Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.
Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs.
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DOI：
10.1210/endrev/bnab030
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发表时间：
2022-03-09
影响因子：
20.3
通讯作者：
Ward CW
中科院分区：
文献类型：
--
作者：
Rodgers BD;Ward CW
肌肉萎缩性疾病指征是最令人衰弱和往往致命的非传染性疾病状态之一。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、慢性肺和肾脏疾病、周围神经病变、炎症性疾病以及肌肉骨骼损伤有关。目前的治疗策略相对无效，充其量只能限制肌肉退化的速度。这包括营养补充剂和食欲刺激剂以及能够加剧肌肉损失的免疫抑制剂。可以说，开发中最有希望的治疗方法试图破坏肌肉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，几项研究证明了“抑制抑制剂”的临床潜力，增加肌细胞蛋白质合成，减少降解，增强线粒体生物合成，并保护肌肉功能。这些变化可以防止各种疾病动物模型中的肌肉萎缩，但许多靶向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，更常见的是，失败是由于尽管保留了肌肉质量，但无法改善肌肉功能。仍在开发中的药物包括抗体和基因治疗剂，它们都具有不同的靶点，因此，安全性，有效性和拟议的使用概况。每一种都是独特的设计，如果成功的话，可以彻底改变急性和慢性肌肉萎缩的治疗。它们也可以与其他正在开发的治疗方法结合使用，用于相关的肌肉病理甚至代谢疾病。
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 because 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.
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影响因子：
3.4
作者：
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通讯作者：
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