title: Smad4 restricts differentiation to promote expansion of satellite cell derived progenitors during skeletal muscle regeneration.
abstract: Skeletal muscle regenerative potential declines with age, in part due to deficiencies in resident stem cells (satellite cells, SCs) and derived myogenic progenitors (MPs); however, the factors responsible for this decline remain obscure. TGFβ superfamily signaling is an inhibitor of myogenic differentiation, with elevated activity in aged skeletal muscle. Surprisingly, we find reduced expression ofSmad4, the downstream cofactor for canonical TGFβ superfamily signaling, and the targetId1in aged SCs and MPs during regeneration. Specific deletion of Smad4 in adult mouse SCs led to increased propensity for terminal myogenic commitment connected to impaired proliferative potential. Furthermore, SC-specific Smad4 disruption compromised adult skeletal muscle regeneration. Finally, loss of Smad4 in aged SCs did not promote aged skeletal muscle regeneration. Therefore, SC-specific reduction of Smad4 is a feature of aged regenerating skeletal muscle and Smad4 is a critical regulator of SC and MP amplification during skeletal muscle regeneration.
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States.
authors.forename: Nicole D
authors.identifier: 0000-0003-0654-0983
authors.initials: ND
authors.lastname: Paris
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States.|Department of Pathology, University of Rochester Medical Center, Rochester, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Soroka
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States.
authors.forename: Alanna
authors.initials: A
authors.lastname: Klose
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States.|Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, United States.
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States.|Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Rochester, United States.|The Rochester Aging Research Center, University of Rochester Medical Center, Rochester, United States.
authors.forename: Joe V
authors.identifier: 0000-0002-8440-7312
authors.initials: JV
authors.lastname: Chakkalakal
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D017353:Gene Deletion; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051901:Smad4 Protein; C490810:Smad4 protein, mouse
keywords: Smad4; TGFB; aging; developmental biology; mouse; muscle stem cells; sarcopenia; satellite cells; stem cells