Jenni Laitila, Robert A. E. Seaborne, Natasha Ranu, Justin S. Kolb, Carina Wallgren-Pettersson, Nanna Witting, John Vissing, Juan Jesus Vilchez, Edmar Zanoteli, Johanna Palmio, Sanna Huovinen, Henk Granzier, Julien Ochala
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We first conducted <i>in vitro</i> experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term <i>in vivo</i> effects using the conditional nebulin knockout (c<i>Neb</i> 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 c<i>Neb</i> 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 c<i>Neb</i> KO mice. Taken together, our findings emphasize Mavacamten potency <i>in vitro</i> but challenge its short-term efficacy <i>in vivo</i>.\n\n <figure>\n <div><picture>\n <source></source></picture><p></p>\n </div>\n </figure>\n </div>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins.</li>\n \n <li>Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances.</li>\n \n <li>Treating a mouse model of nemaline myopathy <i>in vivo</i> with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins.</li>\n \n <li>Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":"602 20","pages":"5229-5245"},"PeriodicalIF":4.7000,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1113/JP286870","citationCount":"0","resultStr":"{\"title\":\"Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle\",\"authors\":\"Jenni Laitila, Robert A. 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引用次数: 0
摘要
内膜性肌病(Nemaline myopathy,NM)是一种遗传性肌肉疾病,主要由 NEB 基因突变(NEB-NM)引起,肌肉肌球蛋白功能障碍是其主要的分子致病机制。最近,我们观察到 NEB-NM 中肌球蛋白生化超松弛状态明显受损,诱发 ATP 消耗异常增加和病变肌纤维能量蛋白组重塑。众所周知,小分子 Mavacamten 可促进肌球蛋白超松弛状态并减少 ATP 需求,因此我们测试了其在 NEB-NM 中的有效性。我们首先在分离的患者单个肌纤维中进行了体外实验,发现 Mavacamten 成功逆转了肌球蛋白 ATP 过度消耗。随后,我们使用条件性神经球蛋白基因敲除(cNeb KO)小鼠模型评估了它的短期体内效应,并随后在解剖的比目鱼肌纤维中进行了全局蛋白质组学分析。经过 4 周的治疗后,我们在 cNeb KO 小鼠及其野生型同胞中观察到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,这表明短期的马伐卡滕治疗不足以适当平衡 cNeb KO 小鼠代谢失调的蛋白质组。综上所述,我们的研究结果强调了 Mavacamten 在体外的有效性,但对其在体内的短期疗效提出了质疑。要点:神经性肌病是一种遗传性骨骼肌疾病,主要由编码肌丝蛋白的基因突变引起,目前尚无治疗方法。将直接靶向肌丝的小分子 Mavacamten 应用于人类患者的分离膜过滤肌纤维,可恢复肌球蛋白的能量紊乱。用 Mavacamten 对神经性肌病小鼠模型进行为期 4 周的体内治疗后,骨骼肌纤维蛋白质组发生了重塑,但对高能蛋白质没有产生任何明显影响。短期 Mavacamten 治疗可能不足以逆转神经性肌病的肌肉表型。
Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle
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.
期刊介绍:
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