Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
J Physiol. 2024 Oct;602(20):5229-5245. doi: 10.1113/JP286870. Epub 2024 Aug 31.
Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
先天性肌营养不良症（NM）是一种遗传性肌肉疾病，主要由 NEB 基因（NEB-NM）突变引起，其主要的分子发病机制是肌肉肌球蛋白功能障碍。最近，我们观察到 NEB-NM 中肌球蛋白生化超松弛状态显著受损，导致病变肌纤维中 ATP 消耗异常增加和能量蛋白质组重塑。由于小分子 Mavacamten 已知可促进肌球蛋白超松弛状态并降低 ATP 需求，我们在 NEB-NM 背景下测试了它的效力。我们首先在从患者中分离的单个肌纤维进行了体外实验，发现 Mavacamten 成功地逆转了肌球蛋白的 ATP 过度消耗。在此之后，我们使用条件性 nebulin 敲除（cNeb KO）小鼠模型评估了其短期体内效应，并随后对分离的比目鱼肌肌纤维进行了全蛋白质组学分析。经过 4 周的治疗期后，我们观察到 cNeb KO 小鼠及其野生型同窝仔鼠的大量蛋白质发生了重塑。然而，这些变化与能量蛋白质组无关，表明短期 Mavacamten 治疗不足以正确平衡 cNeb KO 小鼠代谢失调的蛋白质组。总之，我们的研究结果强调了 Mavacamten 在体外的效力，但挑战了其在体内的短期疗效。关键点：先天性肌营养不良症是一种遗传性骨骼肌疾病，主要源自编码肌丝蛋白的基因突变，目前尚无治愈方法。将小分子 Mavacamten 直接靶向肌丝应用于从人类患者分离的膜通透化肌纤维中，可恢复肌球蛋白的能量紊乱。用 Mavacamten 体内治疗先天性肌营养不良症的小鼠模型 4 周，重塑了骨骼肌纤维蛋白质组，但对能量蛋白没有明显影响。短期 Mavacamten 治疗可能不足以逆转先天性肌营养不良症的肌肉表型。
