Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs
Solagna, Francesca; Tezze, Caterina; Lindenmeyer, Maja T.; Lu, Shun; Wu, Guochao; Liu, Shuya; Zhao, Yu; Mitchell, Robert; Meyer, Charlotte; Omairi, Saleh; Kilic, Temel; Paolini, Andrea; Ritvos, Olli; Pasternack, Arja; Matsakas, Antonios; Kylies, Dominik; zur Wiesch, Julian Schulze; Turner, Jan Eric; Wanner, Nicola; Nair, Viji; Eichinger, Felix; Menon, Rajasree; Martin, Ina V.; Klinkhammer, Barbara M.; Hoxha, Elion; Cohen, Clemens D.; Tharaux, Pierre Louis; Boor, Peter; Ostendorf, Tammo; Kretzler, Matthias; Sandri, Marco; Kretz, Oliver; Puelles, Victor G.; Patel, Ketan; Huber, Tobias B.
Authors
Francesca Solagna
Caterina Tezze
Maja T. Lindenmeyer
Shun Lu
Guochao Wu
Shuya Liu
Yu Zhao
Robert Mitchell
Charlotte Meyer
Saleh Omairi
Temel Kilic
Andrea Paolini
Olli Ritvos
Arja Pasternack
Antonios Matsakas
Dominik Kylies
Julian Schulze zur Wiesch
Jan Eric Turner
Nicola Wanner
Viji Nair
Felix Eichinger
Rajasree Menon
Ina V. Martin
Barbara M. Klinkhammer
Elion Hoxha
Clemens D. Cohen
Pierre Louis Tharaux
Peter Boor
Tammo Ostendorf
Matthias Kretzler
Marco Sandri
Oliver Kretz
Victor G. Puelles
Ketan Patel
Tobias B. Huber
Abstract
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 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 a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to 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 adeno-associated virus–mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.
Citation
Solagna, F., Tezze, C., Lindenmeyer, M. T., Lu, S., Wu, G., Liu, S., Zhao, Y., Mitchell, R., Meyer, C., Omairi, S., Kilic, T., Paolini, A., Ritvos, O., Pasternack, A., Matsakas, A., Kylies, D., zur Wiesch, J. S., Turner, J. E., Wanner, N., Nair, V., …Huber, T. B. (2021). Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs. Journal of Clinical Investigation, 131(11), Article e135821. https://doi.org/10.1172/JCI135821
