Ca²⁺ storage function is altered in the sarcoplasmic reticulum of skeletal muscle lacking mitsugumin 23

Mitsugumin 23 (MG23) has been identified as a ball-shaped cation channel in the sarcoplasmic reticulum (SR) but its physiological role remains unclear. This study aimed to examine the contribution of MG23 to Ca²⁺ storage function in skeletal muscle by using Mg23-knockout (Mg23^-/-) mice. There was no difference in the isometric specific force of the extensor digitorum longus (EDL) and soleus (SOL) muscles between Mg23^-/- and wild-type (Wt) mice. In Mg23^-/- mice, the calsequestrin 2 content in the EDL muscle and SR Ca²⁺-ATPase 2 content in the SOL were increased. We have examined SR and myofibril functions using mechanically skinned fibers and determined their fiber types based on the response to Sr²⁺, which showed that Mg23^-/- mice, compared with Wt, had: 1) elevated total Ca²⁺ content in the membranous components including SR, mitochondria, and transverse tubular system referred to as endogenous Ca²⁺ content, in both type I and II fibers of the EDL and SOL; 2) increased maximal Ca²⁺ content in both type I and II fibers of the EDL and SOL; 3) decreased SR Ca²⁺ leakage in type I fibers of the SOL; and 4) enhanced SR Ca²⁺ uptake in type I fibers of the SOL, although myofibril function was not different in both type I and II fibers of the SOL and EDL muscles. These results suggest that MG23 decreases SR Ca²⁺ storage in both type I and type II fibers, likely due to increased SR Ca²⁺ leakage.NEW & NOTEWORTHY The function of calcium storage within sarcoplasmic reticulum (SR) plays a pivotal role in influencing the health and disease states of skeletal muscle. In the present study, we demonstrated that mitsgumin 23, a novel non-selective cation channel, modifies SR Ca²⁺ storage in skeletal muscle fibers. These findings provide valuable insights into the physiological regulation of Ca²⁺ in skeletal muscle, offering significant potential for uncovering the mechanisms underlying muscle fatigue, muscle adaptation, and muscle diseases.