| First Author | Mázala DA | Year | 2015 |
| Journal | Am J Physiol Cell Physiol | Volume | 308 |
| Issue | 9 | Pages | C699-709 |
| PubMed ID | 25652448 | Mgi Jnum | J:224014 |
| Mgi Id | MGI:5661101 | Doi | 10.1152/ajpcell.00341.2014 |
| Citation | Mazala DA, et al. (2015) SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models. Am J Physiol Cell Physiol 308(9):C699-709 |
| abstractText | Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca(2)(+) have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca(2)(+)-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr(-/-) mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr +/- mice to generate mdx/Utr(-/-)/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at approximately 12 wk of age for changes in Ca(2)(+) handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca(2)(+)-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr(-/-)/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr(-/-) vs. WT mice, but only 1.5-fold greater in mdx/Utr(-/-)/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr(-/-) vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca(2)(+) control as a therapeutic approach for DMD. |
