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Activation of cardiac AMP-activated protein kinase by LKB1 expression or chemical hypoxia is blunted by increased Akt activity

Cardiovascular Research Group, Departments of Pediatrics and Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

Submitted 15 November 2005 ; accepted in final form 17 January 2006

AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac energy substrate utilization and can be negatively regulated by Akt activation in the heart. It has recently been shown that Akt directly phosphorylates AMPK₁/₂ on Ser^485/491 in vitro and prevents the AMPK kinase (AMPKK) LKB1 from phosphorylating AMPK at its primary activation site, Thr¹⁷² (S Horman, D Vertommen, R Heath, D Neumann, V Mouton, A Woods, U Schlattner, T Wallimann, D Carling, L Hue, and MH Rider. J Biol Chem 281: 5335–5340, 2006). To determine whether this is also the case in the cardiac myocyte, neonatal rat cardiac myocytes (NRCM) were infected with a recombinant adenovirus expressing a constitutively active mutant of Akt1 (myrAkt1) and then with or without adenoviruses expressing the active LKB1 complex. Expression of myrAkt1 blunted LKB1-induced phosphorylation of AMPK at Thr¹⁷², which resulted in a dramatic decrease in phosphorylation of AMPK's target, acetyl CoA-carboxylase. This decrease in AMPK activity was associated with prior Akt1-dependent phosphorylation of AMPK₁/₂ at Ser^485/491. To investigate whether Akt1 activation was also able to prevent other AMPKKs from phosphorylating AMPK, we subjected NRCM to chemical hypoxia and noted a marked increase in phosphorylation of AMPK at Thr¹⁷², despite no change in LKB1 activity. NRCM expressing myrAkt1 demonstrated increased phosphorylation of AMPK₁/₂ at Ser^485/491 and a complete inhibition of chemical hypoxia-induced phosphorylation of AMPK at Thr¹⁷². Taken together, our data show that activation of Akt1 is able to prevent activation of cardiac AMPK by LKB1 and at least one other AMPKK, likely by prior phosphorylation of AMPK₁/₂ at Ser^485/491.

cardiac myocyte; metabolism; insulin; ischemia; AMP-activated protein kinase kinase

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