Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy
Koichi Ojima, … , Atsu Aiba, Hiroyuki Sorimachi
Koichi Ojima, … , Atsu Aiba, Hiroyuki Sorimachi
Published July 1, 2010
Citation Information: J Clin Invest. 2010;120(8):2672-2683. https://doi.org/10.1172/JCI40658.
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Research Article Muscle biology

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

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.

Authors

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, Henk Granzier, Noriko Toyama-Sorimachi, Michiko Sorimachi, Koichi Suzuki, Tatsuya Maeda, Keiko Abe, Atsu Aiba, Hiroyuki Sorimachi

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Figure 6

A model for the p94-mediated signal response to physical stress.

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A model for the p94-mediated signal response to physical stress. In WT m...
In WT mice, when skeletal muscles undergo physical stress such as exercise, p94WT accumulates at the N2A region and MARP2 translocates from the N2A region to the myonuclei to promote the adaptive response to stress. In contrast, in the p94KI mice, in response to physical stress, the p94:C129S protein accumulates slowly at the N2A region, and the MARP2 induction is lower than in WT mice. Consequently, MARP2 signaling does not function properly in the p94KI mice. Thus, the p94 protease activity is required for the adaptive response to physical stress in skeletal muscles. Black and gray arrows indicate the proper and compromised mobility in response to physical stress in WT and p94KI mice, respectively.