Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy
Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy
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DOI：
10.1172/jci40658
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Sorimachi, Hiroyuki
中科院分区：
文献类型：
--
作者：
Ojima, Koichi;Kawabata, Yukiko;Sorimachi, Hiroyuki
肢带型肌营养不良症2A型（LGMD 2A）是一种遗传性疾病，由钙蛋白酶3基因（CAPN 3）突变引起，该基因编码骨骼肌特异性钙蛋白酶，钙蛋白酶3（也称为p94）。然而，p94在这种疾病的发病机制中发挥作用的确切机制仍不清楚。在这里，使用p94基因敲入小鼠（本文称为p94 KI小鼠），其中内源性p94被蛋白水解无活性但结构完整的p94：C129 S突变体蛋白取代，我们已经证明，伸展依赖性p94在肌节中的分布在LGMD 2A的发病机制中起着至关重要的作用。p94 KI小鼠发展为进行性肌营养不良症，其通过运动而加重。p94 KI小鼠运动诱导的肌肉变性与伸展肌节中p94：C129 S的无效再分布有关。此外，p94 KI小鼠表现出对身体应激的适应受损，这伴随着运动时肌肉锚定重复蛋白-2和hsp的上调受损。这些发现表明，拉伸诱导的p94的动态再分布依赖于其蛋白酶活性，并且对于保护肌肉免受退化是必不可少的，特别是在物理应力条件下。此外，我们的数据提供了直接的证据，即p94蛋白酶活性的丧失可能导致LGMD 2A和分子洞察这是如何发生的。
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.