Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia.
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.
Mora
Alfonso
A
MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Davies
Anthony M
AM
Bertrand
Luc
L
Sharif
Isam
I
Budas
Grant R
GR
Jovanović
Sofija
S
Mouton
Véronique
V
Kahn
C Ronald
CR
Lucocq
John M
JM
Gray
Gillian A
GA
Jovanović
Aleksandar
A
Alessi
Dario R
DR
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D004452:Echocardiography; D004789:Enzyme Activation; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics*; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000502:physiology*; D009206:Myocardium / Q000473:pathology*; D025481:Phosphofructokinase-2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; D025481:Phosphofructokinase-2; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases