Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1‐independent mechanism

Bacquer, Olivier Le; Lanchais, Kassandra; Combe, Kristell; Berghe, L. Van Den; Walrand, Stéphane

doi:10.1002/jcp.30034

Cited by 13 publications

(14 citation statements)

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“…The treatment of satellite cells with rimonabant increased their differentiation and the number of regenerated myofibres, and prevented the loss of mobility in mdx mice 14 . Last, in a recent study, we demonstrated that acute inhibition of the ECS by rimonabant was able to prevent dexamethasone‐induced atrophy and to stimulate protein synthesis in a model of myotubes in culture 15 …”

Section: Introductionmentioning

confidence: 74%

“…14 Last, in a recent study, we demonstrated that acute inhibition of the ECS by rimonabant was able to prevent dexamethasone-induced atrophy and to stimulate protein synthesis in a model of myotubes in culture. 15 Whether sarcopenia is associated with modifications of endocannabinoid tone and alterations of the ECS is, to our knowledge, unknown. Therefore, the aim of the present study was (1) to characterize the changes of the circulating and tissue levels of endocannabinoids in a context of sarcopenia, (2) to characterize the alterations of the ECS genes in the adipose tissue and skeletal muscle, and (3) to analyse whether these alterations can be associated with muscle mass, function, and mobility in old rats.…”

Section: Introductionmentioning

confidence: 96%

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Alterations of the endocannabinoid system and circulating and peripheral tissue levels of endocannabinoids in sarcopenic rats

Bacquer

Salles

Piscitelli

et al. 2021

J cachexia sarcopenia muscle

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Background Activation of the endocannabinoid system (ECS) is associated with the development of obesity and insulin resistance, and with perturbed skeletal muscle development. Age-related sarcopenia is a progressive and generalized skeletal muscle disorder involving an accelerated loss of muscle mass and function, with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance. Hence, both obesity and sarcopenia share a common set of pathophysiological alterations leading to skeletal muscle impairment. The aim of this study was to characterize how sarcopenia impacts the ECS and if these modifications were related to the loss of muscle mass and function associated with aging in rats. Methods Six-month-old and 24-month-old male rats were used to measure the contractile properties of the plantarflexors (isometric torque-frequency relationship & concentric power-velocity relationship) and to evaluate locomotor activity, motor coordination, and voluntary gait by open field, rotarod, and catwalk tests, respectively. Levels of endocannabinoids (AEA & 2-AG) and endocannabinoid-like molecules (OEA & PEA) were measured by LCF-MS/MS in plasma, skeletal muscle, and adipose tissue, while the expression of genes coding for the ECS were investigated by quantitative reverse transcription PCR (RT-qPCR). Results Sarcopenia in old rats was exemplified by a 49% decrease in hindlimb muscle mass (P < 0.01), which was associated with severe impairment of isometric torque, power, voluntary locomotor activity, motor coordination, and gait quality. Sarcopenia was associated with (1) increased 2-AG (+32%, P = 0.07) and reduced PEA and OEA levels in the plasma (À25% and À40%, respectively, P < 0.01); (2) an increased content of AEA, PEA, and OEA in subcutaneous adipose tissue (P < 0.01); and (3) a four-fold increase of 2-AG content in the soleus (P < 0.01) and a reduced OEA content in EDL (À80%, P < 0.01). These alterations were associated with profound modifications in the expression of the ECS genes in the adipose tissue and skeletal muscle. Conclusions Taken together, these findings demonstrate that circulating and peripheral tissue endocannabinoid tone are altered in sarcopenia. They also demonstrate that OEA plasma levels are associated with skeletal muscle function and loss of locomotor activity in rats, suggesting OEA could be used as a circulating biomarker for sarcopenia.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 96%

Alterations of the endocannabinoid system and circulating and peripheral tissue levels of endocannabinoids in sarcopenic rats

Bacquer

Salles

Piscitelli

et al. 2021

J cachexia sarcopenia muscle

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“…However, Le Bacquer et al (2022) co-incubated C2C12 myotubes with dexamethasone and rimonabant for 24 h, and the atrophy was prevented in myotubes exposed to rimonabant, without affecting the atrogin-1/MAFbx ratio. The authors also found that rimonabant stimulates protein synthesis and CB1 agonists are unable to modulate protein synthesis, suggesting a CB1-independent mechanism [ 59 ]. In vitro and in vivo models, mouse strains, and rimonabant doses can explain these controversial results.…”

Section: Discussionmentioning

confidence: 99%

The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice

et al. 2023

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The endocannabinoid system (ECS) regulates energy metabolism, has been implicated in the pathogenesis of metabolic diseases and exerts its actions mainly through the type 1 cannabinoid receptor (CB1). Likewise, autophagy is involved in several cellular processes. It is required for the normal development of muscle mass and metabolism, and its deregulation is associated with diseases. It is known that the CB1 regulates signaling pathways that control autophagy, however, it is currently unknown whether the ECS could regulate autophagy in the skeletal muscle of obese mice. This study aimed to investigate the role of the CB1 in regulating autophagy in skeletal muscle. We found concomitant deregulation in the ECS and autophagy markers in high-fat diet-induced obesity. In obese CB1-KO mice, the autophagy-associated protein LC3 II does not accumulate when mTOR and AMPK phosphorylation levels do not change. Acute inhibition of the CB1 with JD-5037 decreased LC3 II protein accumulation and autophagic flux. Our results suggest that the CB1 regulates autophagy in the tibialis anterior skeletal muscle in both lean and obese mice.

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“…Pekkala et al found that CB 1 antagonism in human myotubes increased protein synthesis, as well as the expression of the downstream mediators of the anabolic mammalian target of rapamycin complex 1 (mTORC1) pathway (S6K1, S6rp, and 4E‐BP1), which occurred in an ERK1/2‐dependent but, interestingly, mTORC1‐independent way (Pekkala et al, 2015). Accordingly, treatment with the CB 1 antagonist rimonabant prevented dexamethasone‐induced atrophy in C 2 C 12 cells via an increase in protein synthesis and mTOR expression, as well as intracellular Ca 2+ levels (Le Bacquer, Lanchais, et al, 2021). In contrast to Pekkala et al (2015), the increase in protein synthesis was not mediated by CB 1 , indicating that different mechanisms explain the anabolic potential of rimonabant, independent from CB 1 (Le Bacquer, Lanchais, et al, 2021).…”

Section: Cannabinoid System and Muscle Homeostasis: Paths And Challengesmentioning

confidence: 99%

“…Accordingly, treatment with the CB 1 antagonist rimonabant prevented dexamethasone‐induced atrophy in C 2 C 12 cells via an increase in protein synthesis and mTOR expression, as well as intracellular Ca 2+ levels (Le Bacquer, Lanchais, et al, 2021). In contrast to Pekkala et al (2015), the increase in protein synthesis was not mediated by CB 1 , indicating that different mechanisms explain the anabolic potential of rimonabant, independent from CB 1 (Le Bacquer, Lanchais, et al, 2021). It cannot be excluded that other receptors that physically and functionally interact with CB 1 , such as the β2‐adrenoceptor, stimulated protein synthesis upon CB 1 antagonist treatment (Figure 4).…”

Section: Cannabinoid System and Muscle Homeostasis: Paths And Challengesmentioning

confidence: 99%

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

Dalle

Schouten

Meeus

et al. 2022

Journal Cellular Physiology

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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.

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Acute rimonabant treatment promotes protein synthesis in C2C12 myotubes through a CB1‐independent mechanism

Cited by 13 publications

References 70 publications

Alterations of the endocannabinoid system and circulating and peripheral tissue levels of endocannabinoids in sarcopenic rats

Alterations of the endocannabinoid system and circulating and peripheral tissue levels of endocannabinoids in sarcopenic rats

The CB1 cannabinoid receptor regulates autophagy in the tibialis anterior skeletal muscle in mice

Molecular networks underlying cannabinoid signaling in skeletal muscle plasticity

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