| First Author | Arai S | Year | 2017 |
| Journal | Am J Physiol Cell Physiol | Volume | 312 |
| Issue | 1 | Pages | C29-C39 |
| PubMed ID | 27806939 | Mgi Jnum | J:313956 |
| Mgi Id | MGI:6810289 | Doi | 10.1152/ajpcell.00090.2016 |
| Citation | Arai S, et al. (2017) Functional loss of DHRS7C induces intracellular Ca2+ overload and myotube enlargement in C2C12 cells via calpain activation. Am J Physiol Cell Physiol 312(1):C29-C39 |
| abstractText | Dehydrogenase/reductase member 7C (DHRS7C) is a newly identified NAD/NADH-dependent dehydrogenase that is expressed in cardiac and skeletal muscle and localized in the endoplasmic/sarcoplasmic reticulum (ER/SR). However, its functional role in muscle cells remains to be fully elucidated. Here, we investigated the role of DHRS7C by analyzing mouse C2C12 myoblasts deficient in DHRS7C (DHRS7C-KO cells), overexpressing wild-type DHRS7C (DHRS7C-WT cells), or expressing mutant DHRS7C [DHRS7C-Y191F or DHRS7C-K195Q cells, harboring point mutations in the NAD/NADH-dependent dehydrogenase catalytic core domain (YXXXK)]. DHRS7C expression was induced as C2C12 myoblasts differentiated into mature myotubes, whereas DHRS7C-KO myotubes exhibited enlarged cellular morphology after differentiation. Notably, both DHRS7C-Y191F and DHRS7C-K195Q cells also showed similar enlarged cellular morphology, suggesting that the NAD/NADH-dependent dehydrogenase catalytic core domain is pivotal for DHRS7C function. In DHRS7C-KO, DHRS7C-Y191F, and DHRS7C-K195Q cells, the resting level of cytosolic Ca(2+) and total amount of Ca(2+) storage in the ER/SR were significantly higher than those in control C2C12 and DHRS7C-WT cells after differentiation. Additionally, Ca(2+) release from the ER/SR induced by thapsigargin and 4-chloro-m-cresol was augmented in these cells and calpain, a calcium-dependent protease, was significantly activated in DHRS7C-KO, DHRS7C-Y191F, and DHRS7C-K195Q myotubes, consistent with the higher resting level of cytosolic Ca(2+) concentration and enlarged morphology after differentiation. Furthermore, treatment with a calpain inhibitor abolished the enlarged cellular morphology. Taken together, our findings suggested that DHRS7C maintains intracellular Ca(2+) homeostasis involving the ER/SR and that functional loss of DHRS7C leads to Ca(2+) overload in the cytosol and ER/SR, resulting in enlarged cellular morphology via calpain activation. |
