Abstract
Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MBwt/MBmdx) and mesenchymal stem cells (MBwt/MSCmdx) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 106) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 –MBwt/MBmdx and 5.22% ± 1.10 – MBwt/MSCmdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.
Highlights
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene
Structural analysis of hematoxylin & eosin (H&E) stained cross-section of heart samples revealed decrease in fibrosis in cardiac muscle of mice injected with Myoblast from wild type snj (MBwt)/ MBmdx or MBwt/MSCmdx Dystrophin Expressing Chimeric (DEC) lines when compared to the mdx mice injected with vehicle and not-fused MBwt + MBmdx and MBwt + MSCmdx (Fig. 2c)
In the DMD mouse model, cardiac hypertrophy has been reported to develop as early as 16–21 weeks of age, correlating to an increase in cardiomyocyte size seen on hematoxylin and eosin staining and to ventricular wall fibrosis seen on Masson’s trichrome staining [23]
Summary
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder caused by a mutation in the dystrophin gene. Cardiomyopathy is a significant cause of morbidity and mortality in DMD patients [2,3,4]. Histopathological evidence suggests that the fibro-fatty replacement of cardiomyocytes is a significant pathophysiological mechanism in the development of cardiomyopathy in the mdx mice [5,6,7]. Studies on echocardiographic assessment confirm increases in the left ventricular posterior wall thickness in the mdx mice when compared to the wild type controls, presumably due to fibrous deposition. Current treatments of DMD related cardiomyopathy have aimed to decrease cardiac mortality by preventing cardiac fibrosis [4, 8,9,10]. Several studies have shown that common blood pressure medications such as angiotensin-converting enzyme inhibitors, aldosterone antagonists, and angiotensin receptor blockers
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