Abstract 14191: Deletion of Mtor in the Adult Mouse Heart Impairs Fatty Acid Utilization but Not Glucose Utilization
mTOR has been shown to regulate mitochondrial oxidative capacity in skeletal muscle through transcriptional regulation of PGC-1α by YY1. To determine if mTOR signaling regulates mitochondrial biogenesis and function in the heart, we generated inducible and cardiac specific mTOR deficient mice (abbreviated as iCmTORKO). mTOR floxed mice were crossed with mice harboring a doxycycline (DOX) inducible TetO Cre governed by cardiac-restricted expression of reverse tetracycline transactivator (rtTA) protein. 4 weeks after DOX injection, there was an 83.2% decrease in mTOR protein in iCmTORKO hearts compared to controls, while mTOR protein levels in liver or skeletal muscle were maintained. In iCmTORKO hearts, insulin stimulated S6, 4E-BP1 and Akt Ser473 phosphorylation was blunted, consistent with decreased signaling from mTORC1 and mTORC2. Cardiac output, cardiac power, and LV Dev pressure in ex vivo working hearts were unchanged 4 weeks after DOX injection. However, myocardial palmitate oxidation (POX) was reduced by 16.4%, and oxygen consumption was reduced by 24.9% in iCmTORKO hearts. Glycolysis was not changed but glucose oxidation in iCmTORKO hearts was increased by 53.7%. Consistent with reduced POX, expression of fatty acid metabolism genes FABP3, MCAD, HADHA, HADHB was reduced, and CPT1 and CPT2 enzymatic activity was decreased by 41% and 32% respectively. However protein levels of PGC-1α and mRNA for PGC-1α and PGC-1β were unchanged. Mitochondrial function was determined using saponin-permeabilized cardiac fibers. Mitochondrial respiration with palmitoyl carnitine as substrate was reduced by 20.0% in iCmTORKO cardiac fibers, and was accompanied by an 18.9% reduction in ATP production rates. ATP/O ratios were not changed, indicating that mitochondria were not uncoupled. By contrast, pyruvate respiration and ATP production rates were unchanged in iCmTORKO cardiac fibers. Thus deletion of mTOR specifically impairs mitochondrial fatty acid metabolism but not glucose utilization in the heart via mechanisms that are independent of changes in PGC1 content.
- © 2012 by American Heart Association, Inc.