Abstract/Summary

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 factors, including 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 of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors combined with lack of kidney clearance facilitate a vicious signalling kidney-muscle cycle, leading to an exacerbated blood accumulation, and thereby skeletal muscle wasting. Systemic pharmacological blockade of Activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific AAV-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that Activin A is a key step in CKD-induced cachexia. In summary, we uncover a previously unrecognized crosstalk between kidney and muscle and propose modulation of Activin signalling as a potential therapeutic strategy for skeletal muscle wasting in CKD.