Dystrophin-deficient cardiomyopathy is becoming the dominant cause of death in patients with Duchenne muscular dystrophy (DMD), but its developmental process remains elusive.
Heart failure invariably affects patients with various forms of Muscular Dystrophy (MD), but the onset and molecular sequelae of altered structure and function resulting from full-length dystrophin (Dp427) deficiency in MD heart tissue are poorly understood.To better understand the role of dystrophin in cardiomyocyte development and the earliest phase of DMD cardiomyopathy, we studied human cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs) obtained from the urine of a Deuchenne Muscular Dystrophy (DMD) patient.
Improving skeletal muscle function without restoring dystrophin expression in cardiac tissue may exacerbate cardiomyopathy due to increased voluntary activity.
In the current preclinical study, we demonstrate the therapeutic potential of sarcospan (SSPN) overexpression to alleviate cardiomyopathy associated with Duchenne muscular dystrophy (DMD) utilizing dystrophin-deficient mdx mice with utrophin haploinsufficiency that more accurately represent the severe disease course of human DMD.
Previously, treatment with β-blockers showed beneficial effects on the development of cardiomyopathy in dystrophin-deficient (mdx) mice, but not in δ-sarcoglycan-deficient (Sgcd-/-) mice.
Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy.
We identified a novel dystrophin mutation (p.1667 del Ala), resulting in BMD-associated cardiomyopathy that demonstrated the pathological features of significant fibrofatty replacement in the sub-epicardial layer of the ventricle; further, the high-throughput sequencing is helpful for making an early diagnosis of BMD.
In conclusion, this study demonstrated that allogeneic WT-MPC-Exo transplantation transiently restored dystrophin gene expression and improved cardiac function in MDX mice, suggesting that allogenic exosomal delivery may serve as an alternative treatment for cardiomyopathy of DMD.
Duchenne muscular dystrophy (DMD) is caused by abnormalities in the dystrophin gene and is clinically characterised by childhood muscle degeneration and cardiomyopathy.
We and others have shown that mosaic dystrophin expression at the wild-type level, depending on the percentage of dystrophin positive cardiomyocytes, can either delay the onset of or fully prevent cardiomyopathy in dystrophin-null mdx mice.
This work demonstrates that high levels of cardiac dystrophin restored by Pip peptide-AOs prevents further deterioration of cardiomyopathy and pathology following exercise in dystrophic DMD mice.
However, 2.5-7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X-chromosome inactivation (XCI).
Mutations of the dystrophin gene leading to a complete loss of the protein cause Duchenne muscular dystrophy (DMD), frequently associated with severe cardiomyopathy.