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

Fabio A. Iannotti (), Ester Pagano, Ombretta Guardiola, Simone Adinolfi, Valentina Saccone, Silvia Consalvi, Fabiana Piscitelli, Elisabetta Gazzerro, Giuseppe Busetto, Diego Carrella, Raffaele Capasso, Pier Lorenzo Puri, Gabriella Minchiotti and Vincenzo Di Marzo ()
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Fabio A. Iannotti: National Research Council (CNR)
Ester Pagano: University of Naples Federico II
Ombretta Guardiola: National Research Council (CNR)
Simone Adinolfi: National Research Council (CNR)
Valentina Saccone: IRCCS Fondazione Santa Lucia Rome
Silvia Consalvi: IRCCS Fondazione Santa Lucia Rome
Fabiana Piscitelli: National Research Council (CNR)
Elisabetta Gazzerro: Gaslini Children’s Hospital
Giuseppe Busetto: University of Verona
Diego Carrella: Telethon Institute of Genetics and Medicine (TIGEM)
Raffaele Capasso: University of Naples Federico II
Pier Lorenzo Puri: IRCCS Fondazione Santa Lucia Rome
Gabriella Minchiotti: National Research Council (CNR)
Vincenzo Di Marzo: National Research Council (CNR)

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06267-1

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