Abstract 11185: Expression of Slow Skeletal TnI Confers Metabolic Protection to Ischemia via Increased Glycolysis
Changes in metabolic profiles coincide with modifications of contractile proteins in developing and stressed hearts. However, reciprocal adaptations between contractile and metabolic phenotypes are not well understood. This study explores metabolic adaptations to changes in sarcomeric protein isoforms. Adult cardiomyocytes express cardiac troponin I, while the fetal isoform is slow skeletal muscle troponin (ssTnI). The influence of ssTnI on the metabolic response to ischemia was examined in hearts of adult male mice (5 mos): a transgenic (TG) model of cardiac ssTnI expression and nontransgenic littermates (NTG). 31P NMR of isolated hearts perfused with glucose + palmitate showed no ATP loss over 5 minutes of global ischemia in TG-ssTnI (n=6), while NTG (n=6) showed continual ATP loss. TG-ssTnI also retained more ATP than NTG by 7 min ischemia (P<0.05). Other hearts, perfused with 10 mM [1,6–13C2] glucose plus 0.4 mM unlabeled palmitate, were frozen at 2 or 5 min zero flow ischemia. Glycolytic end products, lactate and alanine, were elevated in TG-ssTnI (n=8) by 38%; over NTG (n=8) at 2 min and by 27%; at 5 min (ss-TnI, n=9; NTG, n=7), indicating elevated anaerobic glycolysis in TG-ssTnI. TG-ssTnI had greater 13C enrichment of lactate (ssTnI = 43±5%;, NTG = 30±7) and alanine (ssTnI = 46±5%;, NTG=31±7), showing increased use of exogenous glucose versus glycogen. 13C lactate and 13C alanine accounted for the difference in total glycolytic end product between groups, suggesting greater glucose uptake and/or preferential use of exogenous glucose. TG-ssTnI contained more glycogen than NTG at 5 min ischemia (TG-ssTnI = 14.2±4 micromole glucosyl units/g dw; NTG = 7.4±2). Baseline AMPK phosphorylation was elevated in ssTnI (50±0.3%;) over NTG (30±0.4), but ischemia increased AMPK activation to similar levels in both groups, with no differences in glucose transporter content. Thus, expression of a fetal contractile protein in adult mouse hearts induced a metabolic phenotype consistent with the increased metabolic resistance to hypoxia characteristic of the fetal heart. The findings indicate that metabolism adjusts to myofilament activity, and ssTnI confers metabolic protection to ischemia by enhanced glycolysis, possibly linked to elevated baseline AMPK activation.
- © 2010 by American Heart Association, Inc.