Decreased Expression and Secretion of the Myokine Fndc5/Irisin by Cisplatin Treatment in Mouse Skeletal Muscle.

Abstract

The systemic administration of cisplatin has been shown to substantially reduce skeletal muscle mass. This is a serious concern, as muscle loss is correlated with increased mortality in patients with cancer. Cisplatin also contributes to cognitive decline, but the exact mechanism thereof remains unclear. In this study, we focused on fibronectin type III domain-containing 5 (Fndc5), a gene that produces irisin, a myokine that is important for brain health. Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for 4 consecutive days. Twenty-four h after final injection of cisplatin, quadriceps muscles were isolated. C2C12 myotubes were treated with cisplatin with/without AICAR. In male C57BL/6J mice treated with cisplatin, a reduced expression of the key regulator PGC-1α was observed, along with reduced levels of Fndc5/irisin mRNA and protein in the mice quadriceps muscles. Similar findings were seen in cisplatin-treated C2C12 myotube cells, where the activation of PGC-1α with AICAR partially offset these effects. These results suggest that cisplatin inhibits the synthesis of Fndc5/irisin and may contribute to the metabolic changes and cognitive decline observed in patients with cancer who receive this treatment.