The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels

Fabio A. Iannotti, Cristoforo Silvestri, Enrico Mazzarella, Andrea Martella, Daniela Calvigioni, Fabiana Piscitelli, Paolo Ambrosino, Stefania Petrosino, G. Czifra, T. Bíró, Tibor Harkany, Maurizio Taglialatela, Vincenzo Di Marzo

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Abstract

Little is known of the involvement of endocannabinoids and cannabinoid receptors in skeletal muscle cell differentiation. We report that, due to changes in the expression of genes involved in its metabolism, the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are decreased both during myotube formation in vitro from murine C2C12 myoblasts and during mouse muscle growth in vivo. The endocannabinoid, as well as the CB1 agonist arachido-noyl- 2-chloroethylamide, prevent myotube formation in a manner antagonized by CB1 knockdown and by CB1 antagonists, which, per se, instead stimulate differentiation. Importantly, 2-AG also inhibits differentiation of primary human satellite cells. Muscle fascicles from CB1 knockout embryos contain more muscle fibers, and postnatal mice show muscle fibers of an increased diameter relative to wild-type littermates. Inhibition of K v7.4 channel activity, which plays a permissive role in myogenesis and depends on phosphatidylinositol 4,5-bisphosphate (PIP2), underlies the effects of 2-AG. We find that CB1 stimulation reduces both total and K v7.4-bound PIP2 levels in C2C12 cells and inhibits Kv7.4 currents in transfected CHO cells. We suggest that 2-AG is an endogenous repressor of myoblast differentiation via CB1-mediated inhibition of Kv7.4 channels.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number24
DOIs
Publication statusPublished - 2014

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Cannabinoid Receptor CB1
Endocannabinoids
Muscle Cells
Cell Differentiation
Skeletal Muscle
Muscles
Myoblasts
Skeletal Muscle Fibers
Cannabinoid Receptors
Muscle Development
CHO Cells
Phosphatidylinositols
Embryonic Structures
Gene Expression
2-arachidonylglycerol
Growth

ASJC Scopus subject areas

  • General

Cite this

The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels. / Iannotti, Fabio A.; Silvestri, Cristoforo; Mazzarella, Enrico; Martella, Andrea; Calvigioni, Daniela; Piscitelli, Fabiana; Ambrosino, Paolo; Petrosino, Stefania; Czifra, G.; Bíró, T.; Harkany, Tibor; Taglialatela, Maurizio; Di Marzo, Vincenzo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 24, 2014.

Research output: Contribution to journalArticle

Iannotti, FA, Silvestri, C, Mazzarella, E, Martella, A, Calvigioni, D, Piscitelli, F, Ambrosino, P, Petrosino, S, Czifra, G, Bíró, T, Harkany, T, Taglialatela, M & Di Marzo, V 2014, 'The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 24. https://doi.org/10.1073/pnas.1406728111
Iannotti, Fabio A. ; Silvestri, Cristoforo ; Mazzarella, Enrico ; Martella, Andrea ; Calvigioni, Daniela ; Piscitelli, Fabiana ; Ambrosino, Paolo ; Petrosino, Stefania ; Czifra, G. ; Bíró, T. ; Harkany, Tibor ; Taglialatela, Maurizio ; Di Marzo, Vincenzo. / The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 24.
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