Myofiber Baf60c controls muscle regeneration by modulating Dkk3-mediated paracrine signaling

Xu et al. define Baf60c in skeletal myofibers as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling on muscle stem cells. They also uncover that Baf60c interacts with transcription factor Six4 to synergistically suppress Dkk3 expression in myocytes. Obesity and type 2 diabetes (T2D) are the leading causes of the progressive decline in muscle regeneration and fitness in adults. The muscle microenvironment is known to play a key role in controlling muscle stem cell regenerative capacity, yet the underlying mechanism remains elusive. Here, we found that Baf60c expression in skeletal muscle is significantly downregulated in obese and T2D mice and humans. Myofiber-specific ablation of Baf60c in mice impairs muscle regeneration and contraction, accompanied by a robust upregulation of Dkk3, a muscle-enriched secreted protein. Dkk3 inhibits muscle stem cell differentiation and attenuates muscle regeneration in vivo. Conversely, Dkk3 blockade by myofiber-specific Baf60c transgene promotes muscle regeneration and contraction. Baf60c interacts with Six4 to synergistically suppress myocyte Dkk3 expression. While muscle expression and circulation levels of Dkk3 are markedly elevated in obese mice and humans, Dkk3 knockdown improves muscle regeneration in obese mice. This work defines Baf60c in myofiber as a critical regulator of muscle regeneration through Dkk3-mediated paracrine signaling.

Automated summary

Xu et al. have demonstrated that Baf60c plays a critical role in muscle regeneration by mediating paracrine signaling through Dkk3 in skeletal myofibers. They found that Baf60c interacts with Six4 to suppress Dkk3 expression in myocytes. This study also reveals the downregulation of Baf60c in obese and T2D individuals, and the upregulation of Dkk3 in muscle-specific Baf60c-deficient mice, leading to impaired muscle regeneration.