View the Current Issue

Article

  • The EMBO Journal (2003) 22, 4666 - 4676
  • doi:10.1093/emboj/cdg469

Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia

Alfonso Mora1, Anthony M. Davies2, Luc Bertrand3, Isam Sharif4, Grant R. Budas2, Sofija Jovanovic acute2, Véronique Mouton3, C. Ronald Kahn5, John M. Lucocq6, Gillian A. Gray4, Aleksandar Jovanovic acute2 and Dario R. Alessi1

  1. MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK
  2. Maternal and Child Health Sciences, Tayside Institute of Child Health, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  3. Hormone and Metabolic Research Unit, Institute of Cellular Pathology and University of Louvain Medical School, Belgium
  4. Centre for Cardiovascular Science, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
  5. Joslin Diabetes Centre, Department of Medicine, Harvard Medical School, Boston, MA, USA
  6. Division of Cell Biology and Immunology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK

Correspondence to:

Alfonso Mora, E-mail: a.m.corral@dundee.ac.uk

Received 14 February 2003; Accepted 28 July 2003; Revised 10 July 2003

We employed Cre/loxP technology to generate mPDK1-/- mice, which lack PDK1 in cardiac muscle. Insulin did not activate PKB and S6K, nor did it stimulate 6-phosphofructo-2-kinase and production of fructose 2,6-bisphosphate, in the hearts of mPDK1-/- mice, consistent with PDK1 mediating these processes. All mPDK1-/- mice died suddenly between 5 and 11 weeks of age. The mPDK1-/- animals had thinner ventricular walls, enlarged atria and right ventricles. Moreover, mPDK1-/- muscle mass was markedly reduced due to a reduction in cardiomyocyte volume rather than cardiomyocyte cell number, and markers of heart failure were elevated. These results suggested mPDK1-/- mice died of heart failure, a conclusion supported by echocardiographic analysis. By employing a single-cell assay we found that cardiomyocytes from mPDK1-/- mice are markedly more sensitive to hypoxia. These results establish that the PDK1 signalling network plays an important role in regulating cardiac viability and preventing heart failure. They also suggest that a deficiency of the PDK1 pathway might contribute to development of cardiac disease in humans.

  • Keywords:

    • cardiac muscle,
    • heart failure,
    • hypoxia,
    • PDK1,
    • PI 3-kinase,
    • PKB,
    • Akt