Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

Abstract

The cannabinoid system is ubiquitously present and is classically considered to engage in neural and immunity processes. Yet, the role of the cannabinoid system in the whole body and tissue metabolism via central and peripheral mechanisms is increasingly recognized. The present review provides insights in (i) how cannabinoid signaling is regulated via receptor-independent and -dependent mechanisms and (ii) how these signaling cascades (might) affect skeletal muscle plasticity and physiology.Receptor-independent mechanisms include endocannabinoid metabolism to eicosanoids and the regulation of ion channels. Alternatively, endocannabinoids can act as ligands for different classic (cannabinoid receptor 1 [CB 1 ], CB 2 ) and/or alternative (e.g., TRPV1, GPR55) cannabinoid receptors with a unique affinity, specificity, and intracellular signaling cascade (often tissue-specific). Antagonism of CB 1 might hold clues to improve oxidative (mitochondrial) metabolism, insulin sensitivity, satellite cell growth, and muscle anabolism, whereas CB 2 agonism might be a promising way to stimulate muscle metabolism and muscle cell growth. Besides, CB 2 ameliorates muscle regeneration via macrophage polarization toward an anti-inflammatory phenotype, induction of MyoD and myogenin expression and antifibrotic mechanisms. Also TRPV1 and GPR55 contribute to the regulation of muscle growth and metabolism. Future studies should reveal how the cannabinoid system can be targeted to improve muscle quantity and/or quality in conditions such as ageing, disease, disuse, and metabolic dysregulation, taking into account challenges that are inherent to modulation of the cannabinoid system, such as central and peripheral side effects.

Quantal size increase induced by the endocannabinoid 2‐arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses

“…We suggested that muscle contractions could provide some retrograde messenger that could be probably necessary for the CGRP‐dependent posttetanic enhancement of MEPP amplitude. Regulation of motor synapse activity by such muscle‐derived molecules is widely discussed (Lanuza et al., 2019; Obis et al., 2015; Simó et al., 2018), and among these molecules, ECs have also been identified in skeletal musculature (Crespillo et al., 2011; Dalle et al., 2022; Hutchins‐Wiese et al., 2012; Morsch et al., 2018). Here we also show that ECs could play the role of muscle‐derived regulatory factors in mouse motor synapses.…”

“…This differs from the well‐known inhibitory effects of ECs on transmitter secretion in CNS synapses (Cristino et al., 2020; Ohno‐Shosaku & Kano, 2014). Enzymes providing EC synthesis have been found in skeletal muscles (Crespillo et al., 2011; Hutchins‐Wiese et al., 2012), and EC paracrine action on muscle fibers has been reported (Dalle et al., 2022). But the detailed mechanisms of EC regulatory activity and their possible interaction with other signaling molecules in peripheral motor synapses have not been established yet.…”

Genetic Manipulation of CB1 Cannabinoid Receptors Reveals a Role in Maintaining Proper Skeletal Muscle Morphology and Function in Mice

“…Over-activity of the ECS and alteration of the cannabinoid tone had been described in a large number of disorders, including muscle diseases such as Duchenne Muscular Dystrophy (DMD) [ 35 ], obesity [ 36 , 37 ] and aging [ 38 ]. Hence, CB1 antagonism has been proposed as a promising target to treat cachexia and sarcopenia through modulation of the metabolism and muscle regenerative capacity [ 39 ], and more recently as an add-on therapy in DMD which could decrease the usage of steroidal anti-inflammatory drugs, presenting serious side effects.…”

“…Previous studies revealed CB1R expression in murine and human skeletal muscles [ 31 ], but the relevance, if any, of muscle CB1Rs in muscle biology has remained elusive. Nevertheless, CB1 has been described as a negative regulator of oxidative metabolism, muscle anabolism, satellite cell growth and muscle regeneration [ 38 ].…”

“…In human muscle tissues, CB1 expression was found to be higher in slow-twitch type I fibers (seen in high abundance in elite endurance athletes, such as long-distance runners and cyclists) compared to fast-twitch IIa and IIx fibers (abundant in elite power athletes, such as weightlifters and sprinters) [ 39 ]. Likewise in mice, CB1 protein expression was described as rather conflicting: some laboratories found higher CB1 protein expression in predominantly fast (e.g., gastrocnemius , tibialis anterior ) vs. slow (e.g., soleus ) muscles [ 43 ], while others reported the opposite [ 38 ]. Our present results are in agreement with the latter, which from a metabolic perspective seems indeed more logical: CB1 is known to be an important regulatory player in peripheral oxidative capacity; thus, one would expect it to be more abundant in type I fibers, which exhibit a higher oxidative capacity than type II fibers.…”