Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), an X-linked disorder caused by loss-of-function mutations in the dystrophin gene, is characterized by progressive muscle degeneration and weakness. Enhanced store-operated Ca(2+) entry (SOCE), a Ca(2+) influx mechanism coordinated by STIM1 sensors of luminal Ca(2+) within the sarcoplasmic reticulum (SR) and Ca(2+)-permeable Orai1 channels in the sarcolemma, is proposed to contribute to Ca(2+)-mediated muscle damage in DMD. To directly determine the impact of Orai1-dependent SOCE on the dystrophic phenotype, we crossed mdx mice with tamoxifen-inducible, muscle-specific Orai1 knockout mice (mdx-Orai1 KO mice). Both constitutive and SOCE were significantly increased in flexor digitorum brevis fibers from mdx mice, while SOCE was absent in fibers from both Orai1 KO and mdx-Orai1 KO mice. Compared with WT mice, fibers from mdx mice exhibited (1) increased resting myoplasmic Ca(2+) levels, (2) reduced total releasable Ca(2+) store content, and (3) a prolonged rate of electrically evoked Ca(2+) transient decay. These effects were partially normalized in fibers from mdx-Orai1 KO mice. Intact extensor digitorum longus muscles from mdx mice exhibited a significant reduction of maximal specific force, which was rescued in muscles from mdx-Orai1 KO mice. Finally, during exposure to consecutive eccentric contractions, muscles from mdx mice displayed a more pronounced decline in specific force compared with that of WT mice, which was also significantly attenuated by Orai1 ablation. Together, these results indicate that enhanced Orai1-dependent SOCE exacerbates the dystrophic phenotype and that Orai1 deficiency improves muscle pathology by both normalizing Ca(2+) homeostasis and promoting sarcolemmal integrity/stability.