**1. Introduction**

## **1.1 Description of the endocannabinoid system (ECS)**

The term endocannabinoid system (ECS) was originally coined in the 1990s after the discovery of brain receptors, responsive to ∆9-tetrahydrocannabinol-THC (the primary psychoactive substance of *Cannabis sativa*) and the class of their endogenous ligands identified immediately thereafter [1]. Since these discoveries, the number of molecules functionally associated with the activity of the endocannabinoid system has grown exponentially.

Nowadays, the ECS is considered to be a very complex network of connected signaling molecules, and key components of this system include (a) the two most potent endogenous agonists of cannabinoid receptors, anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), also named endocannabinoids; (b) endocannabinoid-related molecules including N-oleoylethanolamine (OEA) and N-palmitoylethanolamide (PEA); (c) the enzymes regulating the endocannabinoid biosynthesis (NAPE-PLD, ABDH4, GDE1, PTPN22 for AEA, and DAGLα and DAGLβ for 2-AG) and degradation (FAAH for AEA and MAGL, ABDH6, ABDH12, and FAAH for 2-AG); (d) the two endocannabinoids responsive to G-proteincoupled receptors known as cannabinoid receptor of type 1 (CB1) and type 2 (CB2); and (e) the cation permeant transient receptor potential vanilloid type-1 (TRPV1) [2–4]. Recently, AEA and 2-AG were also shown to have affinity for non-cannabinoid receptors including GABA-A, PPARγ, adenosine A3, and GPR55 [5]. In this complex scenario, also other endogenous AEA and 2-AG analogues, including other N-acyl-ethanolamines (NAEs), monoacylglycerols, N-acyl amino acids, and N-acyldopamines/taurines/serotonins, were suggested to share, to some extent, either anabolic or catabolic pathways, or both, with endocannabinoids (**Figure 1**) [6].

As also mentioned previously, the endocannabinoid system (ECS) is critically involved in regulating a variety of metabolic and cognitive processes. An overactive endocannabinoid/CB1R system has been associated with the development of obesity, insulin resistance, and dyslipidemia [7–10] as well as during the progression of neurological disorders such as Alzheimer's disease, multiple sclerosis, amyotrophic

#### **Figure 1.**

*Synthesis, inactivation, and mechanism of action of the two endocannabinoids anandamide and 2-AG. Thick black arrows indicate the biochemical reactions that starting from the precursor membranes lead to the synthesis of the two endocannabinoids anandamide and 2AG. ABDH4, α β-hydrolase 4; ABDH6, α β-hydrolase 6; ABDH12, α β-hydrolase 12; CB1 and CB2, cannabinoid receptor of types 1 and 2; COX2, cyclooxygenase 2; DAG, diacylglycerol; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiester phosphodiesterase 1; MAGL, monoacylglycerol lipase; NAPE-PLD, N-acyl-phosphatidylethanolamine-selective phosphodiesterase; NATs, N-acyltransferases; PA, phosphatidic acid; PLCbeta, phospholipase Cbeta; PLD, phospholipase D; 15-LOX, 15-lipoxygenase; PTPN22, protein tyrosine phosphatase, non-receptor type 22; PGF2α, prostaglandin F2alpha; 15 HAEA, 15(S)-HETE ethanolamide; PGE2, prostaglandin E2; TRPV1, transient receptor potential, vanilloid subtype 1 receptor (this figure was copied directly from Arturo, Iannotti Fabio, and Fabiana, Piscitelli (Nov. 2018) Endocannabinoidome. In: eLS. John Wiley & Sons Ltd, Chichester). http://www.els.net [doi: 10.1002/9780470015902.a0028301].*

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lism in skeletal muscle cells.

*Pharmacological Actions and Potential Therapeutic Use of Cannabinoids in Duchenne's…*

lateral sclerosis, Parkinson's disease, and Huntington's chorea [4, 11]. Nevertheless, the potential role of the ECS in skeletal muscle disorders remains largely unknown.

**2. What is known about the role of endocannabinoid systems in skeletal** 

**2.1 The role of the endocannabinoid system on glucose metabolism and insulin** 

The first evidence demonstrating that CB1 receptors are functionally expressed

Few years later, Cavuoto and colleagues in two parallel studies demonstrated first that not only CB1 but also CB2, TRPV1, and FAAH are expressed in human and rodent skeletal muscle. Then, in human primary myotubes isolated from lean and obese donors, they found that the exposure to AEA or AM251 (another largely used selective CB1 antagonist), separately or in combination for 24 hours, induces significant changes in transcript levels of key genes regulating the metabolism such as AMP-activated protein kinase (AMPK) alpha 1 (alpha1) and alpha 2 (alpha2), pyruvate dehydrogenase kinase 4 (PDK4), and peroxisome proliferator-activated

Thus, these pioneering studies have paved the way for other studies through which the role of the ECS in regulating energy balance at the skeletal muscle level was further strengthened. In this regard, Esposito and colleagues showed that in differentiated L6 myotubes, the pharmacological blockade by SR141716 or genetic silencing of CB1 small interfering RNA sequences increased 2-deoxyglucose uptake (2-DG) in a time- and dose-dependent manner. The authors also demonstrated that, the activity of phosphatidylinositol-3-kinase (PI3K) that in turn has stimulatory effects phosphoinositide-dependent kinase-1, Akt/ protein kinase B, and protein kinase Cζ, resulted increased by SR141716 [16]. Accordingly, Eckardt et al. found that in human skeletal muscle cells 24 hours of incubation with adipocyte-conditioned medium (CM) or anandamide (AEA) impaired insulin-stimulated Akt(Ser473) phosphorylation. By contrast, pretreatment with rimonabant or AM251 reduced the effect of CM by about one-half, while the effect of AEA was fully prevented. The reduction of insulin-stimulated glucose uptake by CM was completely prevented by rimonabant. In addition, AEA was found to transiently activate ERK1/ERK2 and p38 mitogen-activated protein kinase and impaired insulin-stimulated Akt (Ser473) phosphorylation, but had no effect on Akt (Thr308) and glycogen synthase kinase 3 alpha/beta phosphorylation. Surprisingly, after 24 hours of treatment, an enhanced IRS-1 (Ser307) phosphorylation induced by AEA was observed in human skeletal muscle cells [17]. Furthermore, activation or inhibition of CB1 receptor activity exerts a differential effect with regard to MAP kinase- and PKB-directed signaling [18]. In conclusion, all these studies provide robust evidence that the endocannabinoid "tone" (hence CB1 signaling) is dysregulated during the obesity where its overactivity generates detrimental consequences on insulin sensitivity and consequently glucose catabo-

receptor-gamma coactivator-1alpha (PGC-1alpha) [14, 15].

in skeletal muscle tissues came out in 2005, when Liu and colleagues reported the effects of SR141716 (commonly known as rimonabant), one of the most used selective CB1 antagonists/inverse agonists [12], on energy expenditure and glucose uptake in isolated soleus muscle of obese *Lep(ob)/Lep(ob)* mice. In particular, the authors found that 5 days after daily treatment, SR141716 resulted in a significant reduction of daily food intake and body weight. While after 7 days, SR141716 had also positive effects on basal oxygen consumption and glucose uptake [13].

*DOI: http://dx.doi.org/10.5772/intechopen.85131*

**sensitivity in skeletal muscles**

**muscle**

lateral sclerosis, Parkinson's disease, and Huntington's chorea [4, 11]. Nevertheless, the potential role of the ECS in skeletal muscle disorders remains largely unknown.
