Tarpey 2019 J Biol Chem

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Tarpey MD, Amorese AJ, Balestrieri NP, Fisher-Wellman KH, Spangenburg EE (2019) Doxorubicin causes lesions in the electron transport system of skeletal muscle mitochondria that are associated with a loss of contractile function. J Biol Chem 294:19709-22.

» PMID:31690631 Open Access

Tarpey MD, Amorese AJ, Balestrieri NP, Fisher-Wellman KH, Spangenburg EE (2019) J Biol Chem

Abstract: Doxorubicin is an anthracycline based chemotherapeutic that causes myotoxicity with symptoms persisting beyond treatment. Patients experience muscle pain, weakness, fatigue and atrophy, but the underlying mechanisms are poorly understood. Studies investigating doxorubicin-induced myotoxicity have reported disrupted mitochondrial function. Mitochondria are responsible for regulating both cellular energy status and Ca2+ handling, both of which impact contractile function. Moreover, loss of mitochondrial integrity may initiate muscle atrophy. Skeletal muscle mitochondrial dysregulation may therefore contribute to an overall loss of skeletal muscle quality and performance that may be mitigated by appropriately targeted mitochondrial therapies. We therefore assessed the impact of doxorubicin on muscle performance and applied a multiplexed assay platform to diagnose alterations in mitochondrial respiratory control. Mice received a clinically relevant dose of doxorubicin delivered systemically and were euthanized 72 h later. We measured extensor digitorum longus and soleus muscle forces, fatigue, and contractile kinetics were measured in vitro, along with Ca2+ uptake in isolated sarcoplasmic reticulum (SR). Isolated skeletal muscle mitochondria were used for real-time respirometry or frozen for protein content and activity assays. Doxorubicin impaired muscle performance indicated by reduced force production, fatigue resistance, and SR-Ca2+ uptake, which were associated with a substrate-independent reduction in respiration and membrane potential, but no changes in the NAD(P)H/NAD(P)+ redox state. Protein content and dehydrogenase activity results corroborated these findings, indicating that doxorubicin-induced mitochondrial impairments are located upstream of ATP synthase within the electron transport system (ETS). Collectively, doxorubicin-induced lesions likely span mitochondrial complexes I-IV, providing potential targets for alleviating doxorubicin myotoxicity.

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Keywords: Anthracycline drug, Bioenergetics, Doxorubicin, Electron transport system (ETS), Mitochondrial metabolism, Mitochondriopathy, Muscle physiology, Muscle wasting, Myotoxicity, Skeletal muscle Bioblast editor: Plangger M


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue, Isolated mitochondria 

Regulation: PCr;Cr  Coupling state: LEAK, ET  Pathway: F, N, S, CIV  HRR: Oxygraph-2k 

Labels, 2019-11