The multifaceted view of heart problem in Duchenne muscular dystrophy

Abstract

Dystrophin is a large protein serving as local scaffolding repetitively bridging cytoskeleton and the outside of striated muscle cell. As such dystrophin is a critical brick primarily in dystrophin-associated protein complex (DAGC) and in a larger submembranous unit, costamere. Accordingly, the lack of functional dystrophin laying at the root of Duchenne muscular dystrophy (DMD) drives sarcolemma instability. From this point on, the cascade inevitably leading to the death of myocyte begins. In cardiomyocytes, intracellular calcium overload and related mitochondrial-mediated cell death mainly contribute to myocardial dysfunction and dilation while other protein dysregulation and/or mislocalization may affect electrical conduction system and favor arrhythmogenesis. Although clinically DMD manifests as progressive muscle weakness and skeletal muscle symptoms define characteristic of DMD, it is the heart problem the biggest challenge that most often develop in the form of dilated cardiomyopathy (DCM). Current standards of treatment and recent progress in respiratory care, introduced in most settings in the 1990s, have improved quality of life and median life expectancy to 4th decade of patient’s age. At the same time, cardiac causes of death related to DMD increases. Despite preventive and palliative cardiac treatments available, the prognoses remain poor. Direct therapeutic targeting of dystrophin deficiency is critical, however, hindered by the large size of the dystrophin cDNA and/or stochastic, often extensive genetic changes in DMD gene. The correlation between cardiac involvement and mutations affecting specific dystrophin isoforms, may provide a mutation-specific cardiac management and novel therapeutic approaches for patients with CM. Nonetheless, the successful cardiac treatment poses a big challenge and may require combined therapy to combat dystrophin deficiency and its after-effects (critical in DMD pathogenesis). This review locates the multifaceted heart problem in the course of DMD, balancing the insights into basic science, translational efforts and clinical manifestation of dystrophic heart disease.

Cardiomyopathies in Children: Genetics, Pathomechanisms and Therapeutic Strategies

“…Thus, in inherited CMs, genetic defects may occur in genes encoding proteins of the sarcomere, including the Z-disc proteins, structural proteins (e.g., costameric, desmosomal, cytoskeletal, nucleoskeletal proteins), mitochondrial or Ca 2þ -handling proteins, signaling proteins such as Ras, or proteins of the Notch signaling pathway, and even mutations in non-coding regions of the genome have been described (see also Figure 2). Other causes of pediatric CMs might be inflammation due to viral or bacterial infections and toxins, including chemotherapeutics or neurohormonal or metabolic disorders [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62]. Inborn errors of metabolism associated with…”

Hydrogen sulfide as a therapeutic option for the treatment of Duchenne muscular dystrophy and other muscle-related diseases

“…The first incidence of cardiomyopathy occurs at the age of 6 years. Symptoms manifest themselves in dilated cardiomyopathy, which progresses to end-stage heart failure with accompanying supraventricular and ventricular arrhythmias [ 6 ]. Unfortunately, until now, DMD is an incurable disease, and even with optimal care, patients die between the second and fourth decade of life [ 7 , 8 ] (Fig.…”

Amelioration of Morphological Pathology in Cardiac, Respiratory, and Skeletal Muscles Following Intraosseous Administration of Human Dystrophin Expressing Chimeric (DEC) Cells in Duchenne Muscular Dystrophy Model

“…In normal muscles, the differences in muscle fiber sizes are minimal; however, in dystrophic muscles significant fiber size variations are observed. Therefore, the DMD-affected muscles of mdx mice are more heterogeneous, as indicated by the increased distribution of muscle fiber sizes with diameters below 20 μm and above 70 μm in skeletal muscles [ 6 , 7 ], decreased mean minimal Feret’s diameters of diaphragm myofibers [ 8 ], and diffuse variation in cardiac fiber sizes [ 9 ]. Another common characteristic of muscle fibers in DMD is a smaller average fiber size when compared to normal muscle tissue [ 6 ].…”