R-spondin 3 is a myokine that mediates type I fiber determination during skeletal muscle regeneration.

BACKGROUND: In recent years, skeletal muscle has been recognized not only as a locomotor organ but also as a secretory organ. The bioactive molecules it releases, known as myokines, act on distant organs through the circulation and locally on muscle tissue. Previously, we identified R-spondin 3 (Rspo3) as a Type I fiber-specific myokine that promotes myoblast differentiation into Type I fibers in vitro. In this study, we further investigated whether Rspo3 is involved in regulating Type I fiber determination in vivo. METHODS AND RESULTS: We generated tamoxifen-induced muscle-specific Rspo3-deficient mice and found that Rspo3 deficiency impaired Type I fiber determination during muscle regeneration. In contrast, transient overexpression of Rspo3 through in vivo electroporation enhanced the regeneration of Type I fibers, supporting its functional role in fiber-type specification. CONCLUSION: This work reveals that Rspo3 as a Type I fiber specific myokine promotes Type I fiber determination during muscle regeneration in vivo.