Division of Pharmacodynamics, Keio University Faculty of Pharmacy, Tokyo, Japan.
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
J Cachexia Sarcopenia Muscle. 2023 Feb;14(1):553-564. doi: 10.1002/jcsm.13159. Epub 2022 Dec 23.
Targeting of the apelin-apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)-induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin-Apj system in CKD-induced skeletal muscle atrophy.
The 5/6-nephrectomized mice were used as CKD models. AST-120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1 μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD-induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro.
Skeletal muscle atrophy developed over time following nephrectomy at 12 weeks, as confirmed by a significant increase of atrogin-1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P < 0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P < 0.05) and elabela, another Apj endogenous ligand, tended to show a non-significant decrease at 12 weeks after nephrectomy. Administration of AST-120 inhibited the decline of muscle weight and increase of atrogin-1 and myostatin expression. Apelin and elabela expression was slightly improved by AST-120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0 μmol/kg for 4 weeks to CKD mice suppressed the increase of atrogin-1 and myostatin, increased apelin and Apj mRNA expression at 30 min after apelin administration and significantly ameliorated weight loss and a decrease of the cross-sectional area of hindlimb skeletal muscle.
This study demonstrated for the first time the association of the Apj endogenous ligand-uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin-Apj system.
靶向阿片肽-阿片肽受体（Apj）系统可能是治疗慢性肾脏病（CKD）引起的骨骼肌萎缩的一种有用的治疗干预手段。我们研究了阿片肽-Apj 系统在 CKD 引起的骨骼肌萎缩中的作用和疗效。
使用 5/6 肾切除术小鼠作为 CKD 模型。将 AST-120（一种尿毒症毒素的活性炭吸附剂（饮食中 8 w/w%））或阿片肽（1 μmol/kg）施用于 CKD 小鼠，以研究阿片肽对 CKD 引起的骨骼肌萎缩的机制和治疗潜力。使用体外小鼠成肌细胞（C2C12 细胞）评估尿毒症毒素吲哚硫酸或阿片肽对骨骼肌萎缩的影响。
肾切除术后 12 周，随着时间的推移，骨骼肌萎缩逐渐发展，胃（GA）肌中 atrogin-1 和肌生成素 mRNA 表达显著增加（P < 0.05、0.01 和 0.05），下肢骨骼肌重量下降（P < 0.05、0.01 和 0.05）。GA 肌肉中的阿片肽表达明显下降（P < 0.05），另一种 Apj 内源性配体 elabela 在肾切除后 12 周时也呈非显著下降趋势。AST-120 的给药抑制了肌肉重量的下降和 atrogin-1 和肌生成素表达的增加。AST-120 给药略微改善了阿片肽和 elabela 的表达，但 Apj 的表达没有改善，提示尿毒症毒素参与了内源性 Apj 配体的表达。在 CKD 小鼠中给予 1.0 μmol/kg 的阿片肽 4 周可抑制 atrogin-1 和肌生成素的增加，在给予阿片肽 30 分钟后增加阿片肽和 Apj mRNA 表达，并显著改善体重减轻和后肢骨骼肌横截面积减少。
本研究首次证明了 Apj 内源性配体-尿毒症毒素轴与 CKD 中的骨骼肌萎缩有关，并且治疗性靶向阿片肽-Apj 系统具有实用性。
