Comparative Analysis of Muscle Hypertrophy Models Reveals Divergent Gene Transcription Profiles and Points to Translational Regulation of Muscle Growth through Increased mTOR Signaling.

Marcelo G Pereira,Francesco Chemello,Martina Baraldo,Elena Germinario,Leonardo Nogara,Kenneth A Dyar,Hendrik Nolte,Manuela Marabita,Vanina Romanello,Bert Blaauw,Francesca Solagna

doi:10.3389/fphys.2017.00968

Abstract

Skeletal muscle mass is a result of the balance between protein breakdown and protein synthesis. It has been shown that multiple conditions of muscle atrophy are characterized by the common regulation of a specific set of genes, termed atrogenes. It is not known whether various models of muscle hypertrophy are similarly regulated by a common transcriptional program. Here, we characterized gene expression changes in three different conditions of muscle growth, examining each condition during acute and chronic phases. Specifically, we compared the transcriptome of Extensor Digitorum Longus (EDL) muscles collected (1) during the rapid phase of postnatal growth at 2 and 4 weeks of age, (2) 24 h or 3 weeks after constitutive activation of AKT, and (3) 24 h or 3 weeks after overload hypertrophy caused by tenotomy of the Tibialis Anterior muscle. We observed an important overlap between significantly regulated genes when comparing each single condition at the two different timepoints. Furthermore, examining the transcriptional changes occurring 24 h after a hypertrophic stimulus, we identify an important role for genes linked to a stress response, despite the absence of muscle damage in the AKT model. However, when we compared all different growth conditions, we did not find a common transcriptional fingerprint. On the other hand, all conditions showed a marked increase in mTORC1 signaling and increased ribosome biogenesis, suggesting that muscle growth is characterized more by translational, than transcriptional regulation.

Highlights

The regulation of skeletal muscle mass reflects changes in protein synthesis and protein degradation
In order to understand if muscle hypertrophy during different conditions depends on a common transcriptional profile, we compared the transcriptome of three different conditions of muscle growth; i.e., postnatal growth, mechanical overload by tenotomy, and hyperactivation of Akt only in skeletal muscle
In the mechanical overload of the Extensor Digitorum Longus (EDL) muscle we used a tenotomy of the Tibialis Anterior (TA) muscle, which is known to lead to a significant hypertrophy with less damage than the very drastic synergist ablation model (Bruusgaard et al, 2010)

Summary

Introduction

The regulation of skeletal muscle mass reflects changes in protein synthesis and protein degradation. It has been established that one of the major pathways regulating adult muscle mass is the IGF-1-Akt-mTORC1 pathway, which is thought to act mainly through increases in protein synthesis by modulating translation initiation (Manning and Toker, 2017). Despite this important role for protein translation in muscle hypertrophy, there are various examples in which transcription factors regulate adult muscle mass. A role for the transcriptional coactivator PGC1-α4 (Ruas et al, 2012; Mammucari et al, 2015), and the muscle-specific transcription factor MRF4, was suggested to stimulate adult muscle hypertrophy These results show that muscle growth can be regulated by transcriptional mechanisms, which do not always require full activation of mTORC1 signaling. While some studies have examined changes in the transcriptome during different conditions of muscle hypertrophy (Chaillou et al, 2013, 2015; Barbé et al, 2017), a comparative analysis of the transcriptional changes in various models of muscle growth is still missing

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Conclusion