Caspase-12 ablation preserves muscle function in the mdx mouse
Caspase-12 ablation preserves muscle function in the mdx mouse
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DOI：
10.1093/hmg/ddu249
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发表时间：
2014-10-15
影响因子：
3.5
通讯作者：
Barton, Elisabeth R.
中科院分区：
文献类型：
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作者：
Moorwood, Catherine;Barton, Elisabeth R.
杜氏肌营养不良症（DMD）是由肌营养不良蛋白突变引起的破坏性肌肉消耗性疾病。肌营养不良蛋白缺乏的几个下游后果是内质网（ER）应激的触发因素，包括钙稳态的丧失、缺氧和氧化应激。在内质网应激期间，错误折叠的蛋白质在内质网腔中积累，并且未折叠蛋白质反应（UPR）被触发，导致适应或凋亡。我们假设内质网应激在营养不良的肌肉中升高，并有助于DMD的病理学。与对照组相比，我们观察到DMD患者活检组织中ER应激标志物BiP和裂解的caspase-4增加，并且肌营养不良蛋白缺陷型mdx小鼠肌肉中多种UPR途径增加。然后，我们将mdx小鼠与caspase-12无效的小鼠杂交，caspase-12是人类caspase-4的鼠等效物，其对ER应激具有抗性。我们发现，删除caspase-12保留了mdx肌肉功能，导致比力产生和离心收缩阻力恢复75%。在没有半胱天冬酶-12的情况下，通常在mdx肌肉中发现的代偿性肥大正常化;发现这是由于纤维尺寸减小，而不是纤维类型转变或纤维化减少。纤维中心成核没有显着改变，在半胱天冬酶-12的情况下，但在mdx小鼠中发现的肌纤维变性几乎减少到野生型水平。总之，我们已经确定了增强的ER应激和异常的UPR信号作为营养不良表型的新贡献者。因此，Caspase-4是DMD的潜在治疗靶点。
Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin. Several downstream consequences of dystrophin deficiency are triggers of endoplasmic reticulum (ER) stress, including loss of calcium homeostasis, hypoxia and oxidative stress. During ER stress, misfolded proteins accumulate in the ER lumen and the unfolded protein response (UPR) is triggered, leading to adaptation or apoptosis. We hypothesized that ER stress is heightened in dystrophic muscles and contributes to the pathology of DMD. We observed increases in the ER stress markers BiP and cleaved caspase-4 in DMD patient biopsies, compared with controls, and an increase in multiple UPR pathways in muscles of the dystrophin-deficient mdx mouse. We then crossed mdx mice with mice null for caspase-12, the murine equivalent of human caspase-4, which are resistant to ER stress. We found that deleting caspase-12 preserved mdx muscle function, resulting in a 75% recovery of both specific force generation and resistance to eccentric contractions. The compensatory hypertrophy normally found in mdx muscles was normalized in the absence of caspase-12; this was found to be due to decreased fibre sizes, and not to a fibre type shift or a decrease in fibrosis. Fibre central nucleation was not significantly altered in the absence of caspase-12, but muscle fibre degeneration found in the mdx mouse was reduced almost to wild-type levels. In conclusion, we have identified heightened ER stress and abnormal UPR signalling as novel contributors to the dystrophic phenotype. Caspase-4 is therefore a potential therapeutic target for DMD.