Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies.

Satvik Mareedu,Gopal J Babu,Dongsheng Duan,Emily D Million

doi:10.3389/fphys.2021.647010

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by the loss of dystrophin. DMD is associated with muscle degeneration, necrosis, inflammation, fatty replacement, and fibrosis, resulting in muscle weakness, respiratory and cardiac failure, and premature death. There is no curative treatment. Investigations on disease-causing mechanisms offer an opportunity to identify new therapeutic targets to treat DMD. An abnormal elevation of the intracellular calcium () concentration in the dystrophin-deficient muscle is a major secondary event, which contributes to disease progression in DMD. Emerging studies have suggested that targeting Ca2+-handling proteins and/or mechanisms could be a promising therapeutic strategy for DMD. Here, we provide an updated overview of the mechanistic roles the sarcolemma, sarcoplasmic/endoplasmic reticulum, and mitochondria play in the abnormal and sustained elevation of levels and their involvement in DMD pathogenesis. We also discuss current approaches aimed at restoring Ca2+ homeostasis as potential therapies for DMD.

Highlights

Duchenne muscular dystrophy (DMD) is X-linked and is the most common form of muscle wasting disease
DMD is caused by mutations in the dystrophin gene, which leads to the loss of a functional dystrophin protein (Monaco et al, 1986)
These studies further suggest dystrophin, and the dystrophin-associated glycoprotein complex (DAGC) may regulate the interaction between L-type Ca2+ channels and RyR, which is necessary for Excitation and contraction (EC) coupling (Friedrich et al, 2004, 2008)

Summary

INTRODUCTION

Duchenne muscular dystrophy (DMD) is X-linked and is the most common form of muscle wasting disease. Friedrich et al found that Cav1.1 activity is significantly reduced in the fast-twitch muscles of mdx mice (Friedrich et al, 2004) These studies further suggest dystrophin, and the DAGC may regulate the interaction between L-type Ca2+ channels and RyR, which is necessary for EC coupling (Friedrich et al, 2004, 2008). The expression of phosphorylation mimic Cx43 in mdx cardiomyocytes shows improved Ca2i + signaling, a reduction of NOX2/ROS production and prevention of arrhythmias (Himelman et al, 2020) Taken together, these studies indicate that Cx overexpression and lateralization contribute to abnormal Ca2i + homeostasis in dystrophin-deficient cardiac and skeletal muscles. Cyclophilin D blocker mdx mice, patient-derived cells mdx mice and Canine model mdx mice mdx:utr−/− mice mdx and mdx:utr−/− mice Zebrafish model

CONCLUSIONS AND FUTURE DIRECTIONS

DISCLOSURE