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 6

Pharmacological inhibition of activin A prevents muscle wasting in experimental CKD.

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Pharmacological inhibition of activin A prevents muscle wasting in exper...
(A) Schematic representation of experimental design: treatment of WT and Kif3aΔTub mice twice weekly by intraperitoneal (i.p.) injections of vehicle treatment or 10 mg/kg sActRIIB starting at 2 weeks of age for 4 weeks. (B) Left panel: representative image of 6-week-old body size of WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice. Right panel: growth curve of WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice (n = 5 mice). (C) GC weight of WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice (n = 13 mice). (D) Analysis of the number of fibers per muscle in WT and Kif3aΔTub mice and Kif3aΔTub sActRIIB mice (n = 3 mice). (E) Frequency histogram showing the distribution of cross-sectional areas (μm2) in TA of WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice (n = 3 mice). (F) Quantification of satellite cell number on freshly isolated EDL fibers in WT and Kif3aΔTub mice and Kif3aΔTub sActRIIB mice (n = 2 mice). Data of WT and Kif3aΔTub have already been presented in Figure 2B. (G) Tetanic specific force measurement in EDL muscle of WT and Kif3aΔTub mice and Kif3aΔTub sActRIIB mice. Data of WT and Kif3aΔTub have already been presented in Figure 1H (n = 5 mice). (H) Quantification of SS and IMF mitochondrial density and size. One-way ANOVA followed by Bonferroni’s multiple-comparison tests. Data of WT and Kif3aΔTub have already been presented in Figure 2F (n = 3 mice). (I) Quantitative gene expression of UPRmt genes in GC muscle from 6-week-old WT, Kif3aΔTub, and Kif3aΔTub sActRIIB mice (n = 4 mice). Data shown as mean ± SEM of 3 independent experiments. Comparisons of more than 2 groups were calculated using 1-way ANOVA with Tukey’s multiple-comparison tests: *when comparing WT vs. Kif3aΔTub, §when comparing WT vs. Kif3aΔTub sActRIIB,#when comparing Kif3aΔTub vs. Kif3aΔTub sActRIIB. *,§,#P < 0.05, **,§§P < 0.01, ***,§§§,###P < 0.001.