Calpain‐mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin‐induced cardiomyopathy

Abstract

Studies from our laboratory demonstrated that alterations in the dystrophin‐glycoprotein complex (DGC), mainly dystrophin, and myofibrilar disruption are associated with increased sarcolemmal permeability in doxorubicin (DOX)‐induced cardiomyopathy. These alterations could be consequent to activation of calcium‐dependent proteases, mainly calpain, as cause of dystrophin and cellular constituents disruption.This study tested the hypothesis that calpain is overexpressed in DOX‐treated rats and that dantrolene (DT), sarcoplasmic reticulum calcium inhibitor, could abrogate DGC alterations.Rats received DOX only (cumulative dose 15 mg/kg); rats treated with DOX plus DT (5 mg/kg, i.p. immediately after each dose of DOX); control rats treated either with saline or saline plus DT. Fourteen days after the last injection, the hearts were collected for light microscopy, immunofluorescence and western blotting. Cardiac function was evaluated by echocardiography.Increased expression of calpain, loss of dystrophin and cardiac dysfunction were observed in hearts treated with DOX only. In contrast, DT prevented increased calpain expression, dystrophin loss/reduction, and cardiac dysfunction, similarly to observed in controls. These findings support the opinion that calpain mediate dystrophin loss/reduction and it might be a structural culprit behind DOX‐induced heart failure. FAPESP.