Universite Pierre et Marie Curie, Institut de Myologie, Unite mixte de recherche UPMC-AIM UM 76, INSERM U 974, CNRS UMR 7215, 47-83, boulevard de l'Hopital, 75651 Paris Cedex 13, France.
Curr Gene Ther. 2012 Jun;12(3):245-59. doi: 10.2174/156652312800840577.
Since the discovery of the myostatin/ActRIIB signaling pathway 15 years ago, numerous strategies were developed to block its inhibitory function during skeletal muscle growth. Accumulating evidence demonstrates that abrogation of myostatin/ActRIIB signaling ameliorates pathology and function of dystrophic muscle in animal models for Duchenne muscular dystrophy (DMD). Therapeutic trials in healthy man and muscular dystrophy patients suggest feasibility of blockade strategies for potential clinical use. However, many key questions on the effect of myostatin/ActRIIB blockade remain unresolved; such as the underlying molecular mechanism that triggers muscle growth, the effect on muscle regeneration and adult muscle stem cell regulation and whether it causes long term metabolic alterations. Current therapeutic strategies aim to systemically abrogate myostatin/ActRIIB signaling. Although this ensures widespread effect on musculature, it also interferes with ActRIIB signaling in other tissues than skeletal muscle, thereby risking adverse effects. This review discusses current knowledge on myostatin/ActRIIB signaling and its potential value as a therapeutic target for DMD.
自 15 年前发现肌肉生长抑制素/ActRIIB 信号通路以来，人们已经开发出许多策略来阻断其在骨骼肌生长过程中的抑制功能。越来越多的证据表明，阻断肌肉生长抑制素/ActRIIB 信号可以改善杜氏肌营养不良症（DMD）动物模型中肌肉的病理和功能。在健康人和肌肉疾病患者中的治疗试验表明，阻断策略具有潜在的临床应用可行性。然而，肌肉生长抑制素/ActRIIB 阻断的许多关键问题仍然没有得到解决；例如，触发肌肉生长的潜在分子机制、对肌肉再生和成年肌肉干细胞调节的影响，以及是否会导致长期代谢改变。目前的治疗策略旨在系统地阻断肌肉生长抑制素/ActRIIB 信号。尽管这确保了对肌肉的广泛作用，但它也会干扰骨骼肌以外的其他组织中的 ActRIIB 信号，从而有产生不良反应的风险。这篇综述讨论了目前关于肌肉生长抑制素/ActRIIB 信号的知识及其作为 DMD 治疗靶点的潜在价值。
