Department of Nephrology, Xuanwu Hospital Capital Medical University, 45 Changchun Street, Xicheng District, Beijing, 10000, China.
Calcif Tissue Int. 2024 Nov;115(5):712-724. doi: 10.1007/s00223-024-01283-4. Epub 2024 Sep 16.
Muscle atrophy is a common complication of chronic kidney disease (CKD). Irisin, a novel muscle cytokine, protects against muscle atrophy, but its specific role in CKD-associated muscle atrophy requires further elucidation. Because the ubiquitin-proteasome system (UPS) plays an important role in CKD muscle atrophy, our study will explore whether irisin affects UPS and alleviate CKD-associated muscle atrophy. In this study, an adenine-fed mouse model of CKD and urotension II (UII)-induced C2C12 myotubes were used as in vivo and in vitro models of muscle atrophy. The results showed that renal function, mouse weight, and the cross-sectional area (CSA) of skeletal muscles were significantly improved in CKD mice treated with irisin. Moreover, irisin effectively mitigated the decreases in phosphorylated Forkhead box O 3a (p-FOXO3A) levels and increases in the levels of E3 ubiquitin ligases, such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin1), in both the muscles of CKD mice and UII-induced C2C12 myotubes. In addition, irisin significantly increased the expression levels of myogenic differentiation factor D (MyoD) in the muscles of CKD mice. Our study is the first to demonstrate that irisin ameliorates skeletal muscle atrophy by inhibiting UPS upregulation and improving satellite cell differentiation in CKD.
肌肉萎缩是慢性肾脏病（CKD）的常见并发症。鸢尾素是一种新型的肌肉细胞因子，可预防肌肉萎缩，但它在 CKD 相关肌肉萎缩中的具体作用仍需进一步阐明。由于泛素-蛋白酶体系统（UPS）在 CKD 肌肉萎缩中发挥着重要作用，我们的研究将探讨鸢尾素是否会影响 UPS 并减轻 CKD 相关的肌肉萎缩。在这项研究中，腺嘌呤喂养的 CKD 小鼠模型和尾加压素 II（UII）诱导的 C2C12 肌管被用作肌肉萎缩的体内和体外模型。结果表明，用鸢尾素治疗 CKD 小鼠可显著改善肾功能、小鼠体重和骨骼肌横截面积（CSA）。此外，鸢尾素可有效减轻 CKD 小鼠肌肉和 UII 诱导的 C2C12 肌管中磷酸化叉头框 O3a（p-FOXO3A）水平降低和 E3 泛素连接酶（如肌肉环指蛋白 1（MuRF1）和肌肉萎缩 F 盒（MAFbx/atrogin1））水平升高。此外，鸢尾素可显著增加 CKD 小鼠肌肉中肌生成分化因子 D（MyoD）的表达水平。本研究首次证明，鸢尾素通过抑制 UPS 的上调和改善 CKD 中卫星细胞的分化来改善骨骼肌萎缩。
