Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
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DOI：
10.1097/nen.0b013e318293b1cc
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发表时间：
2013-06-01
影响因子：
3.2
通讯作者：
Ochala, Julien
中科院分区：
文献类型：
--
作者：
Lindqvist, Johan;Cheng, Arthur J.;Ochala, Julien
杆状体肌病是最常见的先天性肌病，由多种基因（如编码骨骼肌α -肌动蛋白的ACTA1基因）突变引起。它与肢体和呼吸肌的无力相关。尽管临床和科研关注度不断提高，但导致这种肌无力的分子和细胞事件仍然未知，这阻碍了特异性治疗干预措施的发展。为了揭示相关的潜在机制，我们从一种表达在人类患者中发现的ACTA1 His40Tyr肌动蛋白突变的严重杆状体肌病敲入小鼠模型中解剖了下肢和膈肌。然后我们研究了广泛的结构和功能特性，评估了单肌纤维收缩、蛋白质表达和电子显微镜观察。在膈肌中的一个主要发现是存在大量无收缩区域（包括破坏的肌节结构和杆状体）。这大大减少了功能性肌节的数量，降低了肌纤维水平的力量产生能力，并且很可能导致呼吸肌无力。相比之下，在肢体肌肉中，无收缩区域较少，并且它们似乎在肌无力的发病机制中没有主要作用。这些不同的肌肉特异性结果为严重杆状体肌病的病理生理学提供了新的重要见解，并为未来治疗策略的发展提供了关键信息。
Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.