title: Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte.
abstract: A necessary mediator of cardiac myocyte enlargement is protein synthesis, which is controlled at the levels of both translation initiation and elongation. Eukaryotic elongation factor-2 (eEF2) mediates the translocation step of peptide-chain elongation and is inhibited through phosphorylation by eEF2 kinase. In addition, p70S6 kinase can regulate protein synthesis by phosphorylating eEF2 kinase or via phosphorylation of ribosomal protein S6. We have recently shown that eEF2 kinase is also controlled by phosphorylation by AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. Moreover, the mammalian target of rapamycin has also been shown to be inhibited, indirectly, by AMPK, thus leading to the inhibition of p70S6 kinase. Although AMPK activation has been shown to modulate protein synthesis, it is unknown whether AMPK could also be a regulator of cardiac hypertrophic growth. Therefore, we investigated the role of AMPK activation in regulating protein synthesis during both phenylephrine- and Akt-induced cardiac hypertrophy. Metformin and 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside were used to activate AMPK in neonatal rat cardiac myocytes. Activation of AMPK significantly decreased protein synthesis induced by phenylephrine treatment or by expression of constitutively active Akt. Activation of AMPK also resulted in decreased p70S6 kinase phosphorylation and increased phosphorylation of eEF2, suggesting that inhibition of protein synthesis involves the eEF2 kinase/eEF2 axis and/or the p70S6 kinase pathway. Together, our data suggest that the inhibition of protein synthesis by pharmacological activation of AMPK may be a key regulatory mechanism by which hypertrophic growth can be controlled.
authors.affiliation: Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Chan
authors.forename: Carrie-Lynn M
authors.initials: CL
authors.lastname: Soltys
authors.forename: Martin E
authors.initials: ME
authors.lastname: Young
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins; D006984:Hypertrophy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D008164:Luminescent Proteins / Q000378:metabolism; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D012266:Ribose / Q000031:analogs & derivatives; D038601:Ribosomal Protein S6 / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D007004:Hypoglycemic Agents; D008164:Luminescent Proteins; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D038601:Ribosomal Protein S6; D049452:Green Fluorescent Proteins; D010656:Phenylephrine; D000620:Aminoimidazole Carboxamide; D012266:Ribose; D008687:Metformin; C517691:Eef2k protein, rat; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D054736:Elongation Factor 2 Kinase; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus