Key points are not available for this paper at this time.
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-β-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. 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-β-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. Cardiac hypertrophy is characterized by an enlargement of the cardiac myocyte that often occurs in response to increased hemodynamic load arising from a variety of conditions, including exercise, hypertension, and valvular heart disease. These morphological changes are adaptive responses that allow the heart to maintain cardiac output. Indeed, exercise-induced hypertrophy is not detrimental to the function of the myocardium and appears to be advantageous (1Richey P.A. Brown S.P. J. Sports Sci. 1998; 16: 129-141Google Scholar). However, hypertrophy arising from pathological conditions, such as sustained pressure overload, can become maladaptive and lead to cardiomyopathy, heart failure, and sudden death (see Ref. 2Lorell B.H. Carabello B.A. Circulation. 2000; 102: 470-479Google Scholar for review). Although initially adaptive, an alteration in cardiac energy substrate utilization involving a decrease in fatty acid oxidation and an increase in glucose utilization (3Allard M.F. Schonekess B.O. Henning S.L. English D.R. Lopaschuk G.D. Am. J. Physiol. 1994; 267: H742-H750Google Scholar, 4Xia Y. Wen H.Y. Young M.E. Guthrie P.H. Taegtmeyer H. Kellems R.E. J. Biol. Chem. 2003; 278: 13143-13150Google Scholar) can become maladaptive (5Lehman J.J. Kelly D.P. Heart Fail Rev. 2002; 7: 175-185Google Scholar). This switch in substrate utilization is also consistent with re-induction of several fetal gene products that regulate metabolism in the hypertrophied heart (see Ref. 5Lehman J.J. Kelly D.P. Heart Fail Rev. 2002; 7: 175-185Google Scholar for review). As a result, the altered metabolic profile found in the hypertrophic heart may play an important role in the development of hypertrophy and/or the progression to heart failure. At the molecular level, cardiac hypertrophy is characterized by an increase in myocardial cell size, a higher degree of sarcomeric organization, re-activation of the fetal gene program, and changes in gene transcription and translation resulting in enhanced protein synthesis (6Sugden P.H. Clerk A. J. Mol. Med. 1998; 76: 725-746Google Scholar). A necessary mediator of cardiac myocyte enlargement is protein synthesis, which is controlled by both translation initiation and peptide-chain elongation (7Hannan R.D. Jenkins A. Jenkins A.K. Brandenburger Y. Clin Exp. Pharmacol. Physiol. 2003; 30: 517-527Google Scholar, 8Browne G.J. Proud C.G. Eur. J. Biochem. 2002; 269: 5360-5368Google Scholar). The eukaryotic elongation factor-2 (eEF2) 1The abbreviations used are: eEF2, eukaryotic elongation factor-2; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; DMEM, Dulbecco's modified Eagle's medium; AICAR, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside; Ad, adenovirus; GFP, green fluorescent protein; TBS, Tris-buffered saline; ACC, acetyl CoA carboxylase; m.o.i., multiplicity of infection. 1The abbreviations used are: eEF2, eukaryotic elongation factor-2; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; DMEM, Dulbecco's modified Eagle's medium; AICAR, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside; Ad, adenovirus; GFP, green fluorescent protein; TBS, Tris-buffered saline; ACC, acetyl CoA carboxylase; m.o.i., multiplicity of infection. is responsible for mediating the translocation step of peptide-chain elongation (9Nairn A.C. Palfrey H.C. J. Biol. Chem. 1987; 262: 17299-17303Google Scholar). eEF2 is phosphorylated and inhibited by a calcium/calmodulin-dependent protein kinase called eEF2 kinase, which modifies threonine residue 56 (10Redpath N.T. Price N.T. Severinov K.V. Proud C.G. Eur. J. Biochem. 1993; 213: 689-699Google Scholar). Phosphorylation at Thr-56 results in the inactivation of eEF2 by causing a structural alteration that reduces its affinity for the ribosome, thereby preventing its ability to catalyze translocation (11Carlberg U. Nilsson A. Nygard O. Eur. J. Biochem. 1990; 191: 639-645Google Scholar). eEF2 kinase is also subjected to regulation by phosphorylation, and a number of phosphorylation sites have been identified that lead to subsequent activation or inhibition of activity (12Diggle T.A. Subkhankulova T. Lilley K.S. Shikotra N. Willis A.E. Redpath N.T. Biochem. J. 2001; 353: 621-626Google Scholar, 13Wang L. Gout I. Proud C.G. J. Biol. Chem. 2001; 276: 32670-32677Google Scholar, 14Knebel A. Haydon C.E. Morrice N. Cohen P. Biochem. J. 2002; 367: 525-532Google Scholar, 15Browne G.J. Proud C.G. Mol. Cell. Biol. 2004; 24: 2986-2997Google Scholar). Most recently, we have shown that AMP-activated protein kinase (AMPK), which is a key regulator of cellular energy homeostasis, phosphorylates eEF2 kinase at a novel site in the regulatory domain, serine 398 (16Browne G.J. Finn S.G. Proud C.G. J. Biol. Chem. 2004; 279: 12220-12231Google Scholar), and activates it. In cardiac myocytes, Horman et al. (17Horman S. Beauloye C. Vertommen D. Vanoverschelde J.L. Hue L. Rider M.H. J. Biol. Chem. 2003; 278: 41970-41976Google Scholar) have shown that AMPK activation leads to increased eEF2 phosphorylation via eEF2 kinase activation, resulting in the inhibition of protein synthesis. In addition, AMPK has recently been shown to be involved in modulating the activity of the mammalian target of rapamycin (mTOR) (18Cheng S.W. Fryer L.G. Carling D. Shepherd P.R. J. Biol. Chem. 2004; 279: 15719-15722Google Scholar). mTOR is a kinase that responds to nutritional status and amino acid availability and is centrally involved in cell growth and proliferation (19Proud C.G. Biochem. Biophys. Res. Commun. 2004; 313: 429-436Google Scholar, 20Fingar D.C. Salama S. Tsou C. Harlow E. Blenis J. Genes Dev. 2002; 16: 1472-1487Google Scholar). Activated mTOR is able to phosphorylate p70S6 kinase (21Isotani S. Hara K. Tokunaga C. Inoue H. Avruch J. Yonezawa K. J. Biol. Chem. 1999; 274: 34493-34498Google Scholar), which can inactivate eEF2 kinase (22Wang X. Li W. Williams M. Terada N. Alessi D.R. Proud C.G. EMBO J. 2001; 20: 4370-4379Google Scholar) as well as phosphorylate the 40 S ribosomal protein S6 (23Proud C.G. Trends Biochem. Sci. 1996; 21: 181-185Google Scholar). Recent work has also suggested that AMPK can inhibit mTOR signaling through the phosphorylation of TSC2, an upstream regulator of mTOR (24Inoki K. Zhu T. Guan K.L. Cell. 2003; 115: 577-590Google Scholar). Because AMPK may inhibit protein synthesis via a number of different pathways, it is possible that AMPK is also a key regulator of cardiac hypertrophy. AMPK is a serine/threonine protein kinase, which is activated by cellular stresses that deplete ATP (25Corton J.M. Gillespie J.G. Hardie D.G. Curr. Biol. 1994; 4: 315-324Google Scholar). AMPK responds to increases in the AMP/ATP ratio by switching off ATP-consuming pathways and switching on pathways for ATP generation. It is a heterotrimeric protein comprised of a catalytic α subunit and two regulatory subunits, β and γ (26Stapleton D. Gao G. Michell B.J. Widmer J. K. T. J. Biol. Chem. 1994; 269: Scholar, A. J. Carling D. J. Biol. Chem. 1996; Scholar). The α subunit the kinase domain, and phosphorylation at threonine of subunit results in increased AMPK activity A. Carling D. Biochem. J. 2000; Scholar). Although that AMPK activation synthesis (17Horman S. Beauloye C. Vertommen D. Vanoverschelde J.L. Hue L. Rider M.H. J. Biol. Chem. 2003; 278: 41970-41976Google Scholar, S. G. U. J. Vertommen D. L. A. Hue L. Proud C. Rider M. Curr. Biol. 2002; Scholar) and AMPK activation has also been shown to with the development of hypertrophy N. J. M.F. Circulation. 2001; Scholar, M. M. Li D. A. S. C.E. J.G. Circulation. 2003; Scholar). pressure hypertrophy has been shown to be with increased AMPK activity N. J. M.F. Circulation. 2001; Scholar). In addition, AMPK has been to and hypertrophic via in the gene the subunit of AMPK M.H. T. A. G. L. N. J. Med. 2001; Scholar, E. C. H. M. J. A. I. H. Mol. 2001; Scholar, T. Carling D. J. Biol. Chem. 2002; Scholar). Although has been AMPK and protein synthesis and/or hypertrophic the of AMPK in the molecular regulating cardiac hypertrophy is Although a number of signaling pathways have been in the regulation of the hypertrophic response (see Ref. N. Rev. Physiol. 2003; Scholar for of the with such as a hypertrophic in of cardiac M. K. Brown J. Biol. Chem. 1993; Scholar). As a result, has become an cellular for the of the hypertrophic In addition, the serine/threonine protein kinase has been in cardiac growth with hypertrophy T. T. S. Mol. Cell. Biol. 2002; Scholar, I. M. Y. A. J. A. K. J. Biol. Chem. 2002; Scholar), and expression of constitutively activated in the cardiac myocyte can be used as a of cardiac hypertrophy. we have shown that activated the phosphorylation of AMPK at its activation resulting in an inhibition of activity of AMPK in the heart S. I. K. J. Biol. Chem. 2003; 278: Scholar). Although cardiac energy metabolism the in that the ability of to regulate AMPK has including protein translation and the hypertrophic Indeed, it is possible that a to Akt-induced hypertrophy may be the of a protein synthesis such as the role of AMPK in protein synthesis with cardiac hypertrophy in both allow a of the pathways involved in the hypertrophic response and may the development of to or inhibit pathological cardiac hypertrophy and heart of to the for involving by the for of and with of used in were kinase of the or of the rat kinase, kinase and kinase from kinase and and were from CoA from from and and were from Dulbecco's modified Eagle's fetal 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside mammalian fatty and were from and and were from from were from the of to neonatal rat as S. I. K. J. Biol. Chem. 2003; 278: Scholar). The were on at a of of were on at a of of neonatal rat cardiac were with and in with and to the growth of of at in were with phenylephrine or or in both the and of in for at neonatal rat cardiac were with or Y. T. D. K. Circulation. 2000; Scholar) at the multiplicity of of to as S. I. K. J. Biol. Chem. 2003; 278: Scholar). for were with or in for were with and of mammalian and to the treatment were and for on and at for at The protein of the with the protein and were subjected to and changes in cell size, of were also as and with and were and as J. J. Cell. 1998; Scholar). were in and as at the of and were for at of to be as M. A. M. P.H. D. S. J. Biol. Chem. Scholar). were with and with acid for at to the The were with and in The resulting which the with and the in a of cell were subjected to in or and to as L. M. K. Am. J. Physiol. 2002; Scholar). were in and at with kinase kinase, kinase kinase kinase CoA or in at the were with in with the of the for the were the data are as of of by the used for the of A of of Metformin and on in Cardiac rat cardiac with phenylephrine a increase in protein synthesis cardiac However, in the of a AMPK G. Li Y. Y. X. J. M. J. T. N. N. M.F. J. 2001; Scholar), protein synthesis significantly AMPK J.M. Gillespie J.G. Hardie D.G. Eur. J. Biochem. Scholar), also significantly protein synthesis at a of to a A of the cell for is shown in of Metformin and on AMPK Activation in Cardiac that and treatment resulted in AMPK activation, from neonatal rat cardiac with phenylephrine in the or of or were subjected to an the α subunit of AMPK phosphorylated at In cardiac with phenylephrine in phosphorylation as with However, the of phosphorylated increased were with or AICAR, of the of The of increased phosphorylation not and or AICAR, AMPK is activated to which to a in protein synthesis A and Because protein synthesis not inhibited by our data suggest that AMPK to be activated to inhibit protein synthesis or that regulatory pathways, from AMPK, also to protein synthesis. Although phosphorylation at is of the activation of we also with CoA to whether altered phosphorylation of on a AMPK target protein such as S.P. Hardie D.G. Eur. J. Biochem. 1990; Scholar). In with AMPK activation, phosphorylation by both and treatment to with Because we have shown that is and AMPK in the cardiac myocyte S. I. K. J. Biol. Chem. 2003; 278: Scholar), we also the levels of phosphorylation in treatment also the phosphorylation of at its phosphorylation Although it is unknown can the K. Res. 1993; Scholar), which has been shown to in increased phosphorylation in the cardiac myocyte T. Cohen J.M. Am. J. Physiol. 2002; Scholar). of the activation of may the of on protein synthesis inhibition that of A and of AMPK Activation on p70S6 kinase, eEF2 and eEF2 Phosphorylation in Cardiac the signaling that protein synthesis in cardiac cell from cardiac as were subjected to kinase and Phosphorylation at sites is to p70S6 kinase activity N. G. Mol. Cell. Biol. 1996; 16: Scholar, R.E. G. EMBO J. Scholar). increased the phosphorylation status of p70S6 kinase which in the of or Although both of AMPK resulted in decreased p70S6 kinase phosphorylation, not as in p70S6 kinase phosphorylation as possible for may be that also activates which has been shown to in p70S6 kinase phosphorylation T. Li L. T. M.H. A. J. Biol. Chem. 2002; Scholar). from cardiac as were also subjected to and kinase treatment of decreased the phosphorylation of eEF2, which is of increased eEF2 activity and consistent with our L. Proud C.G. 2002; Scholar). In treatment of cardiac with or resulted in a increase in the phosphorylation of eEF2 at Thr-56 consistent with the that phosphorylation by AMPK activates eEF2 kinase. Because phosphorylation of eEF2 at Thr-56 results in a decrease in eEF2 activity and inhibition of protein synthesis (9Nairn A.C. Palfrey H.C. J. Biol. Chem. 1987; 262: 17299-17303Google Scholar), the increases in response to or at in the decrease in protein synthesis we in p70S6 kinase phosphorylation in myocytes, phosphorylation of eEF2 kinase at not increased (22Wang X. Li W. Williams M. Terada N. Alessi D.R. Proud C.G. EMBO J. 2001; 20: 4370-4379Google Scholar). In addition, AMPK activation not lead to a in eEF2 kinase phosphorylation at in or myocytes, phenylephrine treatment or in of Metformin and on by of in Cardiac that AMPK activation is able to inhibit protein synthesis, its on Akt-induced hypertrophy is Because we have shown that a regulatory and AMPK S. I. K. J. Biol. Chem. 2003; 278: Scholar), we that regulate phosphorylation of to protein synthesis with cardiac hypertrophy. neonatal rat cardiac were and with a constitutively active or as a in with or Cardiac with increases in the expression of protein levels and a increase in the of phosphorylated at increased activity D.R. M. P. Morrice N. Cohen P. B.A. EMBO J. 1996; Scholar) In addition, cardiac a increase in protein synthesis cardiac with the This Akt-induced increase in protein synthesis significantly by treatment with or of cell also that AMPK activation can Akt-induced hypertrophy of Metformin and on AMPK Activation in Cardiac with that and treatment resulted in AMPK activation, from neonatal rat cardiac with constitutively active and with or were subjected to Cardiac with levels of phosphorylation as with and the of or AICAR, the of on phosphorylation and phosphorylated levels levels in the and increase in phosphorylation to a increase in phosphorylation of at expression of constitutively active on the expression of the α subunit of AMPK protein or of the two of AMPK Activation on p70S6 eEF2 and eEF2 Phosphorylation in Cardiac with from cardiac constitutively active were subjected to kinase and of constitutively active increased the phosphorylation status of p70S6 kinase In the of or AICAR, Akt-induced changes in phosphorylation of p70S6 kinase were from cardiac as were also subjected to and kinase of cardiac with or resulted in a increase in the phosphorylation of eEF2 at Thr-56 eEF2 kinase However, p70S6 kinase phosphorylation in myocytes, changes in eEF2 kinase phosphorylation at in of the treatment not of kinase to eEF2 kinase that is a increase in eEF2 kinase phosphorylation in the as with the The for increase are expression of constitutively active the on the levels of eEF2 and eEF2 kinase. Although AMPK activation has been shown to regulate protein synthesis, it not whether cardiac hypertrophic growth. cardiac myocyte hypertrophy can as a of a number of we to the role of AMPK activation in regulating protein synthesis during both phenylephrine- and Akt-induced cardiac hypertrophy. cardiac an increase in cell size, which with a increase in protein synthesis and However, protein synthesis significantly decreased in the of of AMPK, and Although it is possible that and may regulate protein synthesis of AMPK, are from two of J.M. Gillespie J.G. Hardie D.G. Eur. J. Biochem. Scholar, N. J. Med. 1996; Scholar) that activate AMPK by different J.M. Gillespie J.G. Hardie D.G. Eur. J. Biochem. Scholar, A.E. Hardie D.G. 2002; Scholar). This the that the mechanism by which and inhibit protein synthesis is via AMPK Indeed, both and increased phosphorylation at and increased phosphorylation of at a substrate of AMPK and In the of phenylephrine or constitutively active both and were able to activate AMPK, suggesting that phenylephrine or constitutively active not the by which activate AMPK, the of and Together, data the that is a AMPK and cardiac myocyte growth. In we that inhibition of protein synthesis may in via decreased p70S6 kinase decrease in p70S6 kinase phosphorylation in cardiac with or and is in phosphorylation of eEF2 kinase at and Because of eEF2 kinase is phosphorylated by p70S6 kinase, it is that we not an alteration in its However, of eEF2 kinase is also a substrate for (22Wang X. Li W. Williams M. Terada N. Alessi D.R. Proud C.G. EMBO J. 2001; 20: 4370-4379Google Scholar), and it is possible that the phosphorylation of eEF2 kinase the inhibition of mTOR the data by et al. (18Cheng S.W. Fryer L.G. Carling D. Shepherd P.R. J. Biol. Chem. 2004; 279: 15719-15722Google Scholar), it is possible that AMPK phosphorylates and mTOR, resulting in the decrease in p70S6 kinase In addition, et al. (24Inoki K. Zhu T. Guan K.L. Cell. 2003; 115: 577-590Google Scholar) that AMPK phosphorylation of TSC2, an upstream regulator of mTOR, activity and thus p70S6 kinase phosphorylation via the mTOR pathway. As decreased p70S6 kinase phosphorylation not with changes in eEF2 kinase phosphorylation at in eEF2 kinase, it is also possible that p70S6 kinase role in inhibition of eEF2 that it protein synthesis via an pathway. This may the phosphorylation of the 40 S ribosomal protein which has also been as a mechanism by which p70S6 kinase can activate the translation of of for ribosomal and elongation C. G. Sci. U. S. A. 1994; Scholar, S. C. G. EMBO J. 16: Scholar). Because to a increase in the of the inhibition of p70S6 kinase may to the decreased of protein synthesis in which were a of the role of the 40 S ribosomal protein S6 in Although we not changes in phosphorylation of eEF2 kinase at both phenylephrine treatment and decreased levels of eEF2 phosphorylation and in to increased eEF2 activity and elongation. the decrease in eEF2 phosphorylation resulting from phenylephrine treatment and can be by AMPK activation and Indeed, our data that and activation of AMPK in a increase in eEF2 This response that AMPK activation that protein synthesis occurs during of energy which may be important that protein synthesis a of the Because eEF2 is the substrate for eEF2 kinase (9Nairn A.C. Palfrey H.C. J. Biol. Chem. 1987; 262: 17299-17303Google Scholar), it is that the target of AMPK is eEF2 kinase and not Indeed, we have recently shown that AMPK activation results in the phosphorylation and activation of eEF2 kinase (16Browne G.J. Finn S.G. Proud C.G. J. Biol. Chem. 2004; 279: 12220-12231Google Scholar). This occurs as a of the increased phosphorylation of eEF2 kinase at a novel not shown to be by upstream to be a substrate for AMPK (16Browne G.J. Finn S.G. Proud C.G. J. Biol. Chem. 2004; 279: 12220-12231Google Scholar). It is to that AMPK activation results in increased eEF2 kinase phosphorylation at suggesting that increased eEF2 phosphorylation and decreased protein synthesis are by AMPK through the phosphorylation and activation of eEF2 kinase. Although cardiac eEF2 kinase phosphorylation at site with AMPK (16Browne G.J. Finn S.G. Proud C.G. J. Biol. Chem. 2004; 279: 12220-12231Google Scholar), the levels of eEF2 kinase in have that that activate AMPK increase eEF2 kinase We have shown that activation AMPK activity S. I. K. J. Biol. Chem. 2003; 278: Scholar). In to the the data also as to may myocyte growth on cellular energy The ability of to regulate AMPK may signaling can regulate cardiac growth during development T. T. S. Mol. Cell. Biol. 2002; Scholar, I. M. Y. A. J. A. K. J. Biol. Chem. 2002; Scholar, T. J. J. S. EMBO J. 2000; Scholar). This inactivation of AMPK also mechanism by which can cardiac hypertrophy. it is possible that a to Akt-induced hypertrophy may be the of a protein synthesis such as In to the inhibition of AMPK not to be a necessary of hypertrophic growth induced by phenylephrine Indeed, our data not the that AMPK is a necessary of hypertrophic signaling However, our data that AMPK activation can on at two signaling pathways involved in cardiac hypertrophy. This that at of the pharmacological activation of AMPK is the inhibition of protein synthesis, which may hypertrophic growth. the in the role of AMPK in cardiac hypertrophy has not been In to the results found in et al. N. J. M.F. Circulation. 2001; Scholar) have shown that increased AMPK activity is with the development of induced cardiac hypertrophy. Although the for are it may be to the that AMPK can both and be cardiac energy Because the hypertrophic heart a switch in substrate utilization involving a decrease in fatty acid oxidation and an increase in glucose it is that the progression of hypertrophy is with an were the AMPK become active in response to ATP At it is that an increase in AMPK activity inhibit protein synthesis via activation of eEF2 kinase phosphorylation and subsequent inhibition of eEF2 and/or inhibition of the p70S6 kinase pathway. Therefore, it is to that pharmacological activation of AMPK during the of hypertrophy or the progression of hypertrophic growth. Recent has also activation of AMPK with the of hypertrophic growth in the heart M. M. Li D. A. S. C.E. J.G. Circulation. 2003; Scholar). a results in increase AMPK which hypertrophic growth M. M. Li D. A. S. C.E. J.G. Circulation. 2003; Scholar). However, the of AMPK activity in also resulted in M. M. Li D. A. S. C.E. J.G. Circulation. 2003; Scholar), which has been shown to cardiac hypertrophy M. K. J.G. C.E. J. 2002; Scholar). Therefore, it is unknown AMPK activation hypertrophy or whether it occurs as a of to AMPK Although our data that AMPK activation can inhibit protein synthesis with two cellular to myocyte it is that AMPK activation may not be able to inhibit the pathways to cardiac myocyte growth. This may be the with cardiac hypertrophy. our data that AMPK activation can on at two signaling pathways involved in cardiac hypertrophy. data also that a of AMPK activation is to inhibit protein synthesis via the eEF2 kinase/eEF2 signaling axis and/or the p70S6 kinase pathway. Although it is not whether AMPK activation also signaling involved with hypertrophic the inhibition of protein synthesis by AMPK may be a regulatory mechanism hypertrophic growth. This the that pharmacological activation of AMPK can or the progression of cardiac hypertrophy in of cardiac hypertrophy or in We the of
Chan et al. (Tue,) studied this question.