PDF(Pubmed)
Abstract：
Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.
摘要：
网状肌病是最常见的先天性肌病。ACTA1（NEM3）的变体占所有线虫肌病病例的15-25％。具有ACTA1变异的患者表现出异质性疾病过程，其特征是稳定或进行性肌肉无力，在严重的情况下，呼吸衰竭和死亡。迄今为止,没有具体的治疗方法。由于NEM3是一种基于肌动蛋白的细丝疾病，我们测试了Tirasemtiv的能力,一种快速的骨骼肌肌钙蛋白激活剂，在NEM3小鼠模型中改善骨骼肌功能，在Acta1中包含基于患者的p.Asp286Gly变体。急性和长期的tirasemtiv治疗显着增加了快速抽搐的趾长伸肌和腓肠肌在亚最大刺激频率下的肌肉收缩能力，在体外和体内的中间抽搐diaphragm肌。此外,在NEM3小鼠中长期的tirasemtiv治疗导致呼吸频率降低，保持每分钟的体积，建议更有效的呼吸。总之,我们的数据支持快速骨骼肌肌钙蛋白激活剂在减轻由Acta1:p引起的NEM3小鼠模型中的骨骼肌无力方面的治疗潜力.Asp286Gly变体。
