Regulation of fatty acid metabolism by mTOR in adult murine hearts occurs independently of changes in PGC-1α

Abstract

Mechanistic target of rapamycin (mTOR) is essential for cardiac development, growth, and function, but the role of mTOR in the regulation of cardiac metabolism and mitochondrial respiration is not well established. This study sought to determine cardiac metabolism and mitochondrial bioenergetics in mice with inducible deletion of mTOR in the adult heart. Doxycycline-inducible and cardiac-specific mTOR-deficient mice were generated by crossing cardiac-specific doxycycline-inducible tetO-Cre mice with mice harboring mTOR floxed alleles. Deletion of mTOR reduced mTORC1 and mTORC2 signaling after in vivo insulin stimulation. Maximum and minimum dP/dt measured by cardiac catheterization in vivo under anesthesia and cardiac output, cardiac power, and aortic pressure in ex vivo working hearts were unchanged, suggesting preserved cardiac function 4 wk after doxycycline treatment. However, myocardial palmitate oxidation was impaired, whereas glucose oxidation was increased. Consistent with reduced palmitate oxidation, expression of fatty acid metabolism genes fatty acid-binding protein 3, medium-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein)-α and -β was reduced, and carnitine palmitoyl transferase-1 and -2 enzymatic activity was decreased. Mitochondrial palmitoyl carnitine respiration was diminished. However, mRNA for peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and -1β, protein levels of PGC-1α, and electron transport chain subunits, mitochondrial DNA, and morphology were unchanged. Also, pyruvate-supported and FCCP-stimulated respirations were unchanged, suggesting that mTOR deletion induces a specific defect in fatty acid utilization. In conclusion, mTOR regulates mitochondrial fatty acid utilization but not glucose utilization in the heart via mechanisms that are independent of changes in PGC expression.

Epigenome-Wide Association of Liver Methylation Patterns and Complex Metabolic Traits in Mice

“…In addition, we identified CpGs in chromosome 8 associated with the second principal component and with expression levels of Mtor (Figure 4F). Mtor plays a role in metabolic regulation, response to nutrients, insulin and diabetes (Zhu et al, 2013). …”

Characterization of Mitochondrial Content and Respiratory Capacities of Broiler Chicken Skeletal Muscles with Different Muscle Fiber Compositions

“…Mitochondrial CPT1 and CPT2 activities were measured as previously described (Zhu et al, 2013). Briefly, mitochondria were incubated in assay medium (20 mM HEPES [pH 7.4], 1 mM EGTA, 220 mM sucrose, 40 mM KCl, 100 μM DTNB, 1.3 mg/mL bovine serum albumin, and 40 μM palmitoyl-CoA) prewarmed to 25 °C, to which 1 mM carnitine was added to measure total CPT activity.…”

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

“…A temporal knockout of mTOR in adult heart demonstrated that mTOR is also needed for normal mitochondrial function, fatty acid oxidation, and heart contraction (16). However, the consequences of chronic mTORC1 hyperactivation in adult heart are less well understood.…”

“…Within 10 wk of inducing the knockout, hearts lacking ACSL1 develop mTORC1-dependent hypertrophy (12). mTORC1 activation has many consequences in cells, including stimulation of growth and protein synthesis (13,14), regulation of lipid metabolism (15,16), and inhibition of autophagy (17). Inhibition of mechanistic target of rapamycin (mTOR) is associated with longer life span (18), but total loss of mTOR in the heart inhibits mitochondrial respiratory function and causes heart failure (16).…”