Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice

• Published in: Human molecular genetics Vol. 30; no. 11; pp. 1006 - 1019
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 31.05.2021
• Subjects: Animals; Calcium - metabolism; Disease Models, Animal; Dystrophin - deficiency; Dystrophin - genetics; Humans; Mice; Mice, Inbred mdx; Muscle Contraction - genetics; Muscle Weakness - genetics; Muscle Weakness - pathology; Muscular Atrophy - genetics; Muscular Atrophy - pathology; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - pathology; Phenotype; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum - pathology; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddab100

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.