Abstract 15083: Substitution of Adult Cardiac Troponin I, cTnI, With the Fetal Isoform, ssTnI, in Adult Mice Augments Metabolic Remodeling and Reduces Both Decompensatory Hypertrophy and Contractile Dysfunction During Chronic Pressure Overload
The fetal heart is primarily dependent on glycolysis, but following birth switches to oxidative, long chain fatty acid (LCFA)-dependent metabolism. Adult hearts under pathological stress revert to a fetal metabolic profile. Paralleling metabolic development is the replacement of the fetal isoform of the contractile protein, troponin I (slow skeletal- or ssTnI) by adult cardiac isoform (cTnI). Interestingly, troponin does not revert to its fetal isoform in response to stress unlike other contractile proteins. We previously found adult transgenic mouse hearts expressing ssTnI, to be protected from ischemia by increased glycolytic flux. Since pressure overload induces a fetal metabolic profile, we investigated the response of adult mouse hearts expressing ssTnI to transverse aortic constriction (TAC) for comparison to sham operated mice (Sham).
Transgenic, ssTnI expressing mice and nontransgenic (NTG) littermates (2-3 mos) underwent TAC. At 10 weeks, TAC induced a 25% increase in NTG heart weight:tibila length but only a 7% increase in ssTnI hearts (P<0.05). NTG-TAC hearts developed diastolic dysfunction (↑65% E/A ratio), while E/A actually decreased in ssTnI-TAC hearts. Hearts were isolated at 12-13 weeks post-TAC and perfused with 13C palmitate and unlabeled glucose and lactate or 13C labeled glucose with unlabeled palmitate and lactate for NMR analysis. Isolated NTG-TAC hearts showed reduced cardiac function (cardiac work ↓40%, dp/dt ↓35%), and a low energy charge vs Sham (PCr:ATP ratio↓16%). Surprisingly, no changes in cardiac function were evident in isolated ssTnI-TAC hearts mice and PCr:ATP was normal (2.11±0.18, n=10 vs. 2.19±0.21 ssTnI sham, n=7). The fraction of palmitate oxidized in the TCA cycle was reduced in ssTnI-TAC (0.61±0.02, n=9 vs. 0.70±0.02, n=8 ssTnI-Sham) with increased glucose oxidation, while NTG TAC hearts showed a relatively small shift in palmitate oxidation (0.67±0.02, NTG-TAC n=8 vs. 0.70±0.03 NTG-Sham, n=6).
Expression of a single fetal myofilament protein into adulthood in the ssTnI mouse heart confers protection against cardiac decompensation due to pressure overload by inducing an enhanced metabolic remodeling with preserved energetics.
- © 2013 by American Heart Association, Inc.