Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.
PharmaFox Therapeutics AG, Möhlin, Aargau, Switzerland.
PLoS One. 2020 Mar 11;15(3):e0228653. doi: 10.1371/journal.pone.0228653. eCollection 2020.
Current efforts to improve muscle performance are focused on muscle trophism via inhibition of the myostatin pathway: however they have been unsuccessful in the clinic to date. In this study, a novel protein has been created by combining the soluble activin receptor, a strong myostatin inhibitor, to the C-terminal agrin nLG3 domain (ActR-Fc-nLG3) involved in the development and maintenance of neuromuscular junctions. Both domains are connected via the constant region of an Igg1 monoclonal antibody. Surprisingly, young male mice treated with ActR-Fc-nLG3 showed a remarkably increased endurance in the rotarod test, significantly longer than the single domain compounds ActR-Fc and Fc-nLG3 treated animals. This increase in endurance was accompanied by only a moderate increase in body weights and wet muscle weights of ActR-Fc-nLG3 treated animals and were lower than expected. The myostatin inhibitor ActR-Fc induced, as expected, a highly significant increase in body and muscle weights compared to control animals and ActR-Fc-nLG3 treated animals. Moreover, the prolonged endurance effect was not observed when ActR-Fc and Fc-nLG3 were dosed simultaneously as a mixture and the body and muscle weights of these animals were very similar to ActR-Fc treated animals, indicating that both domains need to be on one molecule. Muscle morphology induced by ActR-Fc-nLG3 did not appear to be changed however, close examination of the neuromuscular junction showed significantly increased acetylcholine receptor surface area for ActR-Fc-nLG3 treated animals compared to controls. This result is consistent with published observations that endurance training in rats increased acetylcholine receptor quantity at neuromuscular junctions and provide evidence that improving nerve-muscle interaction could be an important factor for sustaining long term muscle activity.
目前，提高肌肉性能的努力集中在通过抑制肌肉生长抑制素途径来促进肌肉营养上：然而，迄今为止，它们在临床上尚未取得成功。在这项研究中，通过将可溶性激活素受体（一种强大的肌肉生长抑制素抑制剂）与参与神经肌肉接头发育和维持的 agrin nLG3 结构域（ActR-Fc-nLG3）相结合，创造了一种新型蛋白质。这两个结构域通过 IgG1 单克隆抗体的恒定区连接。令人惊讶的是，用 ActR-Fc-nLG3 治疗的年轻雄性小鼠在转棒试验中表现出显著的耐力增强，明显长于单独用 ActR-Fc 和 Fc-nLG3 治疗的动物。这种耐力的增加仅伴随着 ActR-Fc-nLG3 治疗动物的体重和湿肌肉重量的适度增加，并且低于预期。如预期的那样，肌肉生长抑制素抑制剂 ActR-Fc 与对照动物和 ActR-Fc-nLG3 治疗动物相比，显著增加了体重和肌肉重量。此外，当 ActR-Fc 和 Fc-nLG3 同时作为混合物给药时，并未观察到延长的耐力效应，并且这些动物的体重和肌肉重量与 ActR-Fc 治疗动物非常相似，表明两个结构域需要在一个分子上。然而，ActR-Fc-nLG3 诱导的肌肉形态似乎没有改变，但是，对神经肌肉接头的仔细检查表明，与对照动物相比，ActR-Fc-nLG3 治疗动物的乙酰胆碱受体表面积显著增加。这一结果与发表的观察结果一致，即大鼠的耐力训练增加了神经肌肉接头处的乙酰胆碱受体数量，并提供了证据表明，改善神经肌肉相互作用可能是维持长期肌肉活动的一个重要因素。
