Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient <i>mdx</i> mice
Kenichiro Nogami, Yusuke Maruyama, Fusako Sakai‐Takemura, Norio Motohashi, Ahmed Elhussieny, Michihiro Imamura, Satoshi Miyashita, Megumu Ogawa, S. Noguchi, Yuki Tamura, Jun‐ichi Kira, Yoshitsugu Aoki, Shin’ichi Takeda, Yuko Miyagoe‐Suzuki
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.