Regulation of mitochondrial activity controls the duration of skeletal muscle regeneration in response to injury

Laurence Pessemesse,Emilie Blanchet,Chamroeun Sar,Chantal Wrutniak-Cabello,Remi Demangel,François Casas,Elodie Jublanc,Lionel Tintignac,Gérard Cabello,Fabienne Cortade,Guillaume Py

doi:10.1038/s41598-019-48703-2

Abstract

Thyroid hormone is a major regulator of skeletal muscle development and repair, and also a key regulator of mitochondrial activity. We have previously identified a 43 kDa truncated form of the nuclear T3 receptor TRα1 (p43) which stimulates mitochondrial activity and regulates skeletal muscle features. However, its role in skeletal muscle regeneration remains to be addressed. To this end, we performed acute muscle injury induced by cardiotoxin in mouse tibialis in two mouse models where p43 is overexpressed in or depleted from skeletal muscle. The measurement of muscle fiber size distribution at different time point (up to 70 days) upon injury lead us to unravel requirement of the p43 signaling pathway for satellite cells dependent muscle regeneration; strongly delayed in the absence of p43; whereas the overexpression of the receptor enhances of the regeneration process. In addition, we found that satellite cells derived from p43-Tg mice display higher proliferation rates when cultured in vitro when compared to control myoblasts, whereas p43−/− satellites shows reduced proliferation capacity. These finding strongly support that p43 plays an important role in vivo by controling the duration of skeletal muscle regeneration after acute injury, possibly through the regulation of mitochondrial activity and myoblasts proliferation.

Highlights

In skeletal muscle, satellite cell regeneration is a crucial process in the daily life of normal population to maintain muscle performance after injury as well as during ageing to limit muscle strength decline
Under basal conditions, as previously described, we found that quadriceps, gastrocnemius or tibialis weights were increased in the absence of p43 and decreased in mice overexpressing p43 when compared to controls (Tintignac et al, submitted)
When assessing the number of myofiber, their cross-sectional area (CSA) and their size distribution, we found that the total number of myofibers per tibialis muscle was strongly increased in both p43−/− and p43-Tg mice when compared with controls (Fig. 2B), whereas their median fiber CSA was strongly decreased in particular in absence of p43 (Fig. 2C)

Summary

Introduction

Satellite cell regeneration is a crucial process in the daily life of normal population to maintain muscle performance after injury as well as during ageing to limit muscle strength decline. To conclude the authors suggested that the local control of T3 and TRα plays an essential role during in vivo skeletal muscle regeneration. We demonstrated in vivo that the specific overexpression of p43 in skeletal muscle (p43-Tg) increases mitochondrial respiration and induces a shift in the metabolic and contractile features of muscle fibers toward a slower and more oxidative phenotype[15]. Whereas the absence of p43 leads to an increase of muscle mass[16], its overexpression induces muscle atrophy during aging[17] These sets of data indicate that p43 regulates muscle mass as well as the metabolic and contractile properties of myofibers through the modulation of mitochondrial activity. Indicates that p43 controls myoblasts proliferation through the regulation of mitochondrial activity

Methods

Results

Conclusion