Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, 70 Ship St, Providence, RI, 02903, USA.
Pathobiology Graduate Program, Brown University, Providence, RI, USA.
Skelet Muscle. 2024 May 17;14(1):10. doi: 10.1186/s13395-024-00342-6.
Loss-of-function mutations in MEGF10 lead to a rare and understudied neuromuscular disorder known as MEGF10-related myopathy. There are no treatments for the progressive respiratory distress, motor impairment, and structural abnormalities in muscles caused by the loss of MEGF10 function. In this study, we deployed cellular and molecular assays to obtain additional insights about MEGF10-related myopathy in juvenile, young adult, and middle-aged Megf10 knockout (KO) mice. We found fewer muscle fibers in juvenile and adult Megf10 KO mice, supporting published studies that MEGF10 regulates myogenesis by affecting satellite cell differentiation. Interestingly, muscle fibers do not exhibit morphological hallmarks of atrophy in either young adult or middle-aged Megf10 KO mice. We next examined the neuromuscular junction (NMJ), in which MEGF10 has been shown to concentrate postnatally, using light and electron microscopy. We found early and progressive degenerative features at the NMJs of Megf10 KO mice that include increased postsynaptic fragmentation and presynaptic regions not apposed by postsynaptic nicotinic acetylcholine receptors. We also found perisynaptic Schwann cells intruding into the NMJ synaptic cleft. These findings strongly suggest that the NMJ is a site of postnatal pathology in MEGF10-related myopathy. In support of these cellular observations, RNA-seq analysis revealed genes and pathways associated with myogenesis, skeletal muscle health, and NMJ stability dysregulated in Megf10 KO mice compared to wild-type mice. Altogether, these data provide new and valuable cellular and molecular insights into MEGF10-related myopathy.
MEGF10 功能丧失突变导致一种罕见且研究不足的神经肌肉疾病，称为 MEGF10 相关肌病。目前尚无针对 MEGF10 功能丧失导致的进行性呼吸窘迫、运动障碍和肌肉结构异常的治疗方法。在这项研究中，我们使用细胞和分子测定法获得了有关幼年、年轻成年和中年 Megf10 敲除 (KO) 小鼠的 MEGF10 相关肌病的更多见解。我们发现幼年和成年 Megf10 KO 小鼠的肌肉纤维较少，这支持了 MEGF10 通过影响卫星细胞分化来调节肌发生的已发表研究。有趣的是，无论是年轻成年还是中年 Megf10 KO 小鼠，肌肉纤维都没有表现出萎缩的形态特征。接下来，我们使用光镜和电子显微镜检查了神经肌肉接头 (NMJ)，在该接头中，MEGF10 已被证明在出生后集中存在。我们发现 Megf10 KO 小鼠的 NMJ 存在早期和进行性退行性特征，包括突触后片段增加和突触前区域未被突触后烟碱型乙酰胆碱受体对接。我们还发现周围神经节施万细胞侵入 NMJ 突触裂隙。这些发现强烈表明 NMJ 是 MEGF10 相关肌病的出生后病理学部位。支持这些细胞观察结果，RNA-seq 分析显示与肌发生、骨骼肌健康和 NMJ 稳定性相关的基因和途径在 Megf10 KO 小鼠中与野生型小鼠相比失调。总之，这些数据为 MEGF10 相关肌病提供了新的有价值的细胞和分子见解。
