Na⁺–H⁺exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies

Abstract

Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (␦-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na + overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.Key words: Becker muscular dystrophy, Duchenne muscular dystrophy, heart failure, NHE-1, proton channel. Résumé :On peut observer une cardiomyopathie chez des patients atteints de dystrophie musculaire de Duchenne (DMD) ou de Becker (DMB). Cette atteinte est liée à des maladies musculaires causées par des mutations dans le gène de la dystrophine. Les défauts dans la dystrophine sont présents dans la DMD, mais dans la DMB légère aussi. Le hamster de la souche UM-X7.1, atteint de cardiomyopathie héréditaire, constitue un modèle expérimental particulier d'insuffisance cardiaque (IC) menant à une mort précoce en cas de dystrophie musculaire (carence en dystrophine et mutation dans le gène de la sarcoglycane) et de maladie cardiaque (carence en ␦-sarcoglycane et mutation dans le gène de la dystrophine) chez des humains atteints de DMD. À l'aide de ce modèle, nos travaux précédents ont montré un défaut dans l'homéostasie du sodium intracellulaire avant l'apparition de tout défaut biochimique ou histologique apparent. Nous avons attribué ce phénomène à la présence continuelle de canaux sodiques lents foetaux, que l'on a aussi retrouvés sous une forme active dans la DMD chez l'humain. En raison de l'acidose intracellulaire musculaire, la surcharge intracellulaire de sodium dans la DMD et la DMB était aussi causée par le passage de sodium par l'échangeur sodium-hydrogène NHE-1. Le traitement à vie avec un inhibiteur du NHE-1 permettait de prévenir la surcharge intracellulaire de Na + et le décès précoce causé par l'IC. Nos travaux précédents ont aussi montré que le Hv1 (canal à protons dépendant du voltage), un autre transporteur de protons, existe dans de nombreux type...

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

“…Intracellular calcium overload in DMD cardiomyocytes can also arise form an altered function of other channels, such as Na + -H + exchanger (NHE-1) and proton channels [66]. An increased Na + influx through NHE-1 leads to an intracellular accumulation that, in turn, promotes calcium influx through the Na + -Ca +2 exchanger.…”

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

“…A recently completed study in Golden Retriever muscular dystrophy (GRMD) dogs has confirmed the cardioprotective role of Rimeporide after a treatment in a preventing setting [ 12 ]. Other preclinical experiments [ 13 , 14 ] have underlined the significance of myocardial necrosis, due to pH abnormalities as well as calcium and sodium imbalances in the pathophysiology of heart failure and have demonstrated the beneficial effects of NHE-1 inhibition using Rimeporide in preventing the deleterious effects of Ca2+ and Na + overload [ 14 ].…”

Increase of NADPH oxidase 3 in heart failure of hereditary cardiomyopathy

“…The hereditary cardiomyopathic hamster is one of the best models for hypertrophy and heart failure associated with increased ROS levels (Dhalla et al, 1996;Wu et al, 2012;Mollnau et al, 2005;Escobales and Crespo, 2006). Hence, in this study, using the wellknown animal model of hypertrophy and heart failure, the UM-X7.1 hereditary cardiomyopathic hamster (Jacques and Bkaily, 2018;Bkaily and Jacques, 2017;Bkaily et al, 2015), we verified whether the density of certain types of NOXs particularly NOXs 1 and 3 undergo changes during the development of heart failure.…”