RESUMEN
Chemotherapeutic agents (CAs) can independently promote skeletal muscle dysfunction, fatigue and wasting with mitochondrial toxicity implicated as a possible mechanism. Thus, we aimed to characterise the effects of various CAs on mitochondrial function, viability and oxidant production in C2C12 myoblasts and myotubes. All CAs significantly reduced the viable mitochondrial pool but did not affect mitochondrial functional parameters. Doxorubicin and oxaliplatin increased oxidant production in myotubes while all CAs, except for irinotecan, increased oxidant production in myoblasts and reduced myotube diameter. Our data demonstrate CAs mito-toxic effects, highlighting the potential for mitochondria-protective therapeutics to address chemotherapy-induced skeletal muscle damage.
Asunto(s)
Antineoplásicos/toxicidad , Respiración de la Célula/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Superóxidos/metabolismo , Animales , Doxorrubicina/toxicidad , Irinotecán/toxicidad , Ratones , Oxaliplatino/toxicidadRESUMEN
Chemotherapy has been associated with increased mitochondrial reactive oxygen species production, mitochondrial dysfunction and skeletal muscle atrophy leading to severe patient clinical complications including skeletal muscle fatigue, insulin resistance and wasting. The exact mechanisms behind this skeletal muscle toxicity are largely unknown, and as such co-therapies to attenuate chemotherapy-induced side effects are lacking. Here, we review the current literature describing the clinical manifestations and molecular origins of chemotherapy-induced myopathy with a focus on the mitochondria as the target organelle via which chemotherapeutic agents establish toxicity. We explore the likely mechanisms through which myopathy is induced, using the anthracycline doxorubicin, and the platinum-based alkylating agent oxaliplatin, as examples. Finally, we recommend directions for future research and outline the potential significance of these proposed directions.