The cannabinoid receptor 1 antagonist AM6545 stimulates the Akt-mTOR axis and in vivo muscle protein synthesis in a dexamethasone-induced muscle atrophy model

Skeletal muscle is a highly plastic tissue. Muscle hypertrophy can be reached through resistance exercise and/or protein supplementation, whereas muscle wasting can occur with advancing age, disease and immobility. Currently, (resistance) exercise is considered the primary strategy to gain muscle mass and stimulate beneficial muscular adaptions, e.g. gains in strength, functionality and metabolism. However, this strategy is not always feasible in patient populations or in an elderly, frail population. Besides, older adults and patient populations exhibit a decreased sensitivity towards beneficial anabolic adaptations such as resistance exercise (Kumar et al., 2009) and (protein) feeding (Cuthbertson et al., 2004, 2004v; van Vliet et al., 2018, 2018van Dijk et al., 2015). Therefore, novel (pharmaceutical) strategies are required to optimize the muscle's plasticity in older and patient populations.

The endocannabinoid system (ECS) might be a potential target to reverse muscle degeneration via metabolic (Lipina et al., 2016; González-Mariscal et al., 2019), regenerative (Iannotti et al., 2018) and anabolic (Pekkala et al., 2015; Le Bacquer et al., 2021a) adaptations. The ECS consists of endocannabinoids such as anandamide and 2-arachidonoylglycerol, and (endo)cannabinoid receptors to which they can bind, e.g. the G protein-coupled receptors cannabinoid receptor 1 and 2 (CB1 and CB2). However, endocannabinoids can also exert cellular effects independent from these receptors, e.g. as substrates of cyclo- or lipoxygenase, or via Na + or Ca2+ channels. Upon ligand binding to CBs, G proteins dissociate from the receptor, which results in the activation of intracellular pathways, depending on factors such as cell type, ligand type, ligand concentration and ligand exposure time. In muscle tissue, activation of CB1 results in Gαi/o-dependent inhibition of adenylyl cyclase, which decreases production of the signaling molecular cyclic adenosine monophosphate (cAMP). cAMP-dependent protein kinase A (PKA) is the most common cAMP effector and further orchestrates cellular effects of CB1 (ant)agonism via mitogen-activated protein kinase (MAPKs), metabolic enzymes (e.g. glycogen synthase) (Soderling et al., 1970), ion channels (e.g. Ca2+) (Sculptoreanu et al., 1995) or transcription factors (e.g. CREB (Stewart et al., 2011) and FOXO) (Silveira et al., 2014, 2020). A more elaborate overview of the regulation of cannabinoid signaling in skeletal muscle can be found in the review of Dalle et al. (2022a).

Whereas CB1 is classically considered to play a crucial role in the central regulation of metabolism, more lately, its importance in metabolic regulation of peripheral tissues, such as liver (Bazwinsky-Wutschke et al., 2019), adipose tissue (Sidibeh et al., 2017) and skeletal muscle (González-Mariscal et al., 2019), is increasingly recognized. In murine models of genetically (Liu et al., 2005)-, age (Lipina et al., 2016; González-Mariscal et al., 2019)- or diet (González-Mariscal et al., 2019)-induced metabolic dysregulations, such as obesity and diabetes, CB1 antagonism improved (whole body) oxidative metabolism, mitochondrial capacity and insulin sensitivity. However, the role of CB1 reaches beyond metabolic control. In a murine model of Duchenne muscular dystrophy, CB1 antagonism stimulated satellite cell growth and muscle functional capacity, whereas agonism of CB1 had the opposite effect (Iannotti et al., 2018). Furthermore, CB1 antagonists such as rimonabant (SR141716) and AM251 increased muscle protein synthesis (MPS) in human myotubes (Pekkala et al., 2015) and C2C12 muscle cells (Le Bacquer et al., 2021a), but this has never been confirmed in vivo.

Given the therapeutic potential of CB1 to improve muscle metabolism and anabolism, and given that the cannabinoid signaling (including CB1 expression) is altered with ageing (Lipina et al., 2016; Dalle and Koppo, 2021; Le Bacquer et al., 2021b) and muscular dystrophy (Iannotti et al., 2018), CB1 antagonism might be a viable approach to overcome muscle age- or disease-related degeneration. Therefore, the present study aimed to uncover whether CB1 affects anabolism and metabolism. Mice were chronically and acutely treated with the peripherally-restricted, neutral CB1 antagonist AM6545 to determine whether this would affect i) muscle anabolism (i.e. MPS and Akt-mTOR axis), ii) muscle loss, iii) potential signaling cascades downstream of CB1 (i.e. MAPKs and PKA signaling) and iv) muscle metabolism (e.g. mitochondrial capacity and substrate metabolism). In the chronic experiment, a dexamethasone-induced muscle atrophy model was applied which is characterized by a diminished anabolic response (Liu et al., 2004; Long et al., 2001).

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