Institute for Neuroscience and Muscle Research, The Children's Hospital Westmead, New South Wales 2145, Australia.
Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, New South Wales 2006, Australia.
Nat Commun. 2017 Jan 31;8:14143. doi: 10.1038/ncomms14143.
Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.
杜氏肌营养不良症（DMD）的特征是肌肉退化和进行性无力。疾病的发病和进展在患者之间存在相当大的差异，这可能会影响临床试验的结果。在这里，我们表明 ACTN3 中的常见无效突变（R577X）导致年轻、能行走的 DMD 患者的肌肉力量显著降低，以及 10 米步行测试时间延长；这两者都是临床试验中的主要终点指标。我们已经开发出一种双敲除小鼠模型，该模型也表现出肌肉力量降低，但随着年龄的增长，它能免受拉伸诱导的离心损伤。这表明，α-辅肌动蛋白-3 的缺乏会降低肌肉的基础性能，但能改善肌营养不良病理的进展。从机制上讲，我们表明，α-辅肌动蛋白-3 的缺乏通过激活钙调神经磷酸酶触发氧化肌肉代谢的增加，这可能赋予了保护作用。我们的研究表明，ACTN3 R577X 基因型是 DMD 患者临床表型的修饰因子。
