Enhancing Muscle Membrane Repair by Gene Delivery of MG53 Ameliorates Muscular Dystrophy and Heart Failure in δ-Sarcoglycan-deficient Hamsters

Abstract

Muscular dystrophies (MDs) are caused by genetic mutations in over 30 different genes, many of which encode for proteins essential for the integrity of muscle cell structure and membrane. Their deficiencies cause the muscle vulnerable to mechanical and biochemical damages, leading to membrane leakage, dystrophic pathology, and eventual loss of muscle cells. Recent studies report that MG53, a muscle-specific TRIM-family protein, plays an essential role in sarcolemmal membrane repair. Here, we show that systemic delivery and muscle-specific overexpression of human MG53 gene by recombinant adeno-associated virus (AAV) vectors enhanced membrane repair, ameliorated pathology, and improved muscle and heart functions in δ-sarcoglycan (δ-SG)-deficient TO-2 hamsters, an animal model of MD and congestive heart failure. In addition, MG53 overexpression increased dysferlin level and facilitated its trafficking to muscle membrane through participation of caveolin-3. MG53 also protected muscle cells by activating cell survival kinases, such as Akt, extracellular signal-regulated kinases (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) and inhibiting proapoptotic protein Bax. Our results suggest that enhancing the muscle membrane repair machinery could be a novel therapeutic approach for MD and cardiomyopathy, as demonstrated here in the limb girdle MD (LGMD) 2F model.

Cardioprotection of recombinant human MG53 protein in a porcine model of ischemia and reperfusion injury

“…Consistent with previous studies with overexpression of MG53 in hearts[20, 21], some of pro-survival pathway proteins, such as Akt and GSK-3β, were activated in rhMG53 treated groups ( Fig. 5 ).…”

“…Increased vulnerability to ischemiareperfusion induced injury to the heart was observed in mouse with genetic ablation of MG53 [19, 20]. AAV-mediated delivery of MG53 gene into animal models of muscular dystrophy and cardiomyopathy could rescue certain aspects of the defective muscle and heart function[21]. While overexpression of MG53 could improve membrane repair defects in certain disease conditions, the gene therapy-based approaches necessary to pursue this effort have disadvantages.…”

The mdx mutation in the 129/Sv background results in a milder phenotype: Transcriptome comparative analysis searching for the protective factors

“…Nevertheless, when excluding this category, some differences were noted between the two deficient dystrophin models, including a reduction in endo/exocytic pathway but an increase in the participation of the extracellular matrix, binding to molecules/cells and enzymatic activity . Vesicle trafficking is a necessary process for membrane repair [13] and several studies have shown its importance in the dystrophic phenotype [14,15]. Our findings suggest that the decreased participation of vesicle-related genes in mdx 129 animals is due to a more stable membrane, which can present, consequently, better fiber conservation and functional performance.…”

Gene and cell therapy for muscle regeneration

“…The systemic delivery and overexpression of muscle-specific human gene MG53, by AAV in an animal model with muscular dystrophy and congestive heart defect (CHD), promote the repair of the sarcolemmal membrane, pathology mitigation, and improved muscle and heart function [21].…”