Mitochondrial dysfunction associated with cisplatin-induced muscle atrophy in mouse skeletal muscle

Abstract

Cisplatin is used as first-line therapy for some types of solid tumors, although it can cause muscle atrophy. Mitochondrial dysfunction is expected as one of the causes that promote muscle atrophy because muscle weakness is induced during muscle atrophy. This study aimed to investigate the effects of cisplatin in ATP levels and gene expressions of mitochondrial OXPHOS and the related factors of mitochondrial biosynthesis. C57BL/6J mice were injected with cisplatin for four consecutive days. Quadriceps muscles were isolated 24 hours after the last injection of cisplatin. C2C12 myotubes were also treated with cisplatin. Systemic cisplatin administration decreased quadriceps muscle mass. Additionally, skeletal muscle strength and endurance were reduced by cisplatin administration. ATP levels and gene expressions of mitochondrial OXPHOS-related factors in quadriceps muscle were significantly lower in the cisplatin group. The mitochondrial DNA (mtDNA)/nuclear DNA (nDNA) ratio was also reduced in the cisplatin group. PGC-1α was significantly downregulated among the related factors of mitochondrial biogenesis. The PGC-1α expression was reduced in the cisplatin-treated group, as well as other PGC-1α isoforms. Cisplatin was observed to have similar effects in C2C12 myotubes as in mouse skeletal muscle. PGC-1α downregulation in the skeletal muscle may be one of the key factors that play an important role in mitochondrial dysfunction and reduced ATP levels and may be a factor in muscle weakness during cisplatin-induced muscle atrophy.