Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.
Autor: | Min K; Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, FL, USA., Kwon OS, Smuder AJ, Wiggs MP, Sollanek KJ, Christou DD, Yoo JK, Hwang MH, Szeto HH, Kavazis AN, Powers SK |
---|---|
Jazyk: | angličtina |
Zdroj: | The Journal of physiology [J Physiol] 2015 Apr 15; Vol. 593 (8), pp. 2017-36. Date of Electronic Publication: 2015 Feb 23. |
DOI: | 10.1113/jphysiol.2014.286518 |
Abstrakt: | Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres. (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.) |
Databáze: | MEDLINE |
Externí odkaz: |