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.

We performed single-cell RNA sequencing on 5-week-old Kif3aΔTub and control kidneys.