Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPK alpha 2 but not AMPK alpha 1
MetadataShow full item record
Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPK alpha 2 but not AMPK alpha 1 Recent studies indicate that the LKB1 is a key regulator of the AMP-activated protein kinase ( AMPK), which plays a crucial role in protecting cardiac muscle from damage during ischemia. We have employed mice that lack LKB1 in cardiac and skeletal muscle and studied how this affected the activity of cardiac AMPK alpha 1/alpha 2 under normoxic, ischemic, and anoxic conditions. In the heart lacking cardiac muscle LKB1, the basal activity of AMPK alpha 2 was vastly reduced and not increased by ischemia or anoxia. Phosphorylation of AMPK alpha 2 at the site of LKB1 phosphorylation (Thr(172)) or phosphorylation of acetylCoA carboxylase-2, a downstream substrate of AMPK, was ablated in ischemic heart lacking cardiac LKB1. Ischemia was found to increase the ADP-to-ATP (ADP/ATP) and AMP-to-ATP ratios (AMP/ATP) to a greater extent in LKB1-deficient cardiac muscle than in LKB1-expressing muscle. In contrast to AMPK alpha 2, significant basal activity of AMPK alpha 1 was observed in the lysates from the hearts lacking cardiac muscle LKB1, as well as in cardiomyocytes that had been isolated from these hearts. In the heart lacking cardiac LKB1, ischemia or anoxia induced a marked activation and phosphorylation of AMPK alpha 1, to a level that was only moderately lower than observed in LKB1-expressing heart. Echocardiographic and morphological analysis of the cardiac LKB1-deficient hearts indicated that these hearts were not overtly dysfunctional, despite possessing a reduced weight and enlarged atria. These findings indicate that LKB1 plays a crucial role in regulating AMPK alpha 2 activation and acetyl-CoA carboxylase-2 phosphorylation and also regulating cellular energy levels in response to ischemia. They also provide genetic evidence that an alternative upstream kinase can activate AMPK alpha 1 in cardiac muscle.
License start date
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2006, 290 pp. E780 - E788