Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy.
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.
Ojima
Koichi
K
Calpain Project, The Tokyo Metropolitan Institute of Medical Science Rinshoken, Tokyo, Japan.
Kawabata
Yukiko
Y
Nakao
Harumi
H
Nakao
Kazuki
K
Doi
Naoko
N
Kitamura
Fujiko
F
Ono
Yasuko
Y
Hata
Shoji
S
Suzuki
Hidenori
H
Kawahara
Hiroyuki
H
Bogomolovas
Julius
J
Witt
Christian
C
Ottenheijm
Coen
C
Labeit
Siegfried
S
Granzier
Henk
H
Toyama-Sorimachi
Noriko
N
Sorimachi
Michiko
M
Suzuki
Koichi
K
Maeda
Tatsuya
T
Abe
Keiko
K
Aiba
Atsu
A
Sorimachi
Hiroyuki
H
D000222:Adaptation, Physiological; D000375:Aging / Q000502:physiology; D000818:Animals; D002154:Calpain / Q000032:analysis / Q000502:physiology*; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000502:physiology*; D049288:Muscular Dystrophies, Limb-Girdle / Q000209:etiology* / Q000503:physiopathology; D009210:Myofibrils / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D010805:Physical Conditioning, Animal; D012038:Regeneration; D012097:Repressor Proteins / Q000502:physiology; D013314:Stress, Mechanical
C104844:Ankrd1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D002154:Calpain; C078134:calpain p94