Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function.
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 AMPKalpha2 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.
Jessen
Niels
N
Joslin Diabetes Center, Boston, MA 02215, USA.
Koh
Ho-Jin
HJ
Folmes
Clifford D
CD
Wagg
Cory
C
Fujii
Nobuharu
N
Løfgren
Bo
B
Wolf
Cordula M
CM
Berul
Charles I
CI
Hirshman
Michael F
MF
Lopaschuk
Gary D
GD
Goodyear
Laurie J
LJ
D055372:AMP-Activated Protein Kinases; D000332:Aerobiosis / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics*; D017353:Gene Deletion; D006321:Heart / Q000502:physiology; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D009924:Organ Culture Techniques; D009928:Organ Specificity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases