Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca 2+ ) homeostasis and mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions function were in dystrophic heart at the early stage of pathology. For this purpose, ventricular cardiomyocytes mitochondria isolated from 3-month-old dystrophin-deficient mice ( mdx mice). The number contacts points between SR/ER Ca release channels (IP3R1) porine outer membrane mitochondria, VDAC1, measured using situ proximity ligation assay, was greater cardiomyocytes. Expression levels IP3R1 as well uniporter (MCU) its regulated subunit, MICU1, also increased heart. MICU2 expression however unchanged. Furthermore, uptake kinetics content significantly increased. Meanwhile, -dependent pyruvate dehydrogenase phosphorylation reduced, activity In -free conditions, pyruvate-driven complex I respiration decreased whereas presence , I-mediated boosted. Further, independent intrinsic or expression, which remains unchanged but is accompanied increase reactive oxygen species production. Finally, treated with modulator metformin for 1 month. Metformin normalized SR/ER-mitochondria interaction, MICU1 content, enhanced I-driven respiration. summary, before any sign dilated cardiomyopathy, DMD displays aberrant coupling Such remodeling could be reversed providing novel therapeutic perspective DMD.