Metformin reverses cardiac SR/ER-mitochondria remodeling and mitochondrial complex I dysfunction in Dystrophin-deficient mice

Abstract

Besides skeletal and diaphragmatic muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibit a progressive cardiomyopathy with an altered Ca2 + handling and a defect in mitochondrial respiration capacity. The aim of the present study was to determine if the sarco-endoplasmic reticulum (SR/ER)-mitochondria interaction and mitochondrial Ca2 + homeostasis contribute to the progression of the cardiomyopathy. Ventricular myocytes were isolated from 3-month old Dystrophin-deficient mice (mdx mice). Using proximity ligation assay, we observed an increase interaction between the SR/ER Ca2 + release channels, IP3R1, and the porine of the mitochondria, VDAC1, associated with an increase expression levels of IP3R1 and SIGMA1R. Similarly, the mitochondrial Ca2 + uniporter (MCU) and its regulated subunit, MICU1, expressions levels were enhanced in mdx heart. Furthermore the mitochondrial Ca2 + uptake kinetics and the mitochondrial Ca2 + content were significantly increased. Using oxygraphy experiment, we observed a severe decrease in respiration driven by the complex I with a stimulation in anion superoxide production measured with Mitosox red fluorescent dye. Finally, mdx mice were treated with the complex I modulator metformin at 200 mg/kg/day during one month. Metformin normalize the SR/ER-mitochondria interaction, decreases MICU1 expression and mitochondrial Ca2 + content and tends to restore complex I alteration in cardiomyocytes. In summary, our data demonstrate for the first time that in the DMD heart the mitochondrial dysfunction is linked to an excessive SR/ER-mitochondria coupling with an increase in mitochondrial Ca2 + uptake and complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.