Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Doxorubicin-Induced Skeletal Muscle Atrophy is Mediated by Mitochondrial Permeability Transition

Version 1 : Received: 14 March 2022 / Approved: 16 March 2022 / Online: 16 March 2022 (08:22:57 CET)

How to cite: Travis, S.K.; Skinner, S.K.; Thome, T.; Fitzgerald, L.F.; Cohen, M.S.; Wolan, D.W.; Toth, M.J.; Ryan, T.E.; Hepple, R.T. Doxorubicin-Induced Skeletal Muscle Atrophy is Mediated by Mitochondrial Permeability Transition. Preprints 2022, 2022030225 (doi: 10.20944/preprints202203.0225.v1). Travis, S.K.; Skinner, S.K.; Thome, T.; Fitzgerald, L.F.; Cohen, M.S.; Wolan, D.W.; Toth, M.J.; Ryan, T.E.; Hepple, R.T. Doxorubicin-Induced Skeletal Muscle Atrophy is Mediated by Mitochondrial Permeability Transition. Preprints 2022, 2022030225 (doi: 10.20944/preprints202203.0225.v1).

Abstract

Doxorubicin (Dox) is a commonly used chemotherapeutic that can adversely affect skeletal muscle, including causing muscle atrophy. Dox is known to induce an event known as mitochondrial permeability transition (MPT) in cardiac muscle and this plays an important role in Dox-mediated cardiac toxicity. Further to this, recent evidence identifies MPT as a mechanism of atrophy in skeletal muscle, suggesting that MPT may underlie some of the Dox-related toxicity in skeletal muscle. To test this hypothesis, we used cultured human primary myotubes, C2C12 myotubes, and single adult mouse flexor digitorum brevis (FDB) muscle fibers in experiments involving Dox treatment with or without inhibitors of MPT. Dox treatment of myotubes caused myonuclear translocation of the mitochondrial protein apoptosis inducing factor (AIF) and increased mitochondrial reactive oxygen species (mROS), consistent with the known consequences of MPT. Furthermore, Dox caused atrophy in C2C12 myotubes grown on patterned plates, human primary myotubes, and single muscle fibers from adult mice. Notably, Dox-induced atrophy could be prevented by a wide variety of agents that inhibit MPT, as well as by inhibiting mROS or Caspase 3. In conclusion, our results indicate that MPT plays an important role in driving Dox-mediated skeletal muscle atrophy.

Keywords

chemotherapy; muscle atrophy; Doxorubicin; mitochondria; reactive oxygen species

Subject

MEDICINE & PHARMACOLOGY, Other

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.

We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.