Abstract
Duchenne muscular dystrophy (DMD) leads to disability and death in young men. This disease is caused by mutations in the DMD gene encoding diverse isoforms of dystrophin. Loss of full-length dystrophins is both necessary and sufficient for causing degeneration and wasting of striated muscles, neuropsychological impairment, and bone deformities. Among this spectrum of defects, abnormalities of calcium homeostasis are the common dystrophic feature. Given the fundamental role of Ca2+ in all cells, this biochemical alteration might be underlying all the DMD abnormalities. However, its mechanism is not completely understood. While abnormally elevated resting cytosolic Ca2+ concentration is found in all dystrophic cells, the aberrant mechanisms leading to that outcome have cell-specific components. We probe the diverse aspects of calcium response in various affected tissues. In skeletal muscles, cardiomyocytes, and neurons, dystrophin appears to serve as a scaffold for proteins engaged in calcium homeostasis, while its interactions with actin cytoskeleton influence endoplasmic reticulum organisation and motility. However, in myoblasts, lymphocytes, endotheliocytes, and mesenchymal and myogenic cells, calcium abnormalities cannot be clearly attributed to the loss of interaction between dystrophin and the calcium toolbox proteins. Nevertheless, DMD gene mutations in these cells lead to significant defects and the calcium anomalies are a symptom of the early developmental phase of this pathology. As the impaired calcium homeostasis appears to underpin multiple DMD abnormalities, understanding this alteration may lead to the development of new therapies. In fact, it appears possible to mitigate the impact of the abnormal calcium homeostasis and the dystrophic phenotype in the total absence of dystrophin. This opens new treatment avenues for this incurable disease.
Highlights
The differences in clinical phenotypes, despite mutations affecting the same gene, appear to be caused by the mutation type: The loss-of-frame mutations resulting in the complete absence of dystrophin cause Duchenne muscular dystrophy (DMD), while mutations preserving the reading frame and allowing for the production of partially functional mini-dystrophin proteins result in Becker muscular dystrophy (BMD) [14]
The purpose of this review is to (i) discuss diverse aspects of calcium abnormalimechanisms in cells where dystrophin can bethe a scaffold for proteins engaged in calcium ties across the affected tissues, as the aberrant mechanisms leading to it have cell-specific homeostasis with cells in which calcium alterations cannot be clearly attributed to the components, (ii) compare thedystrophin obvious but and overlooked disconnect between loss of interaction between the calcium toolkit, and pathological (iii) evaluate the mechanisms in cells where dystrophin can be a scaffold for proteins engaged in calcium hoexisting therapeutic approaches for their impact on correcting the calcium overload in meostasis with cells in which calcium alterations cannot be clearly attributed to the loss of dystrophic cells
DMD pathology cannot be currently explained by a single mechanism
Summary
The first DMD defects are detectable in developing mesenchymal cells, before their differentiation into muscle [7]. Progressing skeletal muscle weakness and wasting eventually lead to the loss of ambulation (around the age of 10–12) and to the respiratory impairment, the latter exacerbated by frequent infections. The respiratory and/or cardiac failure develop, leading to the premature death between 20 and 40 years of age [10]. This range reflects the differences in the supportive care available to different patients’. The most important are CNS and bone defects, the first leading to cognitive and behavioural impairments, the latter causing skeletal deformities exacerbating muscle symptoms
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