title: Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy.
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.
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Yefei
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Molecular Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kuroda
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hannon
authors.affiliation: Molecular Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA skuang@purdue.edu.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation; D018101:Mice, Inbred mdx; D009132:Muscles / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000473:pathology*; D051880:Receptors, Notch / Q000172:deficiency* / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch
keywords: Muscular dystrophy; Notch signaling; Stem cell