Phocean Nephrology Institute, Clinique Bouchard, ELSAN, Marseille, France.
Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France.
Nephrol Dial Transplant. 2021 Nov 9;36(11):1986-1993. doi: 10.1093/ndt/gfaa129.
Chronic kidney disease (CKD) patients often exhibit a low muscle mass and strength, leading to physical impairment and an increased mortality. Two major signalling pathways control protein synthesis, the insulin-like growth factor-1/Akt (IGF-1/Akt) pathway, acting as a positive regulator, and the myostatin (Mstn) pathway, acting as a negative regulator. Mstn, also known as the growth development factor-8 (GDF-8), is a member of the transforming growth factor-β superfamily, which is secreted by mature muscle cells. Mstn inhibits satellite muscle cell proliferation and differentiation and induces a proteolytic phenotype of muscle cells by activating the ubiquitin-proteasome system. Recent advances have been made in the comprehension of the Mstn pathway disturbance and its role in muscle wasting during CKD. Most studies report higher Mstn concentrations in CKD and dialysis patients than in healthy subjects. Several factors increase Mstn production in uraemic conditions: low physical activity, chronic or acute inflammation and oxidative stress, uraemic toxins, angiotensin II, metabolic acidosis and glucocorticoids. Mstn seems to be only scarcely removed during haemodialysis or peritoneal dialysis, maybe because of its large molecule size in plasma where it is linked to its prodomain. In dialysis patients, Mstn has been proposed as a biomarker of muscle mass, muscle strength or physical performances, but more studies are needed in this field. This review outlines the interconnection between Mstn activation, muscle dysfunction and CKD. We discuss mechanisms of action and efficacy of pharmacological Mstn pathway inhibition that represents a promising treatment approach of striated muscle dysfunction. Many approaches and molecules are in development but until now, no study has proved a benefit in CKD.
慢性肾脏病（CKD）患者常表现出肌肉量和力量减少，导致身体功能受损和死亡率增加。两种主要的信号通路控制蛋白质合成，胰岛素样生长因子-1/ Akt（IGF-1/Akt）通路作为正调节剂，肌肉生长抑制素（Mstn）通路作为负调节剂。Mstn 也称为生长分化因子-8（GDF-8），是转化生长因子-β超家族的成员，由成熟的肌肉细胞分泌。Mstn 通过激活泛素-蛋白酶体系统抑制卫星肌细胞增殖和分化，并诱导肌肉细胞的蛋白水解表型。目前对 Mstn 通路紊乱及其在 CKD 肌肉减少症中的作用有了更多的了解。大多数研究报告称 CKD 和透析患者的 Mstn 浓度高于健康受试者。几种因素增加了尿毒症条件下 Mstn 的产生：低体力活动、慢性或急性炎症和氧化应激、尿毒症毒素、血管紧张素 II、代谢性酸中毒和糖皮质激素。Mstn 在血液透析或腹膜透析过程中似乎很少被清除，可能是因为其在血浆中的分子量较大，与前肽相连。在透析患者中，Mstn 被提议作为肌肉质量、肌肉力量或身体表现的生物标志物，但在这一领域还需要更多的研究。这篇综述概述了 Mstn 激活、肌肉功能障碍和 CKD 之间的相互关系。我们讨论了药理学 Mstn 通路抑制的作用机制和疗效，这代表了一种有前途的治疗横纹肌功能障碍的方法。许多方法和分子正在开发中，但到目前为止，在 CKD 中没有研究证明有任何益处。
