Abstract

Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders and of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling as these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors”, increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.

中文翻译：

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肌肉中肌生长抑制素/激活素受体配体及减毒药物的开发现状

 抽象的

肌肉萎缩疾病是最使人衰弱且往往致命的非传染性疾病之一。作为一种合并症，肌肉萎缩与不同的神经肌肉疾病和肌病、癌症、心力衰竭、慢性肺病和肾病、周围神经病、炎症性疾病，当然还有肌肉骨骼损伤有关。目前的治疗策略相对无效，最多只能限制肌肉退化的速度。这包括营养补充剂和食欲兴奋剂以及能够加剧肌肉损失的免疫抑制剂。可以说，正在开发的最有希望的治疗方法试图破坏肌生长抑制素和激活素受体信号传导，因为这些循环因子是肌肉生长的有效抑制剂和肌肉祖细胞分化的调节剂。事实上，一些研究证明了“抑制抑制剂”、增加肌肉细胞蛋白质合成、减少降解、增强线粒体生物发生和保持肌肉功能的临床潜力。这些变化可以防止各种疾病动物模型中的肌肉萎缩，但许多针对该途径的药物在临床试验中失败，其中一些是由于严重的治疗相关不良事件和脱靶相互作用。然而，更常见的情况是，尽管保留了肌肉质量，但仍无法改善肌肉功能而导致失败。仍在开发的药物包括抗体和基因疗法，它们都有不同的靶点，因此安全性、有效性和建议的用途也不同。每一种产品的设计都是独一无二的，如果成功的话，可能会彻底改变急性和慢性肌肉萎缩的治疗方法。 它们还可以与其他正在开发的治疗相关肌肉病理甚至代谢疾病的疗法结合使用。