Functional role of truncated dystrophin with deletion exon 45-55

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860306
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: TANIHATA Jun 独立行政法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 流動研究員 (00508426)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 筋ジストロフィー / 筋小胞体 / SERCA / ｎＮＯＳ / カルシウム動態

Outline of Final Research Achievements

Duchenne muscular dystrophy (DMD) is caused by lack of dystrophin. Exon skipping is a promising treatment for DMD and “exon 45-55 skipping” strategy is though to be one of the goals of this therapy, partly because Becker muscular dystrophy patients with exon 45-55 in-frame deletion show very mild skeletal muscle symptoms. However the function of exon 45-55 deleted dystrophin is not well investigated. We generated Tg/mdx mice and extensively analyzed their phenotypes. The improvement of muscle pathology and muscle function of Tg/mdx were confirmed. On the other hand, nNOS of Tg/mdx exists as an activated form and its localization was changed from sarcolemma to cytosol. We found that activated nNOS in Tg/mdx led to hyper-nitrosylation of the RyR1 and subsequent constant Ca2+ release from SR to cytosol. These phenomena were also confirmed in mdx. However, the function of RyR1 stimulated by caffeine and SERCA were maintained in Tg/mdx and wild type but not in mdx.

Free Research Field

筋生理学