Preserving muscle health and wellbeing for long-term cancer survivors.

The anti-tumour activities of anthracycline antibiotics like doxorubicin (DOX) were first established in the 1960s. Since then they rank among the most effective anti-tumour therapeutics. An example of their impact is seen in the shift of 5 year survival rates for childhood cancer, from 30% to 80% since the 1960s (Stěrba et al. 2013). Topoisomerase IIα is a main target of anthracycline anti-tumour activity. Anthracyclines prevent topoisomerase-mediated relaxation of supercoiled DNA and subsequent DNA replication. Along with effectiveness as a cancer chemotherapy come dangerous side effects that include cardiovascular and respiratory muscle toxicity (Gilliam & St Clair, 2011, Stěrba et al. 2013). Toxicity can develop shortly after treatment or decades later, as is seen among childhood cancer survivors (Stěrba et al. 2013). The mechanism of anthracycline-induced muscle toxicity is still in question. Contributing factors include oxidative stress, calcium dysregulation, and calpain degradation of titin (Stěrba et al. 2013). Muscle mitochondria appear to be at the centre of the problem. First, anthracyclines, known for their ability to produce free radicals, concentrate in mitochondria via an affinity for cardiolipin (Stěrba et al. 2013). Cardiolipin is an inner mitochondrial membrane phospholipid associated with cytochrome c (Kroemer et al. 2007). Second, mitochondria subjected to oxidative stress affect cellular calcium dynamics (Kroemer et al. 2007). Thus, concentrated anthracycline-mediated free radical production in mitochondria might alter cellular calcium dynamics, and subsequent calcium-regulated calpain activity. In this issue of The Journal of Physiology, Min et al. (2015) linked DOX-induced mitochondrial oxidative stress to calpain activation and cardiac/skeletal muscle dysfunction. They demonstrated that pretreatment with the mitochondrial specific antioxidant SS-31, or the calpain inhibitor SJA 6017, protected rats from DOX-induced muscle toxicity. SS-31 preserved mitochondrial respiratory function, reduced cellular oxidative stress, and prevented calpain activation. Both SS-31 and SJA preserved diastolic and systolic cardiac function and diaphragm contractile function, and reduced skeletal muscle atrophy. The fact that SS-31 prevented calpain activation in heart and skeletal muscle supports the idea that DOX alters mitochondrial redox balance to stimulate calpain (Fig.​(Fig.1).1). Interestingly, both DOX and SS-31 target mitochondria through interaction with cardiolipin (Szeto, 2014). The key to SS-31 efficacy may lie in this interaction. As mentioned above, cardiolipin associates with a major fraction of mitochondrial cytochrome c and cardiolipin oxidation leads to cytochrome c release (Orrenius & Zhivotovsky, 2005). Thus, disruption of cardiolipin–cytochrome c complexes either by physical interaction with, or oxidation by, DOX could lead to cytochrome c release. The resulting cytosolic cytochrome c would promote Ca2+ release from the endoplasmic reticulum (Orrenius & Zhivotovsky, 2005) to activate calpain (Kroemer et al. 2007). SS-31 disruption of a DOX-cardiolipin interaction or cardiolipin oxidation could prevent the initiation of this cytotoxic cascade. Figure 1 Mitochondria and muscle toxicity In summary, these results provide further evidence that mitochondria are central to anthracycline-induced muscle toxicity. They also define a pathway initiated by DOX that triggers mitochondrial changes which stimulate calpain to promote muscle dysfunction and atrophy. Finally they demonstrate the potential for therapies targeted to mitochondria or calpain that would preserve muscle function and prevent dangerous long-term side effects of cancer chemotherapy.