ZIP13 marks muscle satellite cells and contributes to their quiescent and active phase balance

Loss of ZIP13 causes Ehlers-Danlos syndrome spondylodysplastic type 3 involving connective tissue dysplasias associated with a reduction in muscular strength. However, ZIP13 role in skeletal muscle homeostasis, particularly for the regulation of muscle satellite cells (MuSCs), remains poorly understood. In this study, we investigated Zip13-knockout (KO) mice and found a reduction in MuSCs of Zip13-KO mice, in which the quiescent and activated phase balances were disrupted. To clarify the physiological role and dynamics of ZIP13 expression in MuSCs, we generated Zip13-GFP knock-in (KI) mice encoding GFP at the Zip13 locus, which showed that ZIP13 contributes to the phase balance regulation of quiescent and activated MuSCs and their functions. Indeed, Zip13-KO mice exhibited delayed recovery from skeletal muscle injury, indicating ZIP13 requirement for proper skeletal muscle regeneration. Moreover, GFP expression was reduced in the MuSCs of homozygous Zip13-GFP KI mice whose intact ZIP13 expression was perturbed, suggesting that positive feedback mechanisms exist to maintain ZIP13 expression. Altogether, our results illustrate that ZIP13 might be positively involved in skeletal muscle regeneration by controlling the quiescent/activated phase balance of MuSCs through autoregulatory ZIP13 expression, and that newly generated Zip13-GFP KI mice would be useful for investigating the roles and dynamics of ZIP13-expressing cells.