Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs
Francesca Solagna, … , Ketan Patel, Tobias B. Huber
Francesca Solagna, … , Ketan Patel, Tobias B. Huber
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e135821. https://doi.org/10.1172/JCI135821.
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Research Article Muscle biology Nephrology

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

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.

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

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Figure 7

Pharmacological inhibition of activin restores protein synthesis while inhibiting protein breakdown.

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Pharmacological inhibition of activin restores protein synthesis while i...
(A and B) Activin A, IL-6, and corticosterone blood level determined by ELISA in WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice. A: WT n = 3, Kif3aΔTub n = 5, Kif3aΔTub sActRIIB n = 5.B left panel: WT n = 4, Kif3aΔTub n = 4, Kif3aΔTub sActRIIB n = 4.B right panel: WT n = 10, Kif3aΔTub n = 8, Kif3aΔTub sActRIIB n = 10. (C and D) Total protein extracts from muscle of 6-week-old WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice were immunoblotted with the indicated antibodies (n = 3 mice). (E) Quantification of puromycin incorporation in GC muscle from 6-week-old WT Kif3aΔTub and Kif3aΔTub sActRIIB mice, using in vivo SUnSET technique (n = 3 mice). (F and G) Total protein extracts from muscle of 6-week-old WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice were immunoblotted with the indicated antibodies (n = 3 mice). (H) Autophagy flux analysis with colchicine treatment. Immunoblot analysis of p62 and LC3 of protein extracts from GC muscles from fed and starved 6-week-old WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice (n = 3 mice). Values are mean ± SEM. Comparisons of more than 2 groups were calculated using 1-way ANOVA with Tukey’s multiple-comparison tests. *P < 0.05, **P < 0.01, ***P < 0.001. In H, only statistically significant comparisons are shown.