Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B

Weeghel, Michel van; Abdurrachim, Desiree; Nederlof, Rianne; Argmann, Carmen; Houtkooper, Riekelt H.; Hagen, Jacob; Nabben, Miranda; Denis, Simone; Čiapaitė, Jolita; Kolwicz, Stephen C.; Lopaschuk, Gary D.; Auwerx, Johan; Nicolay, Klaas; Rosiers, Christine Des; Wanders, Ronald J. A.; Zuurbier, Coert J.; Prompers, Jeanine J.; Houten, Sander M.

doi:10.1093/cvr/cvy089

Cited by 37 publications

(24 citation statements)

References 41 publications

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“…Preparations were done as previously reported (24,25). Briefly, mice were anesthetized with fentanyl (0.5 mg/kg), midazolam (9.4 mg/kg) and acepromazine (9.4 mg/kg) and heparinized (15 IU) by intraperitoneal injection.…”

Section: Heart Isolation and Perfusionmentioning

confidence: 99%

NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart

et al. 2020

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BackgroundNOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart.MethodsIsolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13C-glucose or 0.4 mM 13C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA).ResultsNLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption.ConclusionDeletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.

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Section: Heart Isolation and Perfusionmentioning

confidence: 99%

NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart

et al. 2020

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“…The most efficient protocols for CM differentiation rely on basal RPMI 1640 media supplemented with B27 that was originally designed for hippocampal neuronal culture ( Lian et al, 2012 ). Because lipid-poor and glucose-rich media conditions, such as in RPMI/B27 media, can promote de novo lipogenesis and suppress FAO ( Saggerson, 2008 ; van Weeghel et al, 2018 ), we sought to develop media with glucose and oxidative substrates levels adapted to the metabolic needs of CMs. The media contain physiologically appropriate levels of glucose and Ca 2+ and are supplemented with a complex mixture of albumin-bound fatty acid (AlbuMAX), creatine, l -carnitine, and taurine to support CM energetics.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

et al. 2020

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SUMMARY Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na + ) channels and sarcoplasmic reticulum calcium (Ca 2+ ) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na + channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models.

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“…[ 7 ] Insulin-regulated glucose transporter-4 (GLUT-4) is immunolocalized in rat cardiac muscle under conditions of basal and stimulates glucose uptake, which are achieved by fasting and a combined exercise/insulin stimulus, respectively. [ 8 ] Mitochondrial dysfunction has been demonstrated to contribute to heart disease and its clinical manifestations, and damaged mitochondrial homeostasis might lead to heart failure over time. [ 9 ] Consequently, exploration of a new therapeutic strategy to improve mitochondrial function and energy metabolism may have great clinical significance.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II-Induced Cardiac Hypertrophy

Liu

Cheng

Huang

et al. 2018

Chinese Medical Journal

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Background:Shensong Yangxin Capsule (SSYX), traditional Chinese medicine, has been used to treat arrhythmias, angina, cardiac remodeling, cardiac fibrosis, and so on, but its effect on cardiac energy metabolism is still not clear. The objective of this study was to investigate the effects of SSYX on myocardium energy metabolism in angiotensin (Ang) II-induced cardiac hypertrophy.Methods:We used 2 μl (10−6 mol/L) AngII to treat neonatal rat cardiomyocytes (NRCMs) for 48 h. Myocardial α-actinin staining showed that the myocardial cell volume increased. Expression of the cardiac hypertrophic marker-brain natriuretic peptide (BNP) messenger RNA (mRNA) also increased by real-time polymerase chain reaction (PCR). Therefore, it can be assumed that the model of hypertrophic cardiomyocytes was successfully constructed. Then, NRCMs were treated with 1 μl of different concentrations of SSYX (0.25, 0.5, and 1.0 μg/ml) for another 24 h. To explore the time-depend effect of SSYX on energy metabolism, 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h. Mitochondria was assessed by MitoTracker staining and confocal microscopy. mRNA and protein expression of mitochondrial biogenesis-related genes – Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), energy balance key factor – adenosine monophosphate-activated protein kinase (AMPK), fatty acids oxidation factor – carnitine palmitoyltransferase-1 (CPT-1), and glucose oxidation factor – glucose transporter- 4 (GLUT-4) were measured by PCR and Western blotting analysis.Results:With the increase in the concentration of SSYX (from 0.25 to 1.0 μg/ml), an increased mitochondrial density in AngII-induced cardiomyocytes was found compared to that of those treated with AngII only (0.25 μg/ml, 18.3300 ± 0.8895 vs. 24.4900 ± 0.9041, t = 10.240, P < 0.0001; 0.5 μg/ml, 18.3300 ± 0.8895 vs. 25.9800 ± 0.8187, t = 12.710, P < 0.0001; and 1.0 μg/ml, 18.3300 ± 0.8895 vs. 24.2900 ± 1.3120, t = 9.902, P < 0.0001; n = 5 per dosage group). SSYX also increased the mRNA and protein expression of PGC-1α (0.25 μg/ml, 0.8892 ± 0.0848 vs. 1.0970 ± 0.0994, t = 4.319, P = 0.0013; 0.5 μg/ml, 0.8892 ± 0.0848 vs. 1.2330 ± 0.0564, t = 7.150, P < 0.0001; and 1.0 μg/ml, 0.8892 ± 0.0848 vs. 1.1640 ± 0.0755, t = 5.720, P < 0.0001; n = 5 per dosage group), AMPK (0.25 μg/ml, 0.8872 ± 0.0779 vs. 1.1500 ± 0.0507, t = 7.239, P < 0.0001; 0.5 μg/ml, 0.8872 ± 0.0779 vs. 1.2280 ± 0.0623, t = 9.379, P < 0.0001; and 1.0 μg/ml, 0.8872 ± 0.0779 vs. 1.3020 ± 0.0450, t = 11.400, P < 0.0001; n = 5 per dosage group), CPT-1 (1.0 μg/ml, 0.7348 ± 0.0594 vs. 0.9880 ± 0.0851, t = 4.994, P = 0.0007, n = 5), and GLUT-4 (0.5 μg/ml, 1.5640 ± 0.0599 vs. 1.7720 ± 0.0660, t = 3.783, P = 0.0117; 1.0 μg/ml, 1.5640 ± 0.0599 vs. 2.0490 ± 0.1280, t = 8.808, P < 0.0001; n = 5 per dosage group). The effect became more obvious with the increasing concentration of SSYX. When 0.5 μg/ml SSYX was added into cells for 0, 6, 12, 24, and 48 h, the expression of AMPK (6 h, 14.6100 ± 0.6205 vs. 16.5200 ± 0.7450, t = 3.456, P = 0.0250...

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Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B

Abstract: Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating FAO rate in the heart. Chronic elevation of FAO has a relatively subtle impact on cardiac function at least under baseline conditions.

Cited by 37 publications

References 41 publications

NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart

NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart

Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

Effect of the Shensong Yangxin Capsule on Energy Metabolism in Angiotensin II-Induced Cardiac Hypertrophy

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