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Metabolic alterations beyond fatty acid oxidation defects in PPARα null mice hearts
Author(s) -
Gélinas Roselle,
Bouchard Bertrand,
McDuff Janie,
Charron Guy,
Rosiers Christine Des
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1376
Subject(s) - medicine , beta oxidation , endocrinology , preload , glycolysis , citric acid cycle , lactate dehydrogenase , pyruvate carboxylase , pyruvate dehydrogenase complex , fatty acid , in vivo , metabolism , citrate synthase , biology , chemistry , biochemistry , enzyme , hemodynamics , microbiology and biotechnology
Subjects with fatty acid oxidation (FAO) defects develop a cardiomyopathy, yet the underlying mechanism is unclear. Using our established working mouse heart model and 13 C‐methodology, we compared the metabolic and functional response of hearts from PPARα null mice, a model of FAO defect, and control C57BL/6 mice at two workloads. Compared to controls, perfused hearts from PPARα null mice depicted functional parameters similar to controls at 12 mmHg preload, but displayed an impaired response to a raise in preload as reflected by a 20% decline in aortic flow and cardiac efficiency, and enhanced MVO 2 (20%) and lactate dehydrogenase release (2‐fold) (p<0.05). At the metabolic level, these hearts showed the expected shift from FA (4‐fold down) to carbohydrate (CHO: 2‐fold up; P<0.001), yet flux through anaplerotic pyruvate carboxylation (PC) expressed relative to citric acid cycle (CAC) or pyruvate decarboxylation (PDC), as well as CAC intermediate levels, were similar to controls at both preloads. However, glycolytic rates, expressed as absolute values or relative to PDC were differentially affected by preloads, suggesting a potential mismatch between cytosolic and mitochondrial CHO metabolism in PPARα null mice hearts. Interestingly, when clamped in vivo , these hearts showed higher levels of citrate and malate, suggesting additional, yet‐to‐be identified, factor(s) determining CAC intermediate pool size in vivo. Gene expression analysis revealed no change for PC, but 20% lower propionyl‐CoA carboxylase mRNA levels. Collectively, our data highlight metabolic alterations in PPARα null mice hearts, beyond their lower FAO, which may determine their response to increased energy demand. (Supported by NIH & CIHR)