Metabolic Efficiency Promotes Protection From Pressure Overload in Hearts Expressing Slow Skeletal Troponin I

Abstract

Background The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In the present study we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. Methods and Results At 2–3 months of age ssTnI mice or their nontransgenic (NTG) littermates underwent aortic constriction (TAC). TAC induced a 25% increase in NTG heart size but only a 7% increase in ssTnI hearts (P<0.05). NTG TAC developed diastolic dysfunction (65% increased E/A ratio), while the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from NTG TAC mice showed reduced cardiac function and reduced PCr:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting NTG TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in NTG TAC hearts. Elevated glucose oxidation was mediated by a reduction in PDK4 expression, enabling PDH to compete against anaplerotic enzymes for pyruvate carboxylation. Conclusions Expression of a single fetal myofilament protein into adulthood in the ssTnI-TG mouse heart induced downregulation of the gene expression response for PDK to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

“…Reduced expression of aerobic respiratory genes directly correlates with mitochondrial oxidative capacity in the heart; thus, the overwhelming number of aerobic respiratory genes downregulated with DCM and HF are presumed to be indicative of reduced mitochondrial respiration (39–41). Similarly, expression levels of genes regulating glucose metabolism correlate with metabolic flux (42, 43). Thus, we anticipate that the progressive increase in glycolytic gene expression is reflective of increased glucose utilization, possibly through increased nonoxidative glucose metabolism via glycogen synthesis, the hexosamine biosynthetic pathway, and the pentose phosphate shunt.…”

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

“…Following each perfusion, hearts were snap frozen with liquid nitrogencooled tongs. NMR spectroscopy of tissue extracts was used to quantify the fractional enrichment of acetyl-CoA (Fc) from glutamate isotopomers produced from labeled substrate oxidation -ketone or palmitate, as specified in text (54,55).…”

Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy

“…Indeed, in animal models of heart failure and importantly, CHF patients without diabetes, evidence exists for impaired insulin signaling within the cardiomyocytes of the failing heart 13, 14 . With the well-documented reduction of fat oxidation by pathologically hypertrophied hearts, we hypothesized a general systemic and a specific adipose metabolic shift to occur in response to chronic pressure overload of the heart 15–19 . The etiology of cardiac decompensation, as explored here in an animal model of chronic pressure overload, is distinct from heart failure with preserved ejection fraction (HFpEF) that can be either associated with obesity–associated adipose dysfunction and nutrient overload or induced by volume overload, as have recently been associated with beiging of adipose tissue 20 .…”