Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. Issue 11 (5th April 2021)

• Record Type: Journal Article
• Authors: Nogami, Ken'ichiro; Maruyama, Yusuke; Sakai-Takemura, Fusako; Motohashi, Norio; Elhussieny, Ahmed; Imamura, Michihiro; Miyashita, Satoshi; Ogawa, Megumu; Noguchi, Satoru; Tamura, Yuki; Kira, Jun-ichi; Aoki, Yoshitsugu; Takeda, Shin'ichi; Miyagoe-Suzuki, Yuko
• Is Part Of: Human molecular genetics. Volume 30:Issue 11(2021)
• Page Start: 1006
• Page End: 1019
• Publication Date: 2021-04-05
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddab100
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca 2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) takes up cytosolic Ca 2+ 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.