Abstract 1587: Conditional Overexpression of the Oncogene c-Myc Produces Hypertrophic Cardiomyopathy and Results in Mitochondrial Dysfunction at Complex I
c-Myc is transiently expressed early during cardiac pressure overload, but its pathological role is unclear. To address the contribution of c-myc in the genesis of cardiomyopathy, we established a tetracycline-inducible, cardiomyocyte-specific, c-myc-overexpressing bitrans-genic mouse. Doxycyline treatment (DOX) for 2 weeks (Myc-ON, n=5) increased cardiac mass two-fold with myocyte disarray, and increased fiber width and fibrosis compared to control mice (Myc-OFF, n=8); LV fractional shortening (15MHz, Sequoia, Siemens) was less (0.28±0.03(SEM) vs.0.53±0.04) and myocardial performance index was greater (0.91±0.15 vs. 0.36±0.03, both p<0.05) indicating ventricular dysfunction in Myc-ON vs. Myc-OFF. Death resulted from irreversible heart failure. The cell cycle markers PCNA, Ki-67 and cyclin D1 were strongly induced and BrdU incorporation confirmed cell cycle progression to S-phase. To determine if mitochondrial dysfunction contributed to the cardiomyopathy of c-Myc-overexpression, oxidative phosphorylation (OXPHOS) was studied with glutamate/malate (complex I), succinate (complex II) and TMPD-ascorbate (complex IV) as substrates. OXPHOS decreased with glutamate/malate (213±40 vs.329±25 nAO/min/mg, p<0.05) after two weeks of Myc-ON (n=4) vs. control (n=4), but was unaltered with other substrates, localizing a defect to complex I of the electron transport chain. The complex I defect was confirmed by a decrease in NADH:decylubiquinone oxidoreductase activity (561±49 vs.752±38 mU/mg). PGC-1a (a major regulatory mechanism of mitochondrial proliferation) was increased in Myc-ON, and ultrastructural analysis revealed a 2.5-fold increase in mitochondrial number, possibly in response to the OXPHOS defect. Taken together, these findings suggest:
cardiac restricted temporally-defined Myc overexpression turns on cell cycle machinery in cardiomyocytes and produces decompensated hypertrophic cardiomyopathy; and
activation of c-Myc leads to an OXPHOS defect at complex I.
Since complex I defects impair energy production and increase the production of reactive oxygen species, we speculate that mitochondrial dysfunction contributes to the cardiomyopathy that develops when adult cardiomyocytes overexpress c-Myc.