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

Francesca Solagna,Dominik Kylies,Elion Hoxha,Tobias B Huber,Marco Sandri,Ketan Patel,Peter Boor,Yu Zhao,Rajasree Menon,Maja T Lindenmeyer,Tammo Ostendorf,Shuya Liu,Antonios Matsakas,Nicola Wanner,Viji Nair,Saleh Omairi,Ina V Martin,Barbara M Klinkhammer,Matthias Kretzler,Felix Eichinger,Shun Lu,Charlotte Meyer,Guochao Wu,Olli Ritvos,Julian Schulze Zur Wiesch,Clemens D Cohen,Oliver Kretz,Andrea Paolini,Temel Kilic,Caterina Tezze,Arja Pasternack,Victor G Puelles,Pierre‐Louis Tharaux ,Jan Eric Turner ,Robert D Mitchell

doi:10.1172/jci135821

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.

Highlights

Chronic kidney disease (CKD) affects approximately 10%–15% of the world’s population [1] and represents a state of progressive and irreversible loss of kidney function [2]
We identified a strong reduction in mRNA levels of insulin-like growth factor 1 (Igf1), a key regulator of cellular proliferation, in muscles from Kif3aΔTub compared with WT mice
We found that inhibin beta-A (Inhba) was expressed in a subpopulation of fibroblasts, which was only found in the Kif3aΔTub kidney, and in cells from the juxtaglomerular apparatus (Figure 3D)

Summary

Introduction

Chronic kidney disease (CKD) affects approximately 10%–15% of the world’s population [1] and represents a state of progressive and irreversible loss of kidney function [2]. Two-thirds of adults living with CKD show signs of cachexia [3], a wasting syndrome characterized by progressive depletion of skeletal muscle mass that significantly increases morbidity and mortality and compromises patients’ quality of life because of loss of autonomy and fatigue [4, 5]. The kidney plays a pivotal role in the maintenance of body homeostasis, by regulating blood pressure and fluid balance and clearing waste products, and by acting as a major endocrine organ [8]. A direct association between kidney damage and muscle wasting is yet to be established

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Results

Conclusion