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

skeletal muscle regeneration injury

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#1 Engadin

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Posted 29 August 2019 - 11:41 AM


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S O U R C E :   nature

 

 

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.

 

 

INTRODUCTION

 

 

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. Upon muscle injury, the skeletal muscle stem cells (thereafter referred as satellite cells) which are normally quiescent are activated. Once activated, the satellite cells start to proliferate, migrate to the site of injury and subsequently differentiate and fuse to form newly multinucleated fibers to repair and rebuild the damaged myofibers1.

 

Thyroid hormone (TH) is a major regulator of muscle development and metabolism. It stimulates muscle growth by increasing the number and diameter of muscle fibers2,3 and regulates the contractile features of adult muscle fibers4. TH is also a key regulator of mitochondrial activity. These functions of TH involve both TH receptor α (TRα) and β (TRβ). Recently, the role of TH5,6,7 and TRs8 have been investigated in the context of injury induced muscle regeneration. Notably, satellite cell-specific deletion of the 5-deiodinase 3 gene (D3), the enzyme that inactivates T3, severely impairs skeletal muscle regeneration5. In addition, TH Transporters MCT8 and OATP1C1 were recently shown to be required to ensure a normal skeletal muscle regeneration7. Similarly, the introduction of a dominant-negative knock-in mutation of the TRα gene (TRα1PV) in mice results in an impaired regeneration of skeletal muscle whereas a similar mutation in TRβ gene (TRβ1PV) has no effect8. To conclude the authors suggested that the local control of T3 and TRα plays an essential role during in vivo skeletal muscle regeneration. These studies strongly suggest that TRα gene mediates the effects of T3 during skeletal muscle regeneration.

 

However, the putative involvement of p43 during muscle tissue repair after acute injury was not considered. P43 is a 43 Kda truncated form of the nuclear receptor TRα1 which stimulates mitochondrial activity9,10,11. We showed that p43 overexpression stimulates mitochondrial activity and potentiates terminal differentiation in myoblasts, whereas the inhibition of this pathway induces the reverse changes through the control of myogenin, c-Myc, and calcineurin expression12,13,14. In addition, p43 overexpression in these cells induces a prominent increase in type 1 fibers14. More importantly, 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 phenotype15. Conversely, p43 depletion in mice (p43−/−) reduces mitochondrial respiratory chain activities and induces a shift toward a faster and more glycolytic muscle fiber phenotype16. In addition, whereas the absence of p43 leads to an increase of muscle mass16, its overexpression induces muscle atrophy during aging17. 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. However, the involvement of p43 in muscle regeneration process remains to be addressed.

 

Using mouse models overexpressing p43 in skeletal muscle or lacking p43, we report here that p43 plays an important role in vivo by controling the duration of skeletal muscle regeneration after acute injury. Upon acute injury, skeletal muscle regeneration is strongly delayed in the absence of p43, whereas the overexpression of the receptor enhances of the regeneration process. Moreover, we found that satellite cells derived from p43-Tg mice proliferated faster compared to control myoblasts, whereas satellites cells providing from p43−/− proliferated slower. Thus indicates that p43 controls myoblasts proliferation through the regulation of mitochondrial activity.

 

 

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F O R   T H E   R E S T   O F   T H E   A R T I C L E ,   P L E A S E   V I S I T   T H E   S O U R C E .

 

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Also tagged with one or more of these keywords: skeletal muscle, regeneration, injury

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