title: Cannabinoid receptor 1 and acute resistance exercise--In vivo and in vitro studies in human skeletal muscle.
abstract: OBJECTIVE
  This study aimed to determine whether Cannabinoid receptor 1 (CB1) is involved in mammalian target of rapamycin (mTOR) signaling and skeletal muscle protein synthesis.
  
  
  METHODS
  This study used human vastus lateralis skeletal muscle biopsies obtained before and after a resistance exercise (RE) bout in young men (n=18). The signaling mechanisms were studied in vitro in human myotubes. Protein expression was determined by Western blot and confocal microscopy, and gene expression by quantitative PCR. Protein synthesis was measured in vitro using puromycin-based SuNSET technique.
  
  
  RESULTS
  In human skeletal muscle, an anabolic stimulus in the form of RE down-regulated CB1 expression. The negative change in CB1 expression was associated with increased phosphorylation of mTOR signaling proteins. In vitro, CB1 antagonist AM251 induced phosphorylation of mTOR downstream targets, ribosomal protein S6 kinase (S6K1), S6 and eukaryotic initiation factor 4E binding protein (4E-BP1) in human myotubes. These effects were ERK1/2-dependent and insensitive to mTOR inhibitor, rapamycin. Compared to AM251 treatment alone, inhibition of ERK1/2 by UO126 in the presence of AM251 decreased phosphorylation of S6K1, S6 and and 4E-BP1 at Thr(37/46). AM251 increased protein synthesis in cultured human myotubes, which was not rapamycin-sensitive but was ERK1/2-dependent.
  
  
  CONCLUSIONS
  Our results indicate that RE down-regulates CB1 expression. Inhibition of CB1 signaling increases skeletal muscle anabolic signaling down-stream of mTOR and protein synthesis through ERK1/2. Our study may provide base for the development of CB1-blocking drugs to treat or prevent muscle wasting.
authors: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland. Electronic address: satu.p.pekkala@jyu.fi.
authors: Satu
authors: S
authors: Pekkala
authors: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors: Petri
authors: P
authors: Wiklund
authors: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.
authors: Juha J
authors: JJ
authors: Hulmi
authors: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors: Eija
authors: E
authors: Pöllänen
authors: Department of Biological and Environmental Sciences/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland.
authors: Varpu
authors: V
authors: Marjomäki
authors: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
authors: Eveliina
authors: E
authors: Munukka
authors: Centre d'Immunologie de Marseille-Luminy, UM2, Aix-Marseille Université, 13288 Marseille, France; INSERM, U1104, 13288 Marseille, France; CNRS, UMR 7280, 13288 Marseille, France.
authors: Philippe
authors: P
authors: Pierre
authors: Thérapie des maladies du muscle strié, Institut de Myologie, UM76-Université Pierre and Marie Curie, Paris, France; INSERM U974, CNRS UMR 7215, G.H. Pitié-Salpétrière, 47 bd de l'hôpital, Paris, France.
authors: Vincent
authors: V
authors: Mouly
authors: Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylä, Finland.
authors: Antti
authors: A
authors: Mero
authors: Department of Medical Rehabilitation, Oulu University Hospital, and Institute of Health Sciences - University of Oulu, Oulu, Finland.
authors: Markku
authors: M
authors: Alén
authors: Department of Health Sciences, University of Jyväskylä, Jyväskylä, Finland; Department of Physical Education, Shanghai Jiao Tong University, Shanghai, China.
authors: Sulin
authors: S
authors: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055070:Resistance Training; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: Cannabinoid receptor 1; Protein synthesis; Resistance exercise; Skeletal muscle; mTOR signaling