Elucidation of molecular mechanism of limb-girdle muscular dystrophy through comparative analysis of calpain-3 mutant mice

2017 Fiscal Year Final Research Report

• Project/Area Number: 26670166
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: SHINKAI-OUCHI Fumiko 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 主任研究員 (00435710)
• Co-Investigator(Renkei-kenkyūsha): SORIMACHI Hiroyuki 公益財団法人 東京都医学総合研究所, 生体分子先端研究分野, 分野長 (10211327) ; ONO Yasuko 公益財団法人 東京都医学総合研究所, 生体分子先端研究分野, 副参事研究員 (20392376)
• Research Collaborator: SHINDO Mayumi 公益財団法人 東京都医学総合研究所, 基盤技術研究センター, 主席技術研究員 ; ITOH Yoshiki 公益財団法人 東京都医学総合研究所, 生体分子先端研究分野, 研修生
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 肢帯型筋ジストロフィー2A型 / カルパイン-3 / 骨格筋 / 筋成熟遅滞

Outline of Final Research Achievements

Limb-girdle muscular dystrophies (LGMD) exhibit progressive muscle weakness accompanied by degeneration of muscle fibers in the proximal muscle. LGMD2A type accounts for about 30% of LGMD and the responsible gene CAPN3 encodes for a skeletal muscle-specific calpain, an intracellular cysteine protease. Here we tried to elucidate the pathogenic molecular mechanism of LGMD2A by comparing two different mouse models of LGMD2A established by genetic modification of CAPN3. Both model animals, one lacks protease activity of CAPN3 but not the protein, namely, knock-in mouse, and another, CAPN3 knock-out mouse, showed a delay in maturation of muscle fiber. Detailed characterization of the phenomenon suggested that molecular components affected under these two conditions were different from each other. In summary, harmful effects of functional deficiency of CAPN3 in regeneration process induced by degeneration of skeletal muscle should be considered when exploring the pathology of LGMD2A.

Free Research Field

プロテオーム解析を利用した病態生化学