Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy

摘要

Although doxorubicin is a highly effective anti-tumour agent, the administration of this drug is associated with significant side effects, including contractile dysfunction and myopathy of both cardiac and skeletal muscles. The mechanism(s) responsible for doxorubicin-induced contractile dysfunction and myopathy in cardiac and skeletal muscles remains unclear. In the present study, we report that increased mitochondrial oxidant production and calpain activation are major contributors to the development of doxorubicin-induced myopathy. Moreover, treatment with a mitochondrial-targeted peptide protects against doxorubicin-induced mitochondrial dysfunction and myopathy in both heart and skeletal muscles. These experiments provide insight into the mechanisms responsible for DOX-induced contractile dysfunction and myopathy in cardiac and skeletal muscles. Importantly, our results may provide the basis for developing therapeutic approaches to prevent doxorubicin-induced cardiac and skeletal muscle myopathy.