RANKL Inhibition Reduces Cardiac Hypertrophy in <i>mdx</i> Mice and Possibly in Children with Duchenne Muscular Dystrophy
Laetitia Marcadet,
Emma Sara Juracic,
Nasrin Khan,
Zineb Bouredji,
Hideo Yagita,
Leanne M. Ward,
A. Russell Tupling,
Anteneh Argaw,
Jérôme Frenette
Affiliations
Laetitia Marcadet
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l’Université Laval (CHUQ-CHUL), Axe Neurosciences, Université Laval, Quebec City, QC G1V 4G2, Canada
Emma Sara Juracic
Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, ON N2L 3G1, Canada
Nasrin Khan
The Ottawa Pediatric Bone Health Research Group, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Zineb Bouredji
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l’Université Laval (CHUQ-CHUL), Axe Neurosciences, Université Laval, Quebec City, QC G1V 4G2, Canada
Hideo Yagita
Department of Immunology, School of Medicine, Juntendo University, Tokyo 113-8421, Japan
Leanne M. Ward
The Ottawa Pediatric Bone Health Research Group, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
A. Russell Tupling
Department of Kinesiology and Health Sciences, University of Waterloo, Waterloo, ON N2L 3G1, Canada
Anteneh Argaw
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l’Université Laval (CHUQ-CHUL), Axe Neurosciences, Université Laval, Quebec City, QC G1V 4G2, Canada
Jérôme Frenette
Centre Hospitalier Universitaire de Québec, Centre de Recherche du Centre Hospitalier de l’Université Laval (CHUQ-CHUL), Axe Neurosciences, Université Laval, Quebec City, QC G1V 4G2, Canada
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.
