title: Stage-specific effects of Notch activation during skeletal myogenesis.
abstract: Skeletal myogenesis involves sequential activation, proliferation, self-renewal/differentiation and fusion of myogenic stem cells (satellite cells). Notch signaling is known to be essential for the maintenance of satellite cells, but its function in late-stage myogenesis, i.e. post-differentiation myocytes and post-fusion myotubes, is unknown. Using stage-specific Cre alleles, we uncovered distinct roles of Notch1 in mononucleated myocytes and multinucleated myotubes. Specifically, constitutive Notch1 activation dedifferentiates myocytes into Pax7 quiescent satellite cells, leading to severe defects in muscle growth and regeneration, and postnatal lethality. By contrast, myotube-specific Notch1 activation improves the regeneration and exercise performance of aged and dystrophic muscles. Mechanistically, Notch1 activation in myotubes upregulates the expression of Notch ligands, which modulate Notch signaling in the adjacent satellite cells to enhance their regenerative capacity. These results highlight context-dependent effects of Notch activation during myogenesis, and demonstrate that Notch1 activity improves myotube's function as a stem cell niche.
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Bi
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Yue
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, United States.
authors.forename: Sara
authors.initials: S
authors.lastname: Wirbisky
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Tizhong
authors.initials: T
authors.lastname: Shan
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.
authors.forename: Yefei
authors.identifier: 0000-0002-2121-7538
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, United States.
authors.forename: Daoguo
authors.initials: D
authors.lastname: Zhou
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, United States.|Center for Cancer Research, Purdue University, West Lafayette, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freeman
authors.affiliation: Department of Animal Sciences, Purdue University, West Lafayette, United States.|Center for Cancer Research, Purdue University, West Lafayette, United States.
authors.forename: Shihuan
authors.identifier: 0000-0001-9180-3180
authors.initials: S
authors.lastname: Kuang
mesh_terms: D002454:Cell Differentiation; D049109:Cell Proliferation; D006801:Humans; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018482:Muscle, Skeletal / Q000196:embryology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1
keywords: Notch signaling; dedifferentiation; developmental biology; mouse; muscular dystrophy; myogenesis; stem cells