Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).
Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).
复制标题
DOI：
10.1002/ana.25144
复制
发表时间：
2018-03
影响因子：
11.2
通讯作者：
Ottenheijm CAC
中科院分区：
文献类型：
--
作者：
Joureau B;de Winter JM;Conijn S;Bogaards SJP;Kovacevic I;Kalganov A;Persson M;Lindqvist J;Stienen GJM;Irving TC;Ma W;Yuen M;Clarke NF;Rassier DE;Malfatti E;Romero NB;Beggs AH;Ottenheijm CAC
线状肌病 (NM) 是最常见的先天性非营养不良性肌病之一，其特征是肌肉无力，通常从出生起就出现。 ACTA1 突变是 NM（即 NEM3）的常见原因。 ACTA1 编码 α-肌动蛋白 1，它是肌节细丝的主要成分。 ACTA1 突变导致 NEM3 肌无力的机制尚不完全清楚。我们假设肌节功能障碍导致 NEM3 患者肌肉无力。为了检验这一假设，我们对从 14 名具有不同 ACTA1 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。为了确定收缩性受损的结构基础，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最大发力能力降低，这是由大多数患者的肌节收缩力功能失调引起的，正如肌原纤维收缩力测量所揭示的那样。小角度 X 射线衍射和受激发射损耗显微镜表明，NEM3 患者的肌小节收缩力功能障碍涉及肌肉激活过程中与肌动蛋白结合的肌球蛋白头数量较少。这个较低的数字并不是细丝长度减少的结果。有趣的是，一些患者的钙对力的敏感性不受影响，但另一些患者则下降。因此，功能失调的肌节收缩力是大多数 NEM3 患者肌肉无力的重要原因，这一信息对于未来临床试验中的患者分层至关重要。
Nemaline myopathy (NM) is one of the most common congenital non-dystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (i.e. 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 fourteen 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. Thus, dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients, information which is crucial for patient stratification in future clinical trials.
登录
查看更多内容
影响因子：
12.7
作者：
Lindqvist, Johan;Penisson-Besnier, Isabelle;Ochala, Julien
通讯作者：
Ochala, Julien
影响因子：
4
作者：
de Winter JM;Buck D;Hidalgo C;Jasper JR;Malik FI;Clarke NF;Stienen GJ;Lawlor MW;Beggs AH;Ottenheijm CA;Granzier H
通讯作者：
Granzier H
影响因子：
2.8
作者：
Hutchinson, DO;Charlton, A;North, KN
通讯作者：
North, KN
影响因子：
11.2
作者：
Lindqvist J;Levy Y;Pati-Alam A;Hardeman EC;Gregorevic P;Ochala J
通讯作者：
Ochala J
DOI：
10.1097/nen.0b013e318293b1cc
发表时间：
2013-06-01
影响因子：
3.2
作者：
Lindqvist, Johan;Cheng, Arthur J.;Ochala, Julien
通讯作者：
Ochala, Julien