Department of Physiology, VU University Medical Center Amsterdam, Amsterdam, the Netherlands.
Department of Kinesiology and Physical Education, McGill University, Montreal, Quebec, Canada.
Ann Neurol. 2018 Feb;83(2):269-282. doi: 10.1002/ana.25144. Epub 2018 Feb 6.
Nemaline myopathy (NM) is one of the most common congenital nondystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (ie, NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients.
To test this hypothesis, we performed contractility measurements in individual muscle fibers and myofibrils obtained from muscle biopsies of 14 NEM3 patients with different ACTA1 mutations. To identify the structural basis for impaired contractility, low angle X-ray diffraction and stimulated emission-depletion microscopy were applied.
Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force-generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils. Low angle X-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length. Interestingly, the calcium sensitivity of force is unaffected in some patients, but decreased in others.
Dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients. This information is crucial for patient stratification in future clinical trials. Ann Neurol 2018;83:269-282.
肌原纤维病（NM）是最常见的先天性非营养不良性肌病之一，其特征为肌肉无力，通常在出生时就已出现。ACTN1 突变是 NM（即 NEM3）的常见病因。ACTN1 编码 α-肌动蛋白 1，是肌节细肌丝的主要组成部分。ACTN1 突变导致 NEM3 肌肉无力的机制尚未完全清楚。我们假设肌节功能障碍导致 NEM3 患者肌肉无力。
为了验证这一假设，我们对 14 名患有不同 ACTN1 突变的 NEM3 患者的肌肉活检中获得的单个肌纤维和肌原纤维进行了收缩性测量。为了确定收缩功能障碍的结构基础，我们应用了低角度 X 射线衍射和受激发射损耗显微镜。
我们的研究结果表明，NEM3 患者的肌纤维表现出降低的最大产生力能力，这是由于大多数患者的肌节收缩功能障碍所致，通过肌原纤维的收缩性测量可以发现这一点。低角度 X 射线衍射和受激发射损耗显微镜表明，NEM3 患者的肌节收缩功能障碍涉及在肌肉激活过程中结合到肌动蛋白的肌球蛋白头部数量减少。这种减少不是由于细肌丝长度减少所致。有趣的是，在一些患者中，力的钙敏感性不受影响，但在另一些患者中则降低。
肌节收缩功能障碍是大多数 NEM3 患者肌肉无力的一个重要原因。这些信息对于未来临床试验中的患者分层至关重要。神经病学年鉴 2018；83：269-282。
