RANKL Inhibition Reduces Cardiac Hypertrophy in mdx Mice and Possibly in Children with Duchenne Muscular Dystrophy.

Content Provider	Europe PMC
Author	Marcadet, Laetitia Juracic, Emma Sara Khan, Nasrin Bouredji, Zineb Yagita, Hideo Ward, Leanne M. Tupling, A. Russell Argaw, Anteneh Frenette, Jérôme
Editor	Schlüter, Klaus-Dieter
Copyright Year	2023
Abstract	Cardiomyopathy has become one of the leading causes of death in patients with Duchenne muscular dystrophy (DMD). We recently reported that the inhibition of the interaction between the receptor activator of nuclear factor κB ligand (RANKL) and receptor activator of nuclear factor κB (RANK) significantly improves muscle and bone functions in dystrophin-deficient mdx mice. RANKL and RANK are also expressed in cardiac muscle. Here, we investigate whether anti-RANKL treatment prevents cardiac hypertrophy and dysfunction in dystrophic mdx mice. Anti-RANKL treatment significantly reduced LV hypertrophy and heart mass, and maintained cardiac function in mdx mice. Anti-RANKL treatment also inhibited NFκB and PI3K, two mediators implicated in cardiac hypertrophy. Furthermore, anti-RANKL treatment increased SERCA activity and the expression of RyR, FKBP12, and SERCA2a, leading possibly to an improved Ca2+ homeostasis in dystrophic hearts. Interestingly, preliminary post hoc analyses suggest that denosumab, a human anti-RANKL, reduced left ventricular hypertrophy in two patients with DMD. Taken together, our results indicate that anti-RANKL treatment prevents the worsening of cardiac hypertrophy in mdx mice and could potentially maintain cardiac function in teenage or adult patients with DMD.
Journal	Cells
Volume Number	12
PubMed Central reference number	PMC10253225
Issue Number	11
PubMed reference number	37296659
e-ISSN	20734409
DOI	10.3390/cells12111538
Language	English
Publisher	MDPI
Publisher Date	2023-06-03
Access Restriction	Open
Rights License	Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). © 2023 by the authors.
Subject Keyword	RANK RANKL heart Duchenne muscular dystrophy cardiac hypertrophy
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology