Abstract
Carnitine palmitoyl transferase (CPT) 1 is the rate-limiting enzyme controlling long chain fatty acid (LCFA) oxidation in the heart. The muscle isoform, CPT1b, is predominantly expressed in heart along with the liver isoform, CPT1a, that is co-expressed at comparatively low levels. However, CPT1a content increases in response to pathological stress. Both neonatal and pathologically hypertrophied hearts display elevated CPT1a, despite low LCFA oxidation. To understand the role of cardiac CPT1a, cpt1a fl/fl (fl/fl) mice were crossed with mice heterozygous for cre recombinase under the control of the cardiac specific α-MHC promoter to generate cardiac specific cpt1a null mice (cpt1a null). Echocardiography revealed that CPT1a deletion induces age-related declines in systolic function and reduced left ventricular wall thickness. At 5 mos, cpt1a null showed no significant functional defects. At 10 mos, cpt1a null hearts displayed reduced ejection fraction (EF) and fractional shortening (FS) vs fl/fl mice (EF 63±1 fl/fl vs. 21±5 cpt1a null; FS 52±1 fl/fl vs. 18±2 cpt1a null, p<0.0001) with elevated systolic and diastolic volumes. Also at 10 mos, PPARα and PGC1α gene expression declined in CPT1a null hearts by 44% and 22% respectively, vs f/f mice (from arbitrary units referenced to f/f/ control signal, AU). The reduced activation of PPARα and PGC1α genes is the potential consequence of reduced ligand from ATGL-dependent triacylglycerol lipolysis, due to low ATGL gene expression (38% decrease vs. 5 mos f/f, p<0.01, AU). CPT1b gene expression was reduced by 26% (AU) at 10 mos vs f/f/, which is consistent with changes in PPARα, but was not sufficient to alter CPTb protein content. As with CPT1b content, the fractional contribution of exogenous LCFA to oxidative metabolism in hearts perfused with media containing 13C palmitate, glucose, and lactate, was similar among groups, ranging from 0.70-0.73. Therefore, CPT1a does not impact the contribution of LCFA oxidation to mitochondrial energy metabolism in unstressed hearts. However, as hearts age, CPT1a plays a critical role in maintaining transcriptional activation of genes for LCFA metabolism enzymes, via PGC-1α and PPARα and in maintaining normal cardiac function and pathophysiology.
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