Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy

Koichi Ojima, Yukiko Kawabata, Harumi Nakao, Kazuki Nakao, Naoko Doi, Fujiko Kitamura, Yasuko Ono, Shoji Hata, Hidenori Suzuki, Hiroyuki Kawahara, Julius Bogomolovas, Christian Witt, Coen Ottenheijm, Siegfried Labeit, Hendrikus "Henk" Granzier, Noriko Toyama-Sorimachi, Michiko Sorimachi, Koichi Suzuki, Tatsuya Maeda, Keiko AbeAtsu Aiba, Hiroyuki Sorimachi

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that is caused by mutations in the calpain 3 gene (CAPN3), which encodes the skeletal muscle-specific calpain, calpain 3 (also known as p94). However, the precise mechanism by which p94 functions in the pathogenesis of this disease remains unclear. Here, using p94 knockin mice (termed herein p94KI mice) in which endogenous p94 was replaced with a proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated that stretch-dependent p94 distribution in sarcomeres plays a crucial role in the pathogenesis of LGMD2A. The p94KI mice developed a progressive muscular dystrophy, which was exacerbated by exercise. The exercise-induced muscle degeneration in p94KI mice was associated with an inefficient redistribution of p94:C129S in stretched sarcomeres. Furthermore, the p94KI mice showed impaired adaptation to physical stress, which was accompanied by compromised upregulation of muscle ankyrin-repeat protein-2 and hsp upon exercise. These findings indicate that the stretch-induced dynamic redistribution of p94 is dependent on its protease activity and essential to protect muscle from degeneration, particularly under conditions of physical stress. Furthermore, our data provide direct evidence that loss of p94 protease activity can result in LGMD2A and molecular insight into how this could occur.

Original languageEnglish (US)
Pages (from-to)2672-2683
Number of pages12
JournalJournal of Clinical Investigation
Volume120
Issue number8
DOIs
StatePublished - Aug 2 2010

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Calpain
Muscular Dystrophies
Muscles
Sarcomeres
Peptide Hydrolases
Ankyrin Repeat
Inborn Genetic Diseases
Mutant Proteins
Skeletal Muscle
Up-Regulation
Mutation
Genes
Limb-girdle muscular dystrophy type 2A
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy. / Ojima, Koichi; Kawabata, Yukiko; Nakao, Harumi; Nakao, Kazuki; Doi, Naoko; Kitamura, Fujiko; Ono, Yasuko; Hata, Shoji; Suzuki, Hidenori; Kawahara, Hiroyuki; Bogomolovas, Julius; Witt, Christian; Ottenheijm, Coen; Labeit, Siegfried; Granzier, Hendrikus "Henk"; Toyama-Sorimachi, Noriko; Sorimachi, Michiko; Suzuki, Koichi; Maeda, Tatsuya; Abe, Keiko; Aiba, Atsu; Sorimachi, Hiroyuki.

In: Journal of Clinical Investigation, Vol. 120, No. 8, 02.08.2010, p. 2672-2683.

Research output: Contribution to journalArticle

Ojima, K, Kawabata, Y, Nakao, H, Nakao, K, Doi, N, Kitamura, F, Ono, Y, Hata, S, Suzuki, H, Kawahara, H, Bogomolovas, J, Witt, C, Ottenheijm, C, Labeit, S, Granzier, HH, Toyama-Sorimachi, N, Sorimachi, M, Suzuki, K, Maeda, T, Abe, K, Aiba, A & Sorimachi, H 2010, 'Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy', Journal of Clinical Investigation, vol. 120, no. 8, pp. 2672-2683. https://doi.org/10.1172/JCI40658
Ojima, Koichi ; Kawabata, Yukiko ; Nakao, Harumi ; Nakao, Kazuki ; Doi, Naoko ; Kitamura, Fujiko ; Ono, Yasuko ; Hata, Shoji ; Suzuki, Hidenori ; Kawahara, Hiroyuki ; Bogomolovas, Julius ; Witt, Christian ; Ottenheijm, Coen ; Labeit, Siegfried ; Granzier, Hendrikus "Henk" ; Toyama-Sorimachi, Noriko ; Sorimachi, Michiko ; Suzuki, Koichi ; Maeda, Tatsuya ; Abe, Keiko ; Aiba, Atsu ; Sorimachi, Hiroyuki. / Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 8. pp. 2672-2683.
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AU - Ojima, Koichi

AU - Kawabata, Yukiko

AU - Nakao, Harumi

AU - Nakao, Kazuki

AU - Doi, Naoko

AU - Kitamura, Fujiko

AU - Ono, Yasuko

AU - Hata, Shoji

AU - Suzuki, Hidenori

AU - Kawahara, Hiroyuki

AU - Bogomolovas, Julius

AU - Witt, Christian

AU - Ottenheijm, Coen

AU - Labeit, Siegfried

AU - Granzier, Hendrikus "Henk"

AU - Toyama-Sorimachi, Noriko

AU - Sorimachi, Michiko

AU - Suzuki, Koichi

AU - Maeda, Tatsuya

AU - Abe, Keiko

AU - Aiba, Atsu

AU - Sorimachi, Hiroyuki

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N2 - Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that is caused by mutations in the calpain 3 gene (CAPN3), which encodes the skeletal muscle-specific calpain, calpain 3 (also known as p94). However, the precise mechanism by which p94 functions in the pathogenesis of this disease remains unclear. Here, using p94 knockin mice (termed herein p94KI mice) in which endogenous p94 was replaced with a proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated that stretch-dependent p94 distribution in sarcomeres plays a crucial role in the pathogenesis of LGMD2A. The p94KI mice developed a progressive muscular dystrophy, which was exacerbated by exercise. The exercise-induced muscle degeneration in p94KI mice was associated with an inefficient redistribution of p94:C129S in stretched sarcomeres. Furthermore, the p94KI mice showed impaired adaptation to physical stress, which was accompanied by compromised upregulation of muscle ankyrin-repeat protein-2 and hsp upon exercise. These findings indicate that the stretch-induced dynamic redistribution of p94 is dependent on its protease activity and essential to protect muscle from degeneration, particularly under conditions of physical stress. Furthermore, our data provide direct evidence that loss of p94 protease activity can result in LGMD2A and molecular insight into how this could occur.

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