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.
Iannotti, F. A., Pagano, E., Guardiola, O., Adinolfi, S., Saccone, V., Consalvi, S., Piscitelli, F., Gazzerro, E., Busetto, G., Carrella, D., Capasso, R., Puri, P. L., Minchiotti, G., Di Marzo, V., Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy, <<NATURE COMMUNICATIONS>>, 2018; 9 (1): 3950-N/A. [doi:10.1038/s41467-018-06267-1] [http://hdl.handle.net/10807/170573]
Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy
Saccone, V.;
2018
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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