Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy.
The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway.
Zhao
Guixiang
G
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
Jeoung
Nam Ho
NH
Burgess
Shawn C
SC
Rosaaen-Stowe
Kimberly A
KA
Inagaki
Takeshi
T
Latif
Shuaib
S
Shelton
John M
JM
McAnally
John
J
Bassel-Duby
Rhonda
R
Harris
Robert A
RA
Richardson
James A
JA
Kliewer
Steven A
SA
D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000201:enzymology*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014463:Ultrasonography
C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D019289:Pyruvic Acid; D017346:Protein Serine-Threonine Kinases; D019703:Calcineurin