Decision Letter: Smad4 Restricts Differentiation to Promote Expansion of Satellite Cell Derived Progenitors During Skeletal Muscle Regeneration

Chakkalakal et al. investigated the role of SMAD4 in muscle regeneration, focusing on satellite cells in young and aged mice. They discovered that SMAD4 was essential for muscle repair in young adults, as its deletion led to faster differentiation, decreased proliferation, and impaired regeneration. In aged mice, with elevated TGFβ signaling, SMAD4 induction was impaired, and its deletion did not correct age-related defects. The study underscored the complexity of SMAD4's role in muscle repair and the need for further research into the upstream signals affecting SMAD4 during aging, using genetic systems and aged animals up to 2 years. However, challenges remained in fully understanding SMAD4's functions and mechanisms in muscle regeneration.