Open‐chest ³¹P magnetic resonance spectroscopy of mouse heart at 4.7 Tesla

Abstract

Purpose: To develop a rapid, robust, and accurate method for assessing myocardial energetics in mice and demonstrate its applicability to mouse models of acquired and genetic heart disease. Materials and Methods:We combined surface coil localization (10-mm diameter, tunable between 1 H and 31 P, using adiabatic half-passage radiofrequency pulses) and surgery (electrocautery removal of anterior chest wall) to create an open-chest method for acquiring in vivo 31 P nuclear magnetic resonance (NMR) cardiac spectra from mice at 4.7T within 12 minutes. Normal BALB/c mice, BALB/c with myocardial infarction (MI), cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta knockout (KO) (CR-PPARd -/-) and control loxP-flanked Ppard (Ppardflox/flox ) mice were examined. Results:The mean phosphocreatine (PCr)/adenosine triphosphate (ATP) ratios in control BALB/c mice, BALB/c MI mice, Ppard flox/flox mice, and PPAR-␦ KO mice were 2.13 Ϯ 0.09 (N ϭ 11), 1.35 Ϯ 0.07 (N ϭ 9, P Ͻ 0.001 vs. BALB/c control), 1.92 Ϯ 0.09 (N ϭ 5), and 1.31 Ϯ 0.12 (N ϭ 5, P Ͻ 0.005 vs. Ppard flox/flox control), respectively. The significant depression of myocardial PCr/ATP we observed in these genetic/acquired models of heart disease was in accord with previous data from analogous large animal models. No NMR signal contamination from chamber blood or adjacent skeletal muscle was identified. Conclusion: This new technique provides cardiac31 P spectra suitable for accurate quantitative analysis in a relatively short acquisition time, is suitable for terminal studies of mouse myocardial energy metabolism, and could be installed in virtually any NMR laboratory to study myocardial energetics in numerous mouse models of human heart disease.

Peroxisome proliferator-activated receptor δ regulates mitofusin 2 expression in the heart

“…Our previous study demonstrated that myocardial energetic defect and myocardial FAO depression were the main features of mice with cardiomyocyte-restricted PPARδ deficiency (CR-PPARδ −/− ) [20] [25]. To investigate cardiac Mfn2 expression in CR-PPARδ −/− hearts, expression levels of Mfn2 genes were evaluated by Real Time PCR measurement on RNA samples from CR-PPARδ −/− and control mice before overt phenotypic changes.…”

Peroxisome Proliferator-Activated Receptor δ Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart

“…We previously demonstrated that PPARδ is required for normal transcript expression of series essential enzymes that govern myocardial FAO in the long-term cardiomyocyte-restricted PPARδ knockout (CR-PPARδ −/− ) mouse model3, These mice exhibited depressed myocardial FAO and bioenergetics, eventually leading to dilated cardiomyopathy with myocardial lipid accumulation in adult and older mice3, 9. The gene knockout event in the CR-PPARδ −/− mice, mediated by α-MyHC-driven expression of Cre recombinase, is expressed in ventricles during early development and robustly from new born stage.…”

“…In the heart, the three subtypes of PPARs, PPARα, γand δ are expressed at various levels and play important roles in myocardial lipid and glucose metabolisms1–7. We have demonstrated that PPARδ is required for normal transcript expression of series essential enzymes of fatty acid oxidation (FAO) in the heart and that cardiomyocyte-restricted PPARδ knockout resulted in depressed myocardial FAO and bioenergetics, cardiac hypertrophy and heart failure8, 9. Furthermore, there is emerging evidence demonstrating that PPARs may play a role in regulating transcriptional expression of antioxidants, such as Cu/Zn-Superoxide dismutase (SOD1) 10, manganese superoxide dismutase (SOD2)11, 12, and catalase13–15.…”

Peroxisome Proliferator-Activated Receptor β/δ Activation in Adult Hearts Facilitates Mitochondrial Function and Cardiac Performance Under Pressure-Overload Condition

“…4, 7, 8 Long-term, postnatal, cardiomyocyte-restricted PPARβ/δ deletion in mice perturbs myocardial fatty acid oxidation (FAO) and leads to cardiac dysfunction, bioenergetic defect, cardiac hypertrophy and lipotoxic cardiomyopathy. 4, 9 We have recently discovered that PPARβ/δ is essential for the adult heart to maintain mitochondrial capacity and oxidative metabolism. 10 However, little is known about the gain-of-function effects of PPARβ/δ activation in the adult heart.…”