Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified an increased production and elevated blood levels of soluble pro-cachectic factor Activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single cell sequencing data identified the expression of Activin A in specific kidney cell populations, namely a subpopulation of fibroblasts and cells of the juxtaglomerular apparatus. Based on our findings, we propose that persistent and increased kidney production of pro-cachectic factors combined with a lack of kidney clearance facilitate a vicious signalling kidney-muscle cycle, leading to exacerbated blood accumulation of Activin A, and thereby skeletal muscle wasting in CKD.

骨骼肌消耗常与慢性肾脏病（chronic kidney disease, CKD）相关，可导致发病率与死亡率升高。然而，肾脏与肌肉功能之间的关联机制仍未得到充分阐释。本研究采用互补性器官间研究方法，探究慢性肾脏病中的骨骼肌消耗现象。研究发现，可溶性促恶病质因子激活素A（Activin A）的生成量增加且血液水平升高，直接将实验性与人类慢性肾脏病关联至骨骼肌消耗程序。单细胞测序数据显示，激活素A在特定肾脏细胞群中存在表达，具体为成纤维细胞亚群与肾小球旁器细胞。基于本研究结果，我们提出：促恶病质因子的肾脏生成持续增加，加之肾脏清除功能不足，共同促成了恶性循环的肾脏-肌肉信号环路，导致激活素A的血液蓄积加剧，进而引发慢性肾脏病患者的骨骼肌消耗。