Cancer-cell-secreted extracellular vesicles target p53 to impair mitochondrial function in muscle

Skeletal muscle loss and weakness are associated with bad prognosis and poorer quality of life in cancer patients. Tumor-derived factors have been implicated in muscle dysregulation by inducing cachexia and apoptosis. Here, we show that extracellular vesicles secreted by breast cancer cells impair mitochondrial homeostasis and function in skeletal muscle, leading to decreased mitochondrial content and energy production and increased oxidative stress. Mechanistically, miR-122-5p in cancer-cell-secreted EVs is transferred to myocytes, where it targets the tumor suppressor TP53 to decrease the expression of TP53 target genes involved in mitochondrial regulation, including Tfam, Pgc-1 & alpha;, Sco2, and 16S rRNA. Restoration of Tp53 in muscle abolishes mitochondrial myopathology in mice carrying breast tumors and partially rescues their impaired running capacity without significantly affecting muscle mass. We conclude that extracellular vesicles from breast cancer cells mediate skeletal muscle mitochondrial dysfunction in cancer and may contribute to muscle weakness in some cancer patients.

Automated summary

Extracellular vesicles secreted by breast cancer cells impair skeletal muscle mitochondrial homeostasis and function through the transfer of miR-122-5p to myocytes, leading to decreased mitochondrial content and energy production and increased oxidative stress. Restoring Tp53 in muscle can abolish mitochondrial myopathology and partially rescue impaired running capacity in mice carrying breast tumors. These findings suggest that breast cancer cell-derived extracellular vesicles mediate skeletal muscle mitochondrial dysfunction, contributing to muscle weakness in cancer patients.