Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha

Kei Sakamoto, Elham Zarrinpashneh, Grant Budas, Anne-Catherine Pouleur, Anindya Dutta, Alan R. Prescott, Jean-Louis Vanoverschelde, Alan Ashworth, Aleksandar Jovanovic, Dario Alessi, Luc Bertrand

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    Abstract

    Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase (AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPKa1/a2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPKa2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPKa2 at the site of LKB1 phosphorylation (Thr172) or phosphorylation of acetyl-CoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPKa2, significant basal activity of AMPKa1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPKa1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPKa2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPKa1 in cardiac muscle.
    Original languageEnglish
    Pages (from-to)E780-E788
    JournalAmerican Journal of Physiology, Endocrinology and Metabolism
    Volume290
    Issue number5
    DOIs
    Publication statusPublished - 2006

    Keywords

    • Cellular energy metabolism
    • Hypoxia
    • Cardiovascular physiology
    • AMP-activated protein kinase

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    Sakamoto, K., Zarrinpashneh, E., Budas, G., Pouleur, A-C., Dutta, A., Prescott, A. R., Vanoverschelde, J-L., Ashworth, A., Jovanovic, A., Alessi, D., & Bertrand, L. (2006). Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKalpha2 but not AMPKalpha. American Journal of Physiology, Endocrinology and Metabolism, 290(5), E780-E788. https://doi.org/10.1152/ajpendo.00443.2005