Abstract 17888: Cardiac LKB1 Deficiency Promotes Cardiac Dysfunction During Dietary Metabolic Challenge Independent of AMPK
Background: LKB1 is a main activator of the metabolic stress response enzyme, AMP-activated protein kinase (AMPK), as well as members of the AMPK-related kinase (ARK) family. Deletion of cardiac LKB1 causes hypertrophy, contractile dysfunction, arrhythmias and early death, but elimination of AMPK activity has little effect on the unstressed heart, suggesting important cardiac LKB1 targets besides AMPK. Whether AMPK activity is altered in diabetes is controversial, but diet-induced metabolic heart disease leads to decreased LKB1 activity through post-translational modifications. We hypothesized LKB1 is essential to the heart’s response to dietary metabolic challenge by a high-fat/high-sucrose (HFHS) diet independent of AMPK.
Methods: Mice heterozygous for cardiac LKB1 (LKB1+/-) were generated by breeding homozygous floxed LKB1 and αMHC Cre mice, and were compared (n=7-8/group) to WT and AMPK deficient mice (AMPK-KD). Mice were fed normal or HFHS chow (58% kcal fat, 28% kcal sucrose) for 4 months, with measurement of cardiac structure/function by high-resolution echocardiography.
Results: On normal diet, both LKB1+/- and AMPK KD hearts develop normally up to 1 year. LKB1+/- hearts have a 50% decrease in LKB1 expression and activity. Despite a 50% decrease in basal AMPK phosphorylation, ischemic AMPK activation is normal in perfused LKB1+/- hearts. After 4 months of HFHS diet compared to WT, LKB1+/- hearts develop mild hypertrophy (PWd; 1.24 vs. 1.19 mm, p=0.11), but severe systolic dysfunction (%FS; 41% vs. 59%, p<0.01) and increased LV diameter (3.6 vs. 3.2 mm, p<0.05), as well as restrictive diastolic filling (E/A ratio; 5.5 vs. 1.3, p=0.05). In contrast, AMPK KD hearts + HFHS diet develop more significant cardiac hypertrophy vs. WT (1.35 vs. 1.19 mm, p=0.09) but preserved LV systolic function (p=n.s.) and only mildly impaired diastolic relaxation (E/A; 1.3 vs. 2.0, p=0.06).
Conclusions: HFHS dietary challenge leads to profound systolic dysfunction and LV dilation in LKB1+/- hearts, despite normal stimulated AMPK activity. In contrast, AMPK KD hearts on HFHS diet have only mild diastolic dysfunction without systolic compromise. This suggests other pathways downstream of LKB1 play a key role in the heart during metabolic stress, independent of AMPK.
- © 2013 by American Heart Association, Inc.