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

Abstract

Key pointsr 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.r 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.r 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.Abstract 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.

Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction

“…Following doxorubicin administration, soleus mitochondrial NADH-and FADH 2 -supported respiratory capacity is diminished. These findings are consistent with our previous work and other groups demonstrating that doxorubicin causes skeletal muscle mitochondrial dysfunction in a time-dependent manner (12,17,26).…”

“…Min et al (26) reported elevated H 2 O 2 emission in both PmFBs from cardiac and skeletal muscle following doxorubicin administration, along with elevated markers of protein oxidation. Elevated H 2 O 2 -emitting potential in skeletal muscle induced by doxorubicin is likely due to redox modifications within the matrix (e.g., the ETS, redox-buffering system) (12).…”

“…Administration of the mitochondrial-targeted peptide MTP-131 also protects against the loss of skeletal muscle function caused by doxorubicin (26). MTP-131 is thought to exert its cytoprotective effects at least in part by reducing H 2 O 2 emission (37).…”

“…Exposure to the chemotherapeutic agent doxorubicin leads to an increase in ROS in skeletal muscle, as evidenced by elevated cytosolic oxidant activity (13) and markers of protein oxidation (13,36). Mitochondrial H 2 O 2 -emitting potential is elevated in both skeletal and cardiac muscle following doxorubicin administration (12,26), and treatment of cultured myotubes or rats with a cell-permeable mitochondrial-targeting peptide (MTP-131) that reduces ROS production also attenuates doxorubicin-induced oxidant production and accumulation of oxidation markers (15,26). Collectively, these findings suggest that mitochondria are the major source of ROS production in skeletal muscle in response to doxorubicin treatment.…”

The pathogenesis and treatment of cardiac atrophy in cancer cachexia

“…Anticancer treatments also have potent effects on mitochondrial function in the heart with doxorubicin-mediated cardiac toxicity in mice shown to be due, at least in part, to p53-mediated oxidative stress (114). Another study employed a novel mitochondrialtargeted antioxidant and a selective calpain inhibitor to demonstrate that doxorubicin-induced atrophy and dysfunction of skeletal and cardiac muscles involved increased mitochondrial reactive oxygen species production and calpain activation (73). These findings indicate that mitochondrial dysfunction caused by both cancer and its treatments contributes to the atrophy of skeletal and cardiac muscle, and therefore the mitochondria represents a promising therapeutic target for the treatment of skeletal and cardiac muscle cachexia in cancer.…”