an imbalance between the rate of muscle protein synthesis and degradation [1]
The three isoforms are encoded by two distinct genes, Srebf1 and Srebf2, and vary in structure, regulation, and functions: Sterol Regulatory Element Binding Proteins (SREBP)-1a and SREBP-1c proteins are key actors of the regulation of genes related to lipid metabolism, whereas SREBP-2 has been more closely associated to cholesterol synthesis and accumulation [4]
To decipher the molecular mechanisms by which SREBP-1 overexpression induces atrophy in muscle cells, we first examined the impact of SREBP-1a and -1c overexpression on protein synthesis and degradation rates (Figure 1)

Summary

Introduction

Loss of skeletal muscle mass occurs during aging (sarcopenia), disease (cachexia), or inactivity (atrophy) and results from an imbalance between the rate of muscle protein synthesis and degradation [1]. The three isoforms are encoded by two distinct genes, Srebf and Srebf, and vary in structure, regulation, and functions: SREBP-1a and SREBP-1c proteins are key actors of the regulation of genes related to lipid metabolism, whereas SREBP-2 has been more closely associated to cholesterol synthesis and accumulation [4]. Beyond their strong expression in tissues with high lipogenic capacities like liver and adipose tissues, the SREBP-1 proteins are ubiquitous transcription factors with significant expression in muscle cells [5,6]. Several studies have been performed to identify SREBP1 target genes using microarray analysis [11,12,13,14] and to characterize the role of SREBP-1a and -1c in skeletal muscle [2,15,16]

Methods

Results

Conclusion