Letter to the Editor: The Receptor(s) via Which Cannabidiol Affects Muscle Signaling: In Need for More Insights

Dear Editor,

With great interest, we read the work of Langer, Avey, and Baar, in which the effect of cannabidiol (CBD) on anabolic and inflammatory signaling was studied in C₂C₁₂ muscle cells.¹ This in vitro study is an organic follow-up study of the in vivo study from the same group that investigated the effect of CBD treatment on inflammatory and anabolic responses upon eccentric contractions in rats.² We acknowledge the importance of this study in light of the increasing popularity of CBD supplementation in an athletic population, whereas very little, if any, evidence substantiates the ergogenic effect of CBD use.

In their study, Langer et al. conclude that the lack of effects after CBD treatment could be explained by a lack of functional receptors in C₂C₁₂ cells. In addition, they state that cannabinoid receptor 1 (CB₁) is the primary CBD receptor.¹ Indeed, the authors observed a lack of a CB₁ protein band that they attributed to the choice for whole muscle cell lysate and western blot technique, which is in contrast to other studies that analyzed cellular subfractions with immunoprecipitation. We agree with the authors that CB₁ is less abundant in skeletal muscle compared with brain tissues and even other murine metabolic tissues (such as tumor and adipose tissue; Fig. 1).

FIG. 1.

CB₁ expression in whole tissue lysates of Mm tumor, epididymal white adipose, brown adipose, visceral adipose, liver and muscle tissue, and of Hs muscle tissue. Despite more protein bands in different tissues, the most pronounced protein band at ∼53 kDa appeared consistently. Protein bands were obtained with the protein extraction and western blot technique as mentioned previously.³ CB₁, cannabinoid receptor 1; Hs, human; Mm, murine.

However, we³ and others^4–6 yielded clear protein bands in whole muscle (cell) lysate using the western blot technique. It could be that the loading of >10 μg proteins per sample or the use of a different antibody (concentration) might have resulted in clearer protein bands.

Besides, it can be questioned whether the choice of CB₁ as primary CBD receptor is sound. Previous findings indicate that CBD shows low affinity for CB₁ and CB₂.⁷ However, CBD might act as an allosteric modulator of both CB₁ and CB₂ and thereby affect their activity in presence of other ligands.⁸ More likely, CBD might exert its effects on signaling cascades in (muscle) cells through TRPV1 channels. Iannotti et al. reported that CBD treatment (1 μM for 15 min up to 72 h) in C₂C₁₂ cells affected expression levels of myogenic markers (i.e., myogenin and TNNT-1) as well as the fusion index, mainly through TRPV1.⁹

Finally, the exposure to CBD (dose: 1–5 μM and duration: 15–60 min) in the study of Langer et al.¹ was very similar (if not more pronounced) to that in the study of Iannotti et al.⁹ Therefore, it appears that the lack of effects after CBD treatment on anabolic and inflammatory signaling might indicate a missing link between CBD and these outcomes in C₂C₁₂ cells (which was also acknowledged by the authors), and should not be ascribed to the absence of appropriate receptors in muscle cells.

Abbreviations Used

CB₁

cannabinoid receptor 1

Hs

human

Mm

murine

Author Disclosure Statement

No competing financial interests exist.

Funding Information

S.D. has received a postdoctoral fellowship (12Z8622N) from Research Foundation Flanders (FWO).

Cite this article as: Dalle S, Schouten M, Koppo K (2022) Letter to the Editor: The receptor(s) via which cannabidiol affects muscle signaling: in need for more insights, Cannabis and Cannabinoid Research 7:5, 717–718, DOI: 10.1089/can.2021.0210.