Mitsugumin 53 regulates extracellular Ca2+ entry and intracellular Ca2+ release via Orai1 and RyR1 in skeletal muscle

Abstract

Mitsugumin 53 (MG53) participates in the membrane repair of various cells, and skeletal muscle is the major tissue that expresses MG53. Except for the regulatory effects of MG53 on SERCA1a, the role(s) of MG53 in the unique functions of skeletal muscle such as muscle contraction have not been well examined. Here, a new MG53-interacting protein, Orai1, is identified in skeletal muscle. To examine the functional relevance of the MG53-Orai1 interaction, MG53 was over-expressed in mouse primary or C2C12 skeletal myotubes and the functional properties of the myotubes were examined using cell physiological and biochemical approaches. The PRY-SPRY region of MG53 binds to Orai1, and MG53 and Orai1 are co-localized in the plasma membrane of skeletal myotubes. MG53-Orai1 interaction enhances extracellular Ca2+ entry via a store-operated Ca2+ entry (SOCE) mechanism in skeletal myotubes. Interestingly, skeletal myotubes over-expressing MG53 or PRY-SPRY display a reduced intracellular Ca2+ release in response to K+-membrane depolarization or caffeine stimulation, suggesting a reduction in RyR1 channel activity. Expressions of TRPC3, TRPC4, and calmodulin 1 are increased in the myotubes, and MG53 directly binds to TRPC3, which suggests a possibility that TRPC3 also participates in the enhanced extracellular Ca2+ entry. Thus, MG53 could participate in regulating extracellular Ca2+ entry via Orai1 during SOCE and also intracellular Ca2+ release via RyR1 during skeletal muscle contraction.

A focus on extracellular Ca2+ entry into skeletal muscle

“… 82 The overexpression of TRPC1 or TPRC4 enhances SOCE and accelerates the terminal differentiation of human myoblasts to myotubes. 83 Changes in the SOCE in mouse skeletal myotubes involve changes in TPRC4 expression, 84 , 85 but no mechanism has been suggested for these changes. Considering the relatively high expression of TRPC4 in skeletal muscle, more research is needed to reveal the role of TRPC4 in skeletal muscle.…”

“… 123 Recent reports showed that MG53 binds to Orai1 and colocalizes with Orai1 in the sarcolemmal membrane of mouse skeletal myotubes, and established that MG53–Orai1 interaction enhances SOCE along with increases in the expression levels of TRPC3, TRPC4 and calmodulin 1. 84 …”

“…MG53 binds to TRPC3, 84 but the functional relationship remains unknown. On the other hand, MG53 attenuates SERCA1a activity by binding to SERCA1a at a high cytosolic Ca 2+ level (like that seen during skeletal muscle contraction) in mouse skeletal myotubes.…”

With the greatest care, stromal interaction molecule (STIM) proteins verify what skeletal muscle is doing

“…The involvement of STIM1 and/or SOCE in skeletal muscle diseases, by way of proteins such as TRPC3 and MG53, have also been reported in the literature ( 115 – 121 ). In addition, other possible factors that could contribute to skeletal muscle diseases have also been examined in several articles ( 54 , 122 – 124 ).…”

MG53: Biological Function and Potential as a Therapeutic Target

“…This binding attenuates sarcoplasmic reticulum Ca 21 -ATPase 1a activity and subsequently causes muscle stiffness and delayed relaxation (Lee et al, 2012). MG53 has also been found to regulate extracellular Ca 21 entry via Orai1 and intracellular Ca 21 release through Ry receptor 1 during skeletal muscle contraction (Ahn et al, 2016); however, the role of MG53 in muscle electrophysiology merits further study.…”