Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and Regulate Mitochondrial Respiration.
Front. Physiol.. 2016-10-25; 7:
DOI: 10.3389/fphys.2016.00476
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1. Front Physiol. 2016 Oct 25;7:476. eCollection 2016.
Cannabinoid CB1 Receptors Are Localized in Striated Muscle Mitochondria and
Regulate Mitochondrial Respiration.
Mendizabal-Zubiaga J(1), Melser S(2), Bénard G(2), Ramos A(1), Reguero L(1),
Arrabal S(3), Elezgarai I(1), Gerrikagoitia I(1), Suarez J(3), Rodríguez De
Fonseca F(3), Puente N(1), Marsicano G(2), Grandes P(4).
Author information:
(1)Department of Neurosciences, Faculty of Medicine and Nursing, University of
the Basque CountryLeioa, Spain; Achucarro Basque Center for Neuroscience, Bizkaia
Science and Technology ParkZamudio, Spain.
(2)Group « Endocannabinoids and Neuroadaptation, » NeuroCentre Magendie, Institut
National de La Santé et de La Recherche Médicale, U81215Bordeaux, France; Group
« Endocannabinoids and Neuroadaptation, » NeuroCentre Magendie, Université de
BordeauxBordeaux, France.
(3)Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación
Biomédica de Málaga, Hospital Regional Universitario de Málaga Málaga, Spain.
(4)Department of Neurosciences, Faculty of Medicine and Nursing, University of
the Basque CountryLeioa, Spain; Achucarro Basque Center for Neuroscience, Bizkaia
Science and Technology ParkZamudio, Spain; Division of Medical Sciences,
University of VictoriaVictoria, BC, Canada.
The cannabinoid type 1 (CB1) receptor is widely distributed in the brain and
peripheral organs where it regulates cellular functions and metabolism. In the
brain, CB1 is mainly localized on presynaptic axon terminals but is also found on
mitochondria (mtCB1), where it regulates cellular respiration and energy
production. Likewise, CB1 is localized on muscle mitochondria, but very little is
known about it. The aim of this study was to further investigate in detail the
distribution and functional role of mtCB1 in three different striated muscles.
Immunoelectron microscopy for CB1 was used in skeletal muscles (gastrocnemius and
rectus abdominis) and myocardium from wild-type and CB1 -KO mice. Functional
assessments were performed in mitochondria purified from the heart of the mice
and the mitochondrial oxygen consumption upon application of different acute
delta-9-tetrahydrocannabinol (Δ9-THC) concentrations (100 nM or 200 nM) was
monitored. About 26% of the mitochondrial profiles in gastrocnemius, 22% in the
rectus abdominis and 17% in the myocardium expressed CB1. Furthermore, the
proportion of mtCB1 versus total CB1 immunoparticles was about 60% in the
gastrocnemius, 55% in the rectus abdominis and 78% in the myocardium.
Importantly, the CB1 immunolabeling pattern disappeared in muscles of CB1 -KO
mice. Functionally, acute 100 nM or 200 nM THC treatment specifically decreased
mitochondria coupled respiration between 12 and 15% in wild-type isolated
mitochondria of myocardial muscles but no significant difference was noticed
between THC treated and vehicle in mitochondria isolated from CB1 -KO heart.
Furthermore, gene expression of key enzymes involved in pyruvate synthesis,
tricarboxylic acid (TCA) cycle and mitochondrial respiratory chain was evaluated
in the striated muscle of CB1 -WT and CB1 -KO. CB1 -KO showed an increase in the
gene expression of Eno3, Pkm2, and Pdha1, suggesting an increased production of
pyruvate. In contrast, no significant difference was observed in the Sdha and
Cox4i1 expression, between CB1 -WT and CB1 -KO. In conclusion, CB1 receptors in
skeletal and myocardial muscles are predominantly localized in mitochondria. The
activation of mtCB1 receptors may participate in the mitochondrial regulation of
the oxidative activity probably through the relevant enzymes implicated in the
pyruvate metabolism, a main substrate for TCA activity.
DOI: 10.3389/fphys.2016.00476
PMCID: PMC5078489
PMID: 27826249