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Nat Commun. 2018 Sep 27;9(1):3950. doi: 10.1038/s41467-018-06267-1.

Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy.

Author information

1
Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 80078, Pozzuoli, Italy. fabio.iannotti@icb.cnr.it.
2
Department of Pharmacy, University of Naples Federico II, 80131, Naples, Italy.
3
Institute of Genetics and Biophysics, National Research Council (CNR), 80131, Naples, Italy.
4
Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 80078, Pozzuoli, Italy.
5
IRCCS Fondazione Santa Lucia Rome, 00143, Rome, Italy.
6
Gaslini Children's Hospital, L.go Gaslini 5, 16147, Genova, Italy.
7
Muscle Research Unit, Experimental and Clinical Research Center, Charit ´Universitätsmedizin and Max Delbrück Center, Berlin, 13092, Germany.
8
Department of Neuroscience Biomedicine and Movement, Section of Physiology and Psychology, University of Verona, 37134, Verona, Italy.
9
Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.
10
Department of Agricultural Sciences, University of Naples Federico II, Portici, 80055, Italy.
11
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
12
Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), 80078, Pozzuoli, Italy. vdimarzo@icb.cnr.it.
13
Canada Excellence Research Chair, Institut Universitaire de Cardiologie et de Pneumologie de Québec and Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC, G1V 0A6, Canada. vdimarzo@icb.cnr.it.

Abstract

The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. However, the potential role of endocannabinoids in skeletal muscle disorders remains unknown. Here we report the role of the endocannabinoid CB1 receptors in Duchenne's muscular dystrophy. In murine and human models, CB1 transcripts show the highest degree of expression at disease onset, and then decline overtime. Similar changes are observed for PAX7, a key regulator of muscle stem cells. Bioinformatics and biochemical analysis reveal that PAX7 binds and upregulates the CB1 gene in dystrophic more than in healthy muscles. Rimonabant, an antagonist of CB1, promotes human satellite cell differentiation in vitro, increases the number of regenerated myofibers, and prevents locomotor impairment in dystrophic mice. In conclusion, our study uncovers a PAX7-CB1 cross talk potentially exacerbating DMD and highlights the role of CB1 receptors as target for potential therapies.

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