Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
Andrew Soroka
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
Alanna Klose
Center for Musculoskeletal Research, Department of Orthopaedics and Rehabilitation, University of Rochester Medical Center, Rochester, United States
Wenxuan Liu
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
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
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 of Smad4, the downstream cofactor for canonical TGFβ superfamily signaling, and the target Id1 in 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.
