PDF(Pubmed)
Abstract：
Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of \"nemaline bodies\" (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients\' fibroblasts were stained with rhodamine-phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients\' fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.
摘要：
神经肌病（NM）是先天性肌病的最常见形式之一，通过组织病理学检查发现肌纤维中存在“线虫体”（棒）。最常见的NM形式是由肌动蛋白α1（ACTA1）和星云蛋白（NEB）基因突变引起的。临床特征包括张力减退和肌肉无力。不幸的是,目前尚无治愈性治疗,发病机制尚不清楚.在这份手稿中,我们使用来自ACTA1和NEB基因突变患者的真皮成纤维细胞检测了NM的病理生理改变.患者的成纤维细胞用罗丹明-phalloidin染色，通过荧光显微镜分析肌动蛋白丝的聚合。我们发现，与对照成纤维细胞相比，患者成纤维细胞显示出不正确的肌动蛋白丝聚合。肌动蛋白丝聚合缺陷与线粒体功能障碍有关。此外，我们确定了两种增强线粒体的化合物，亚油酸（LA）和左旋肉碱（LCAR），这改善了突变成纤维细胞中肌动蛋白丝的形成并校正了线粒体生物能学。我们的结果表明，细胞模型可用于研究NM涉及的病理生理机制并找到新的潜在疗法。此外，用LA和LCAR靶向线粒体功能障碍可以逆转NM细胞模型中的病理改变。
