Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function

Niels Jessen, Ho Jin Koh, Clifford D. Folmes, Cory Wagg, Nobuharu Fujii, Bo Løfgren, Cordula M. Wolf, Charles I. Berul, Michael F. Hirshman, Gary D. Lopaschuk, Laurie J. Goodyear

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36 Scopus citations

Abstract

Energy deprivation in the myocardium is associated with impaired heart function and increased morbidity. LKB1 is a kinase that is required for activation of AMP-activated protein kinase (AMPK) as well as 13 AMPK-related protein kinases. AMPK stimulates ATP production during ischemia and prevents post-ischemic dysfunction. We used the Cre-Lox system to generate mice where LKB1 was selectively knocked out in cardiomyocytes and muscle cells (LKB1-KO) to assess the role of LKB1 on cardiac function in these mice.Heart rates of LKB1-KO mice were reduced and ventricle diameter was increased. Ex vivo, cardiac function was impaired during aerobic perfusion of isolated working hearts, and recovery of function after ischemia was reduced. Although oxidative metabolism and mitochondrial function were normal, the AMP/ATP ratio was increased in LKB1-KO hearts. This was associated with a complete ablation of AMPK α 2 activity, and a stimulation of signaling through the mammalian target of rapamycin. Our results establish a critical role for LKB1 for normal cardiac function under both aerobic conditions and during recovery after ischemia. Ablation of LKB1 leads to a decreased cardiac efficiency despite normal mitochondrial oxidative metabolism.

Original languageEnglish (US)
Pages (from-to)593-600
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1802
Issue number7-8
DOIs
StatePublished - Jul 1 2010

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Keywords

  • AMP-activated protein kinase
  • Cardiac function
  • LKB1
  • MTOR

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Jessen, N., Koh, H. J., Folmes, C. D., Wagg, C., Fujii, N., Løfgren, B., Wolf, C. M., Berul, C. I., Hirshman, M. F., Lopaschuk, G. D., & Goodyear, L. J. (2010). Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1802(7-8), 593-600. https://doi.org/10.1016/j.bbadis.2010.04.008