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 5

Skeletal muscle atrophy and accumulation of activin A in the blood are common features of different models of kidney fibrosis.

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Skeletal muscle atrophy and accumulation of activin A in the blood are c...
(A) Schematic representation of 2,8-DHA nephropathy model (AN): mice are fed for 21 days with adenine-enriched diet. (B) BUN measurement (n = 5 mice). (C) Body weight (D) and lean mass curve in WT and AN mice (n = 5 mice). (E) GC muscle weights (n = 5 mice). (F) Frequency histogram showing the distribution of cross-sectional areas (μm2) in TA of WT and AN mice (n = 4 mice). (G) Electron micrographs of EDL muscles of WT and AN mice. Scale bar: 2 μm. (H) Quantification of SS and IMF mitochondrial density and size. One-way ANOVA followed by Bonferroni’s multiple-comparison tests. (I) Quantitative RT-PCR analysis of Inhba in different organs (n = 5 mice). (J) In situ hybridization was performed with an RNAscope probe targeting Inhba mRNA. Representative images of WT and AN kidney. Inhba mRNA shown in green and nuclei counterstained with DAPI (blue). Scale bars: 10 μm. (K) Blood levels of activin A in WT and AN mice determined by ELISA (n = 5 mice). Values are mean ± SEM. Student’s t test used for statistical significance, unless otherwise stated. *P < 0.05, **P < 0.01, ***P < 0.001.