Role of p53 in Cisplatin-Induced Myotube Atrophy

Chemotherapy-induced sarcopenia is an unfavorable prognostic factor implicated in the development of postoperative complications and reduces the quality of life of patients with cancer. Skeletal muscle loss due to cisplatin use is caused by mitochondrial dysfunction and activation of muscle-specific ubiquitin ligases Atrogin-1 and muscle RING finger 1 (MuRF1). Although animal studies suggest the involvement of p53 in age-, immobility-, and denervation-related muscle atrophy, the association between cisplatin-induced atrophy and p53 remains unknown. Herein, we investigated the effect of a p53-specific inhibitor, pifithrin-alpha (PFT-a), on cisplatin-induced atrophy in C2C12 myotubes. Cisplatin increased the protein levels of p53, phosphorylated p53, and upregulated the mRNA expression of p53 target genes PUMA and p21 in C2C12 myotubes. PFT-a ameliorated the increase in intracellular reactive oxygen species production and mitochondrial dysfunction, and also reduced the cisplatin-induced increase in the Bax/Bcl-2 ratio. Although PFT-a also reduced the cisplatin-induced increase in MuRF1 and Atrogin-1 gene expression, it did not ameliorate the decrease in myosin heavy chain mRNA and protein levels and muscle-specific actin and myoglobin protein levels. We conclude that cisplatin increases muscle degradation in C2C12 myotubes in a p53-dependent manner, but p53 has minimal involvement in the reduction of muscle protein synthesis.

Automated summary

Chemotherapy-induced sarcopenia is a negative prognostic factor that affects postoperative complications and quality of life in cancer patients. Cisplatin, a commonly used chemotherapy drug, causes skeletal muscle loss by affecting mitochondrial function and activating muscle-specific ubiquitin ligases Atrogin-1 and muscle RING finger 1 (MuRF1). Although p53 has been implicated in muscle atrophy, it is unclear if it plays a role in cisplatin-induced atrophy. This study investigated the effect of a p53-specific inhibitor, pifithrin-alpha (PFT-a), on cisplatin-induced muscle atrophy in C2C12 myotubes. The results showed that cisplatin increased p53 levels and upregulated the expression of p53 target genes in C2C12 myotubes. PFT-a reduced reactive oxygen species production, mitochondrial dysfunction, and the increase in the Bax/Bcl-2 ratio induced by cisplatin. However, PFT-a did not ameliorate the decrease in muscle protein synthesis. Overall, this study suggests that cisplatin-induced muscle degradation is p53-dependent, but p53 has minimal involvement in the reduction of muscle protein synthesis.