Deficiency of myostatin protects skeletal muscle cells from ischemia reperfusion injury

Christoph Wallner,Johannes Maximilian Wagner,Maxi Von Glinski,Mustafa Becerikli,Stephan Hahn,Alexander Sogorski,Marcus Lehnhardt,Marius Drysch,Björn Behr,Sonja Verena Schmidt,Felix Reinkemeier,Mehran Dadras

doi:10.1038/s41598-021-92159-2

Christoph Wallner, Johannes Maximilian Wagner + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-92159-2

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Abstract

Ischemia reperfusion (IR) injury plays a pivotal role in many diseases and leads to collateral damage during surgical interventions. While most studies focus on alleviating its severity in the context of brain, liver, kidney, and cardiac tissue, research as regards to skeletal muscle has not been conducted to the same extent. In the past, myostatin (MSTN), primarily known for supressing muscle growth, has been implicated in inflammatory circuits, and research provided promising results for cardiac IR injury mitigation by inhibiting MSTN cell surface receptor ACVR2B. This generated the question if interrupting MSTN signaling could temper IR injury in skeletal muscle. Examining human specimens from free myocutaneous flap transfer demonstrated increased MSTN signaling and tissue damage in terms of apoptotic activity, cell death, tissue edema, and lipid peroxidation. In subsequent in vivo MstnLn/Ln IR injury models, we identified potential mechanisms linking MSTN deficiency to protective effects, among others, inhibition of p38 MAPK signaling and SERCA2a modulation. Furthermore, transcriptional profiling revealed a putative involvement of NK cells. Collectively, this work establishes a protective role of MSTN deficiency in skeletal muscle IR injury.

Highlights

Ischemia reperfusion (IR) injury plays a pivotal role in many diseases and leads to collateral damage during surgical interventions
Caspase 3, marking the final pathway of apoptosis, displayed the same increase, and 4-HNE as marker lipid peroxidation due to oxidative stress[23] rose threefold (p < 0.01). These findings clearly demonstrated the extent of IR injury in routinely performed free latissimus dorsi myocutaneous flap transfer which is paralleled by an increase in MSTN and its downstream targets, noteworthy p38 MAPK
This work emphasizes the incidence of skeletal muscle IR injury in routinely performed surgery and demonstrates protective effects of MSTN deficiency

Summary

Introduction

Ischemia reperfusion (IR) injury plays a pivotal role in many diseases and leads to collateral damage during surgical interventions. Myostatin (MSTN), primarily known for supressing muscle growth, has been implicated in inflammatory circuits, and research provided promising results for cardiac IR injury mitigation by inhibiting MSTN cell surface receptor ACVR2B. This generated the question if interrupting MSTN signaling could temper IR injury in skeletal muscle. In 2019, Magga et al demonstrated myocardial protection from IR injury by systemic blockade of MSTN receptor A CVR2B19 While these effects have been reported in the heart, pathophysiological considerations suggest similar effects in skeletal muscle

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