MicroRNAs in Dystrophinopathy

Abstract

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), which represent the range of dystrophinopathies, account for nearly 80% of muscle dystrophy. DMD and BMD result from the loss of a functional dystrophin protein, and the leading cause of death in these patients is cardiac remodeling and heart failure. The pathogenesis and progression of the more severe form of DMD have been extensively studied and are controlled by many determinants, including microRNAs (miRNAs). The regulatory role of miRNAs in muscle function and the differential miRNA expression in muscular dystrophy indicate the clinical significance of miRNAs. This review discusses the relevant microRNAs as potential biomarkers and therapeutic targets for DMD and DMD cardiomyopathy as examples of dystrophinopathies.

Gene Therapy for Cardiomyopathy associated with Duchenne Muscular Dystrophy in a Pig Model

“…Interestingly, significantly dysregulated proteins detected in DMD hearts showed a trend towards normalization in the SERCA2a-treated DMD-hearts (Fig.2B). Pro-inflammatory acute phase proteins such as inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) or alpha-2-macroglobulin (A2M), elevated in the instance of DMD, were downregulated upon AAV.SERCA2a, whereas the opposite was found for the mitochondrial protein delta(3,5)-delta(2,4)-dienoyl-CoA isomerase (ECH1) (Fig.2C-E). The cardiomyocyte-specific sarcomere gene myosin heavy chain 6 (MYH6), the most downregulated proteins in DMD-hearts, was significantly increased upon treatment (Fig.…”

“…C The acute phase protein inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and D alpha-2-macroglobulin (A2M) were downregulated by AAV.SERCA2a. E The mitochondrial protein delta(3,5)-delta(2,4)-dienoyl-CoA isomerase (ECH1), and F the sarcomere protein myosin heavy chain 6 (MYH6), downregulated in DMD, were found increased after AAV.SERCA2a application. *=p<0.05, **=p<0.05, ***=p<0.0005.…”

“…Subsequent to progressive skeletal muscle decay, patients loose ambulation in their first decade of life, experience dyspnoea due to thoracic and diaphragm weakness and develop - mostly in the second to third decade of life - a distinct form of cardiomyopathy. In contrast, the phenotype of Becker muscular dystrophy, which occurs at about 1/3 of the DMD rate (3), is attenuated by a shortened, but largely functional dystrophin. Here, symptoms vary from mild to more severe impairment of muscle function, although the majority of boys with Becker dystrophies also develop a distinct cardiomyopathy (1,4,5).…”

Extracellular vesicles and Duchenne muscular dystrophy pathology: Modulators of disease progression

“…Therefore, the upregulation of this miRNA diminishes the ability of DMD cardiomyocytes to protect against stress injury. In line with miRNA deregulation, the myomiRs also appear to be abnormally expressed in the heart of DMD models (Lee et al, 2022). A few examples include, miR-1, involved in the electrical remodeling of the heart and arrhythmia induction if dysregulated (Yang et al, 2007), miR-133, which in case of downregulation causes cardiac hypertrophy (Carè et al, 2007), and the miR-208 family that strongly contributes to cardiac hypertrophy and arrhythmias (Callis et al, 2009).…”

The Emerging Role of RNA in Diseases and Cancers

“…Lee et al examined the role of microRNAs as biomarkers and therapeutic targets for muscle dystrophy, such as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) [ 7 ].…”