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

The study by Chakkalakal et al. investigated the role of SMAD4 in muscle regeneration by deleting it in satellite cells of both adult and aged mice. They discovered that SMAD4 was essential for muscle repair in young adults, as its absence led to faster differentiation, decreased proliferation, and impaired regeneration. In aged mice, despite elevated TGFβ signaling, SMAD4 induction was impaired, and its deletion did not alleviate age-related defects. The research underscored the complexity of TGF signaling in muscle repair and the specific role of SMAD4, suggesting it was a positive regulator of muscle repair. The study also addressed technical concerns, such as the efficiency of SMAD4 deletion and the role of FGF signaling, but found that FGF supplementation might not correct the defects observed. These findings indicated the need for further exploration of the signals influencing SMAD4 levels during regeneration and aging.