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.
Highlights
The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases
To gain a mechanistic understanding relative to the upregulated expression of cannabinoid receptor of type 1 (CB1) gene in Duchenne’s muscle dystrophy (DMD) muscles, and to define the specific muscle cell subpopulation responsible for these changes, we performed RNAsequencing (RNA-seq) experiments on fluorescence-activated cell sorting (FACS)-sorted satellite, macrophage and fibroadipogenic progenitor (FAP) cells freshly isolated from the hind limb muscles of 8-week-old control and mdx mice
We demonstrated that the lack of dystrophin was accompanied by a significant increase in the transcript levels of CB1, occurring exclusively in satellite cells but not in FAP or macrophages (Fig. 1c)
Summary
The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Recent studies demonstrated that dystrophin plays a key role in satellite cells, the muscle stem cells normally deputed to regenerate injured muscle fibers, where the lack of the functional protein causes asymmetric cell division, altered morphogenesis, and inefficient differentiation[6,7]. In both human and murine DMD skeletal muscles the number of satellite cells is higher than healthy tissue, their regenerative capacity is inevitably compromised along with disease progression[7,8,9,10]. We demonstrate the existence of a functional interplay between CB1 and PAX7, a key factor regulating muscle regeneration through satellite cell division, and that antagonism of CB1 prevents the loss of muscle activity in dystrophic mice
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