Dissociation of SH3 and cysteine-rich domain 3 and junctophilin 1 from dihydropyridine receptor in dystrophin-deficient muscles
Dissociation of SH3 and cysteine-rich domain 3 and junctophilin 1 from dihydropyridine receptor in dystrophin-deficient muscles
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DOI：
10.1152/ajpcell.00163.2022
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发表时间：
2022-09-01
影响因子：
5.5
通讯作者：
Yamada, Takashi
中科院分区：
文献类型：
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作者：
Ashida, Yuki;Himori, Koichi;Yamada, Takashi
兴奋-收缩（EC）偶联的破坏和随后肌浆网（SR）中Ca 2+释放的减少已被证明是杜氏肌营养不良症（DMD）患者中观察到的肌无力的原因。在这里，我们研究了mdx 52和DMD-null/NSG小鼠骨骼肌中EC解偶联的潜在机制，这些小鼠是DMD的动物模型，重点是SH 3和富含半胱氨酸的结构域3（STAC 3）和junctophilin 1（JP 1），连接二氢吡啶受体（DHPR）在横小管和SR的ryanodine受体1。等长跖屈扭矩归一化为整个跖屈肌的肌肉重量与其对照小鼠相比，mdx 52和DMD-null/NSG小鼠的肌肉受到抑制。这伴随着钙蛋白酶-1的自溶增加，STAC 3和JP 1含量水平降低，以及STAC 3和JP 1从腓肠肌中的DHPR-a1解离。此外，体外机制实验表明，STAC 3和JP 1进行Ca 2+依赖性蛋白水解，这是不太明显的肌营养不良蛋白缺陷的肌肉，其中钙蛋白酶抑制蛋白，内源性钙蛋白酶抑制剂，上调。离心收缩进一步增强了钙蛋白酶-1的自溶以及STAC 3和JP 1的蛋白水解，这与DMD缺失/NSG小鼠腓肠肌中的严重扭矩抑制有关。这些数据表明，钙依赖性STAC 3和JP 1的蛋白水解可能是一个重要因素，导致肌无力，由于EC耦合失败，肌营养不良蛋白缺乏的肌肉。新&值得注意的是，在肌营养不良蛋白缺乏的肌肉中，兴奋-收缩（EC）偶联中断的潜在机制还没有得到很好的理解。在这里，使用Duchenne型肌营养不良症（DMD）的动物模型，我们显示了钙依赖性蛋白酶（calpain-1）介导的蛋白水解SH 3和富含半胱氨酸的结构域3（STAC 3）和junctophilin 1（JP 1），必需的EC偶联蛋白，在肌营养不良蛋白缺乏的肌肉，并强调的解离STAC 3和JP 1从二氢吡啶受体作为一个致病因素EC解偶联营养不良的肌肉。
The disruption of excitation-contraction (EC) coupling and subsequent reduction in Ca2+ release from the sarcoplasmic reticulum (SR) have been shown to account for muscle weakness seen in patients with Duchenne muscular dystrophy (DMD). Here, we examined the mechanisms underlying EC uncoupling in skeletal muscles from mdx52 and DMD-null/NSG mice, animal models for DMD, focusing on the SH3 and cysteine-rich domain 3 (STAC3) and junctophilin 1 (JP1), which link the dihydropyridine recep-tor (DHPR) in the transverse tubule and the ryanodine receptor 1 in the SR. The isometric plantarflexion torque normalized to muscle weight of whole plantar flexor muscles was depressed in mdx52 and DMD-null/NSG mice compared with their control mice. This was accompanied by increased autolysis of calpain-1, decreased levels of STAC3 and JP1 content, and dissociation of STAC3 and JP1 from DHPR-a1s in gastrocnemius muscles. Moreover, in vitro mechanistic experiments demonstrated that STAC3 and JP1 underwent Ca2+-dependent proteolysis that was less pronounced in dystrophin-deficient muscles where calpastatin, the endogenous calpain inhibitor, was upregulated. Eccentric contractions further enhanced autolysis of calpain-1 and proteolysis of STAC3 and JP1 that were associated with severe torque depression in gastrocnemius muscles from DMD-null/NSG mice. These data suggest that Ca2+-dependent proteolysis of STAC3 and JP1 may be an essential factor causing muscle weakness due to EC coupling failure in dystrophin-deficient muscles. NEW & NOTEWORTHY The mechanisms underlying the disruption of excitation-contraction (EC) coupling in dystrophin-deficient muscles are not well understood. Here, using animal models for Duchenne muscular dystrophies (DMD), we show a Ca2+-de-pendent protease (calpain-1)-mediated proteolysis of SH3 and cysteine-rich domain 3 (STAC3) and junctophilin 1 (JP1), essential EC coupling proteins, in dystrophin-deficient muscle, and highlighting the dissociation of STAC3 and JP1 from dihydropyridine re-ceptor as a causative factor in EC uncoupling of dystrophic muscles.