Abstract
Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7+ and Myf5−) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD.
Highlights
Muscular dystrophies include a spectrum of inherited diseases that lead to progressive muscle degeneration and dysfunction (Wallace and McNally, 2009)
The age-dependent decline in the satellite cell number and activity was found to be correlated to impairments in Notch signaling – an evolutionary conserved signaling cascade that has previously been implicated in muscle stem cell function
Satellite cell number and activity decline with age in mdx mice As satellite cells are necessary for postnatal muscle regeneration (Lepper et al, 2011; Murphy et al, 2011; Sambasivan et al, 2011b), we aimed to examine satellite cell behavior in mdx mice, where muscles are under repetitive degeneration and regeneration
Summary
Muscular dystrophies include a spectrum of inherited diseases that lead to progressive muscle degeneration and dysfunction (Wallace and McNally, 2009). Dystrophin is a cytoskeletal protein that interacts with a group of peripheral membrane and transmembrane proteins, such as dystroglycan and sarcoglycan, to form the dystrophin-associated The sarcolemma becomes fragile to mechanical damage, and normal muscle activity can result in muscle degeneration, chronic inflammation and fibrosis (Petrof et al, 1993). These pathological stimulations alter the tissue environment and compromise muscle function to further deteriorate the dystrophic phenotype. DMD patients typically suffer from rapid progression of muscle degeneration, and are eventually paralyzed and die in their second to third decade of life
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