Cannabinoid signalling inhibits sarcoplasmic Ca2+ release and regulates excitation-contraction coupling in mammalian skeletal muscle

Abstract

Marijuana was found to cause muscle weakness, but it is unknown whether it affects the muscles directly, or modulates only the motor control of the central nervous system. Although the presence of CB1 cannabinoid receptors (CB1R) – responsible for the psychoactive effects of the drug in the brain – have recently been shown in skeletal muscle, it is unclear how CB1R-mediated signalling affects the contraction and Ca²⁺ homeostasis of mammalian skeletal muscle. Here we demonstrate that in vitro CB1R activation increased muscle fatigability, decreased the Ca²⁺-sensitivity of the contractile apparatus, but did not alter the amplitude of single twitch contractions. In myotubes, CB1R agonists neither evoked or influenced IP₃-mediated Ca²⁺ transients, nor altered excitation-contraction coupling. In contrast, in isolated muscle fibres of wild type mice, although CB1R agonists did not evoke IP₃-mediated Ca²⁺ transients too, they significantly reduced the amplitude of the depolarization-evoked transients in a pertussis-toxin sensitive way, indicating a G_i/o protein dependent mechanism. Concurrently, on skeletal muscle fibres isolated from CB1R-knockout animals, depolarization-evoked Ca²⁺ transients, Ca²⁺ release flux via ryanodine receptors (RyRs), and total amount of released Ca²⁺ was significantly greater than those from wild type mice. Our results show that CB1R-mediated signalling exerts both a constitutive and an agonist-mediated inhibition on the Ca²⁺ transients via RyR, regulates the activity of the sarcoplasmic reticulum Ca²⁺ ATPase, and enhances muscle fatigability, which might decrease exercise performance, play a role in myopathies, and should, therefore, be considered during the development of new cannabinoid drugs.

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