Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease characterised by skeletal muscle degeneration and progressive muscle wasting, which is caused by loss-of-function mutations in the DMD gene that encodes for the protein dystrophin. Dystrophin has critical roles in myofiber stability and integrity by connecting the actin cytoskeleton to the extracellular matrix. Absence of dystrophin leads to myofiber fragility and contributes to skeletal muscle degeneration in DMD patients, however, accumulating evidence also indicate that muscle stem cells (also known as satellite cells) are defective in dystrophic muscles, which leads to impaired muscle regeneration. Our recent work demonstrated that dystrophin is expressed in activated satellite cells, where it regulates the establishment of satellite cell polarity and asymmetric cell division. These findings indicate that dystrophin-deficient satellite cells have intrinsic dysfunctions that contribute to muscle wasting and progression of the disease. This discovery suggests that satellite cells could be targeted to treat DMD. Here we discuss how these new findings affect regenerative therapies for muscular dystrophies. Therapies targeting satellite cells hold great potential and could have long-term efficiency owing to the high self-renewal ability of these cells.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects ~ 1 in 3,600 boys that is characterised by progressive debilitating muscle weakness resulting in gradual ambulatory disability, respiratory dysfunction and premature death in the second to third decade of life.[1]
DMD is caused by mutation in the DMD gene, which is the largest gene of the human genome that encompasses ~ 2.2 Mb and encodes for the dystrophin protein.[2,3]
Lack of asymmetric cell division leads to a reduction in the number of myogenic progenitor cells and to impaired muscle regeneration (Figure 1).[18,20]. These findings indicate that there is a cell-autonomous defect in DMD-mutant satellite cells, which contributes to the pathogenesis of DMD
Summary
Targeting muscle stem cell intrinsic defects to treat Duchenne muscular dystrophy Nicolas A Dumont[1,2,3,4] and Michael A Rudnicki[1,2]. Absence of dystrophin leads to myofiber fragility and contributes to skeletal muscle degeneration in DMD patients, accumulating evidence indicate that muscle stem cells ( known as satellite cells) are defective in dystrophic muscles, which leads to impaired muscle regeneration. Our recent work demonstrated that dystrophin is expressed in activated satellite cells, where it regulates the establishment of satellite cell polarity and asymmetric cell division These findings indicate that dystrophin-deficient satellite cells have intrinsic dysfunctions that contribute to muscle wasting and progression of the disease. This discovery suggests that satellite cells could be targeted to treat DMD. Npj Regenerative Medicine (2016) 1, 16006; doi:10.1038/npjregenmed.2016.6; published online 9 June 2016
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