Specification of skeletal muscle fiber-type is determined by the calcineurin/NFATc1 signaling pathway during muscle regeneration

Skeletal muscle fiber type specification is changeable during muscle regeneration following cardiotoxin (CTX) injection; however, the mechanism of muscle fiber shift in regenerating muscle fibers remains unclear. Furthermore, it is unclear as to which factors determine skeletal muscle fiber types in regenerating muscle fibers. Previous studies showed that CTX-induced muscle damage resulted in a temporary hypoxic condition, indicating that hypoxia-inducible factor (HIF)-1a may be involved in muscle fiber type transition. Stabilization of HIF-1a has been shown to result in muscle fiber type transition toward slowtwitch phenotype through the calcineurin/nuclear factor activated T cell 1 (NFATc1) signaling pathway. Therefore, the aim of the present study was to determine whether the calcineurin/NFATc1 pathway is a key mediator of skeletal muscle fiber type transition during muscle regeneration. We found that CTXinduced muscle damage resulted in transient ischemia and HIF-1a expression in skeletal muscle. Additionally, it shifted the muscle fiber type proportion toward a slow-twitch phenotype in the soleus muscle (37.5% in the control muscle vs. 61.3% in the damaged muscle; p < 0.01) three weeks after muscle damage. Moreover, the NFATc1 protein levels increased in damaged muscle, and blockage of the calcineurin/NFATc1 signaling pathway by tacrolimus (FK-506) treatment substantially decreased the number of slow-twitch muscle fibers in the soleus muscle. This study demonstrated that CTX-induced muscle injury results in transient ischemia in hind limb muscle and stabilizes HIF-1a. Moreover, muscle damage increased oxidative phenotype muscle fibers through the calcineurin/NFATc1 signaling pathway during muscle regeneration. (c) 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND

Automated summary

The skeletal muscle fiber type can be changed during muscle regeneration after cardiotoxin injection, but the mechanism of fiber type transition is still unclear. Previous studies have shown that CTX-induced muscle damage leads to temporary hypoxia, suggesting the involvement of HIF-1a in the transition. This study demonstrates that CTX-induced muscle injury causes transient ischemia and stabilizes HIF-1a, leading to an increase in oxidative muscle fibers through the calcineurin/NFATc1 signaling pathway.