Publications by authors named "Stephen C Kolwicz"

35 Publications

Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts.

J Mol Cell Cardiol 2021 May 12;158:1-10. Epub 2021 May 12.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Republican Street 850, 98109 Seattle, WA, USA. Electronic address:

Background: Reduced fatty acid oxidation (FAO) is a hallmark of metabolic remodeling in heart failure. Enhancing mitochondrial long-chain fatty acid uptake by Acetyl-CoA carboxylase 2 (ACC2) deletion increases FAO and prevents cardiac dysfunction during chronic stresses, but therapeutic efficacy of this approach has not been determined.

Methods: Male and female ACC2 f/f-MCM (ACC2KO) and their respective littermate controls were subjected to chronic pressure overload by TAC surgery. Tamoxifen injection 3 weeks after TAC induced ACC2 deletion and increased FAO in ACC2KO mice with pathological hypertrophy.

Results: ACC2 deletion in mice with pre-existing cardiac pathology promoted FAO in female and male hearts, but improved cardiac function only in female mice. In males, pressure overload caused a downregulation in the mitochondrial oxidative function. Stimulating FAO by ACC2 deletion caused unproductive acyl-carnitine accumulation, which failed to improve cardiac energetics. In contrast, mitochondrial oxidative capacity was sustained in female pressure overloaded hearts and ACC2 deletion improved myocardial energetics. Mechanistically, we revealed a sex-dependent regulation of PPARα signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion.

Conclusion: Metabolic remodeling in the failing heart is sex-dependent which could determine the response to metabolic intervention. The findings suggest that both mitochondrial oxidative capacity and substrate preference should be considered for metabolic therapy of heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2021.05.004DOI Listing
May 2021

Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy.

Circulation 2020 Sep 29;142(10):983-997. Epub 2020 Jun 29.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (D.S., S.C.K., P.W., N.D.R., O.V., K.N., Y.-W.A.H., A.C., W.W., R.T.), University of Washington, Seattle.

Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes mellitus-induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acid transport into mitochondria via deletion of acetyl coenzyme A carboxylase 2 (ACC2) does not cause cardiomyopathy in nonobese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology-associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity-induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.

Methods: We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen-inducible model (ACC2 iKO). Control and ACC2 iKO mice were subjected to high-fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function, and mitophagy activity were examined.

Results: Despite both control and ACC2 iKO mice exhibiting a similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD-induced cardiac dysfunction, pathological remodeling, and mitochondria dysfunction, as well. Similarly, increasing FAO by knockdown of ACC2 prevented palmitate-induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was attenuated, in part, in the ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD-induced downregulation of parkin. During stimulation for mitophagy, mitochondria-localized parkin was severely reduced in control HFD-fed mouse heart, which was restored, in part, in ACC2 iKO HFD-fed mice.

Conclusions: These data show that increasing cardiac FAO alone does not cause cardiac dysfunction, but protects against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD-induced obesity is mediated, in part, by the maintenance of mitochondria function through regulating parkin-mediated mitophagy. Our findings also suggest that targeting the parkin-dependent mitophagy pathway could be an effective strategy against the development of obesity-induced cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484440PMC
September 2020

Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate.

JACC Basic Transl Sci 2019 Nov 2;4(7):778-791. Epub 2019 Oct 2.

Department of Neurology, University of Washington, Seattle, Washington.

Mutations in the gene encoding for dystrophin leads to structural and functional deterioration of cardiomyocytes and is a hallmark of cardiomyopathy in Duchenne muscular dystrophy (DMD) patients. Administration of recombinant adeno-associated viral vectors delivering microdystrophin or ribonucleotide reductase (RNR), under muscle-specific regulatory control, rescues both baseline and high workload-challenged hearts in an aged, DMD mouse model. However, only RNR treatments improved both systolic and diastolic function under those conditions. Cardiac-specific recombinant adeno-associated viral treatment of RNR holds therapeutic promise for improvement of cardiomyopathy in DMD patients.
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http://dx.doi.org/10.1016/j.jacbts.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978556PMC
November 2019

Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis.

Circ Res 2020 01 11;126(2):182-196. Epub 2019 Nov 11.

From the Department of Anesthesiology and Pain Medicine (J.R., S.Y., O.V., D.S., Y.-W.A.H., S.C.K., R.T.), Mitochondria and Metabolism Center, University of Washington, Seattle.

Rationale: Hypertrophied hearts switch from mainly using fatty acids (FAs) to an increased reliance on glucose for energy production. It has been shown that preserving FA oxidation (FAO) prevents the pathological shift of substrate preference, preserves cardiac function and energetics, and reduces cardiomyocyte hypertrophy during cardiac stresses. However, it remains elusive whether substrate metabolism regulates cardiomyocyte hypertrophy directly or via a secondary effect of improving cardiac energetics.

Objective: The goal of this study was to determine the mechanisms of how preservation of FAO prevents the hypertrophic growth of cardiomyocytes.

Methods And Results: We cultured adult rat cardiomyocytes in a medium containing glucose and mixed-chain FAs and induced pathological hypertrophy by phenylephrine. Phenylephrine-induced hypertrophy was associated with increased glucose consumption and higher intracellular aspartate levels, resulting in increased synthesis of nucleotides, RNA, and proteins. These changes could be prevented by increasing FAO via deletion of ACC2 (acetyl-CoA-carboxylase 2) in phenylephrine-stimulated cardiomyocytes and in pressure overload-induced cardiac hypertrophy in vivo. Furthermore, aspartate supplementation was sufficient to reverse the antihypertrophic effect of ACC2 deletion demonstrating a causal role of elevated aspartate level in cardiomyocyte hypertrophy. 15N and 13C stable isotope tracing revealed that glucose but not glutamine contributed to increased biosynthesis of aspartate, which supplied nitrogen for nucleotide synthesis during cardiomyocyte hypertrophy.

Conclusions: Our data show that increased glucose consumption is required to support aspartate synthesis that drives the increase of biomass during cardiac hypertrophy. Preservation of FAO prevents the shift of metabolic flux into the anabolic pathway and maintains catabolic metabolism for energy production, thus preventing cardiac hypertrophy and improving myocardial energetics.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315483DOI Listing
January 2020

Fatty Acids Enhance the Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells.

Stem Cell Reports 2019 10 26;13(4):657-668. Epub 2019 Sep 26.

Department of Pathology, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98109, USA; Department of Medicine/Cardiology, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA. Electronic address:

Although human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a novel platform for heart regeneration, disease modeling, and drug screening, their immaturity significantly hinders their application. A hallmark of postnatal cardiomyocyte maturation is the metabolic substrate switch from glucose to fatty acids. We hypothesized that fatty acid supplementation would enhance hPSC-CM maturation. Fatty acid treatment induces cardiomyocyte hypertrophy and significantly increases cardiomyocyte force production. The improvement in force generation is accompanied by enhanced calcium transient peak height and kinetics, and by increased action potential upstroke velocity and membrane capacitance. Fatty acids also enhance mitochondrial respiratory reserve capacity. RNA sequencing showed that fatty acid treatment upregulates genes involved in fatty acid β-oxidation and downregulates genes in lipid synthesis. Signal pathway analyses reveal that fatty acid treatment results in phosphorylation and activation of multiple intracellular kinases. Thus, fatty acids increase human cardiomyocyte hypertrophy, force generation, calcium dynamics, action potential upstroke velocity, and oxidative capacity. This enhanced maturation should facilitate hPSC-CM usage for cell therapy, disease modeling, and drug/toxicity screens.
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http://dx.doi.org/10.1016/j.stemcr.2019.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829750PMC
October 2019

Ketogenic Diets and Exercise Performance.

Nutrients 2019 Sep 26;11(10). Epub 2019 Sep 26.

Heart and Muscle Metabolism Laboratory, Health and Exercise Physiology, Ursinus College, Collegeville, PA 19426, USA.

The ketogenic diet (KD) has gained a resurgence in popularity due to its purported reputation for fighting obesity. The KD has also acquired attention as an alternative and/or supplemental method for producing energy in the form of ketone bodies. Recent scientific evidence highlights the KD as a promising strategy to treat obesity, diabetes, and cardiac dysfunction. In addition, studies support ketone body supplements as a potential method to induce ketosis and supply sustainable fuel sources to promote exercise performance. Despite the acceptance in the mainstream media, the KD remains controversial in the medical and scientific communities. Research suggests that the KD or ketone body supplementation may result in unexpected side effects, including altered blood lipid profiles, abnormal glucose homeostasis, increased adiposity, fatigue, and gastrointestinal distress. The purpose of this review article is to provide an overview of ketone body metabolism and a background on the KD and ketone body supplements in the context of obesity and exercise performance. The effectiveness of these dietary or supplementation strategies as a therapy for weight loss or as an ergogenic aid will be discussed. In addition, the recent evidence that indicates ketone body metabolism is a potential target for cardiac dysfunction will be reviewed.
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http://dx.doi.org/10.3390/nu11102296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835497PMC
September 2019

Myocardial Dysfunction after Severe Food Restriction Is Linked to Changes in the Calcium-Handling Properties in Rats.

Nutrients 2019 Aug 22;11(9). Epub 2019 Aug 22.

Department of Internal Medicine, Botucatu Medical School, São Paulo State University, Botucatu 18618687, Brazil.

Severe food restriction (FR) impairs cardiac performance, although the causative mechanisms remain elusive. Since proteins associated with calcium handling may contribute to cardiac dysfunction, this study aimed to evaluate whether severe FR results in alterations in the expression and activity of Ca-handling proteins that contribute to impaired myocardial performance. Male 60-day-old Wistar-Kyoto rats were fed a control or restricted diet (50% reduction in the food consumed by the control group) for 90 days. Body weight, body fat pads, adiposity index, as well as the weights of the soleus muscle and lung, were obtained. Cardiac remodeling was assessed by morphological measures. The myocardial contractile performance was analyzed in isolated papillary muscles during the administration of extracellular Ca and in the absence or presence of a sarcoplasmic reticulum Ca-ATPase (SERCA2a) specific blocker. The expression of Ca-handling regulatory proteins was analyzed via Western Blot. Severe FR resulted in a 50% decrease in body weight and adiposity measures. Cardiac morphometry was substantially altered, as heart weights were nearly twofold lower in FR rats. Papillary muscles isolated from FR hearts displayed mechanical dysfunction, including decreased developed tension and reduced contractility and relaxation. The administration of a SERCA2a blocker led to further decrements in contractile function in FR hearts, suggesting impaired SERCA2a activity. Moreover, the FR rats presented a lower expression of L-type Ca channels. Therefore, myocardial dysfunction induced by severe food restriction is associated with changes in the calcium-handling properties in rats.
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http://dx.doi.org/10.3390/nu11091985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770438PMC
August 2019

Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury.

J Mol Cell Cardiol 2018 10 27;123:38-45. Epub 2018 Aug 27.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA; Department of Pathology, University of Washington, Seattle, WA, 98195, USA. Electronic address:

Rationale: Ischemic heart disease (IHD) is a leading cause of mortality. The most effective intervention for IHD is reperfusion, which ironically causes ischemia reperfusion (I/R) injury mainly due to oxidative stress-induced cardiomyocyte death. The exact mechanism and site of reactive oxygen species (ROS) generation during I/R injury remain elusive.

Objective: We aim to test the hypothesis that Complex I-mediated forward and reverse electron flows are the major source of ROS in I/R injury of the heart.

Methods And Results: We used a genetic model of mitochondrial Complex I deficiency, in which a Complex I assembling subunit, Ndufs4 was knocked out in the heart (Ndufs4H-/-). The Langendorff perfused Ndufs4H-/- hearts exhibited significantly reduced infarct size (45.3 ± 5.5% in wild type vs 20.9 ± 8.1% in Ndufs4H-/-), recovered contractile function, and maintained mitochondrial membrane potential after no flow ischemia and subsequent reperfusion. In cultured adult cardiomyocytes from Ndufs4H-/- mice, I/R mimetic treatments caused minimal cell death. Reintroducing Ndufs4 in Ndufs4H-/- cardiomyocytes abolished the protection. Mitochondrial NADH declined much slower in Ndufs4H-/- cardiomyocytes during reperfusion suggesting decreased forward electron flow. Mitochondrial flashes, a marker for mitochondrial respiration, were inhibited in Ndufs4H-/- cardiomyocytes at baseline and during I/R, which was accompanied by preserved aconitase activity suggesting lack of oxidative damage. Finally, pharmacological blockade of forward and reverse electron flow at Complex I inhibited I/R-induced cell death.

Conclusions: These results provide the first genetic evidence supporting the central role of mitochondrial Complex I in I/R injury of mouse heart. The study also suggests that both forward and reverse electron flows underlie oxidative cardiomyocyte death during reperfusion.
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http://dx.doi.org/10.1016/j.yjmcc.2018.08.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192835PMC
October 2018

Glucose promotes cell growth by suppressing branched-chain amino acid degradation.

Nat Commun 2018 07 26;9(1):2935. Epub 2018 Jul 26.

Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle, WA, 98109, USA.

Glucose and branched-chain amino acids (BCAAs) are essential nutrients and key determinants of cell growth and stress responses. High BCAA level inhibits glucose metabolism but reciprocal regulation of BCAA metabolism by glucose has not been demonstrated. Here we show that glucose suppresses BCAA catabolism in cardiomyocytes to promote hypertrophic response. High glucose inhibits CREB stimulated KLF15 transcription resulting in downregulation of enzymes in the BCAA catabolism pathway. Accumulation of BCAA through the glucose-KLF15-BCAA degradation axis is required for the activation of mTOR signaling during the hypertrophic growth of cardiomyocytes. Restoration of KLF15 prevents cardiac hypertrophy in response to pressure overload in wildtype mice but not in mutant mice deficient of BCAA degradation gene. Thus, regulation of KLF15 transcription by glucose is critical for the glucose-BCAA circuit which controls a cascade of obligatory metabolic responses previously unrecognized for cell growth.
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http://dx.doi.org/10.1038/s41467-018-05362-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062555PMC
July 2018

An "Exercise" in Cardiac Metabolism.

Front Cardiovasc Med 2018 7;5:66. Epub 2018 Jun 7.

Heart and Muscle Metabolism Laboratory, Health and Exercise Physiology Department, Ursinus College, Collegeville, PA, United States.

Research has demonstrated that the high capacity requirements of the heart are satisfied by a preference for oxidation of fatty acids. However, it is well known that a stressed heart, as in pathological hypertrophy, deviates from its inherent profile and relies heavily on glucose metabolism, primarily achieved by an acceleration in glycolysis. Moreover, it has been suggested that the chronically lipid overloaded heart augments fatty acid oxidation and triglyceride synthesis to an even greater degree and, thus, develops a lipotoxic phenotype. In comparison, classic studies in exercise physiology have provided a basis for the acute metabolic changes that occur during physical activity. During an acute bout of exercise, whole body glucose metabolism increases proportionately to intensity while fatty acid metabolism gradually increases throughout the duration of activity, particularly during moderate intensity. However, the studies in chronic exercise training are primarily limited to metabolic adaptations in skeletal muscle or to the mechanisms that govern physiological signaling pathways in the heart. Therefore, the purpose of this review is to discuss the precise changes that chronic exercise training elicits on cardiac metabolism, particularly on substrate utilization. Although conflicting data exists, a pattern of enhanced fatty oxidation and normalization of glycolysis emerges, which may be a therapeutic strategy to prevent or regress the metabolic phenotype of the hypertrophied heart. This review also expands on the metabolic adaptations that chronic exercise training elicits in amino acid and ketone body metabolism, which have become of increased interest recently. Lastly, challenges with exercise training studies, which could relate to several variables including model, training modality, and metabolic parameter assessed, are examined.
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http://dx.doi.org/10.3389/fcvm.2018.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999753PMC
June 2018

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

Cardiovasc Res 2018 08;114(10):1324-1334

Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY, USA.

Aims: Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism.

Methods And Results: We generated and characterized a knock in mouse model expressing the CPT1BE3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/WT hearts. Metabolomic, proteomic and transcriptomic analysis showed increased levels of malonylcarnitine, decreased concentration of CPT1B protein and a small but coordinated downregulation of the mRNA expression of genes involved in FAO in Cpt1bE3A/E3A hearts, all of which aim to limit FAO. In vivo assessment of cardiac function revealed only minor changes, cardiac hypertrophy was absent and histological analysis did not reveal fibrosis.

Conclusions: 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.
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http://dx.doi.org/10.1093/cvr/cvy089DOI Listing
August 2018

Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism.

PLoS One 2018 1;13(3):e0193553. Epub 2018 Mar 1.

Department of Internal Medicine, São Paulo State University, Botucatu, São Paulo, Brazil.

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832311PMC
July 2018

The effects of fatty acid composition on cardiac hypertrophy and function in mouse models of diet-induced obesity.

J Nutr Biochem 2017 08 25;46:137-142. Epub 2017 May 25.

Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA. Electronic address:

High-fat diets (HFDs) are used frequently to study the development of cardiac dysfunction in animal models of obesity and diabetes. However, impairment in systolic function, often reported as declining ejection fraction, may not consistently occur in a given time frame which could be contributable to a variety of factors within the experimental design. One major factor may be the amounts of saturated and unsaturated fatty acids (FAs) that are present in the diet. To determine whether the FA content and composition were critical determinants in the development of cardiac dysfunction in response to high-fat feeding, we fed adult, male mice Western diet (45% fat, 60% saturated), Surwit diet (60% fat, 90% saturated), milk-fat-based diet (60% fat, 60% saturated) or high-fat Western diet (HFWD, 60% fat, 32% saturated) for 12 weeks. We report that neither the amount of total fat nor the ratio of saturated to unsaturated FAs in the diets differentially affects body weight and adiposity in mice. In addition, no evidence of systolic dysfunction is present after 12 weeks. Interestingly, the HFWD, with equal parts saturated, monounsaturated and polyunsaturated FAs, induces mild cardiac hypertrophy and diastolic dysfunction after 12 weeks, which coincides with elevated serum levels of arachidonic acid. Our results suggest that the dietary FA content and composition may be a primary determinant of diastolic, but not systolic, dysfunction in animal models of diet-induced obesity.
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http://dx.doi.org/10.1016/j.jnutbio.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516950PMC
August 2017

Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury.

Cell Metab 2017 02;25(2):374-385

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address:

Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases, but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (knockout [KO]), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of the hexosamine biosynthetic pathway in KO hearts decreased protein O-linked N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH, resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response.
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http://dx.doi.org/10.1016/j.cmet.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301464PMC
February 2017

Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion.

J Mol Cell Cardiol 2016 Nov 28;100:64-71. Epub 2016 Sep 28.

Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States. Electronic address:

Rationale: Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart.

Objective: To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart.

Methods And Results: We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities.

Conclusion: These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction.
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http://dx.doi.org/10.1016/j.yjmcc.2016.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154855PMC
November 2016

Response to Comment on Kolwicz et al. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress. Diabetes 2015;64:2817-2827.

Diabetes 2016 04;65(4):e19-20

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA

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http://dx.doi.org/10.2337/dbi15-0043DOI Listing
April 2016

Lipid partitioning during cardiac stress.

Biochim Biophys Acta 2016 10 7;1861(10):1472-80. Epub 2016 Apr 7.

Mitochondria and Metabolism Center, University of Washington, School of Medicine, 850 Republican St., Seattle, WA 98109, United States. Electronic address:

It is well documented that fatty acids serve as the primary fuel substrate for the contracting myocardium. However, extensive research has identified significant changes in the myocardial oxidation of fatty acids during acute or chronic cardiac stress. As a result, the redistribution or partitioning of fatty acids due to metabolic derangements could have biological implications. Fatty acids can be stored as triacylglycerols, serve as critical components for biosynthesis of phospholipid membranes, and form the potent signaling molecules, diacylglycerol and ceramides. Therefore, the contribution of lipid metabolism to health and disease is more intricate than a balance of uptake and oxidation. In this review, the available data regarding alterations that occur in endogenous cardiac lipid pathways during the pathological stressors of ischemia-reperfusion and pathological hypertrophy/heart failure are highlighted. In addition, changes in endogenous lipids observed in exercise training models are presented for comparison. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
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http://dx.doi.org/10.1016/j.bbalip.2016.03.028DOI Listing
October 2016

Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts.

Aging (Albany NY) 2016 Feb;8(2):314-27

Department of Pathology, University of Washington, Seattle, WA 98195, USA.

Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment. While TORC1-mediated S6 phosphorylation and TORC2 mediated AKT and PKCα phosphorylation are inhibited throughout the course of treatment, rapamycin inhibits ULK phosphorylation and induces autophagy during just the first week of treatment, returning to baseline at two weeks and after. Concordantly, markers of mitochondrial biogenesis increase over the first two weeks of treatment and return to control levels thereafter. This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolomein vivo. This study demonstrates the differential and dynamic mechanisms following rapamycin treatment and highlights the importance of understanding the temporal regulation of rapamycin effects.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789585PMC
http://dx.doi.org/10.18632/aging.100881DOI Listing
February 2016

Ketones Step to the Plate: A Game Changer for Metabolic Remodeling in Heart Failure?

Circulation 2016 Feb 27;133(8):689-91. Epub 2016 Jan 27.

From Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (S.C.K., R.T.) and Cardiology Division, Department of Medicine (S.A.), University of Washington, Seattle.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826559PMC
February 2016

AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility.

Mol Ther 2016 Feb 21;24(2):240-250. Epub 2015 Sep 21.

Department of Bioengineering, University of Washington, Seattle, Washington, USA; Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA. Electronic address:

Impaired systolic function, resulting from acute injury or congenital defects, leads to cardiac complications and heart failure. Current therapies slow disease progression but do not rescue cardiac function. We previously reported that elevating the cellular 2 deoxy-ATP (dATP) pool in transgenic mice via increased expression of ribonucleotide reductase (RNR), the enzyme that catalyzes deoxy-nucleotide production, increases myosin-actin interaction and enhances cardiac muscle contractility. For the current studies, we initially injected wild-type mice retro-orbitally with a mixture of adeno-associated virus serotype-6 (rAAV6) containing a miniaturized cardiac-specific regulatory cassette (cTnT(455)) composed of enhancer and promotor portions of the human cardiac troponin T gene (TNNT2) ligated to rat cDNAs encoding either the Rrm1 or Rrm2 subunit. Subsequent studies optimized the system by creating a tandem human RRM1-RRM2 cDNA with a P2A self-cleaving peptide site between the subunits. Both rat and human Rrm1/Rrm2 cDNAs resulted in RNR enzyme overexpression exclusively in the heart and led to a significant elevation of left ventricular (LV) function in normal mice and infarcted rats, measured by echocardiography or isolated heart perfusions, without adverse cardiac remodeling. Our study suggests that increasing RNR levels via rAAV-mediated cardiac-specific expression provide a novel gene therapy approach to potentially enhance cardiac systolic function in animal models and patients with heart failure.
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http://dx.doi.org/10.1038/mt.2015.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817808PMC
February 2016

Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress.

Diabetes 2015 Aug 9;64(8):2817-27. Epub 2015 Apr 9.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA

Elevated cardiac triacylglycerol (TAG) content is traditionally equated with cardiolipotoxicity and suggested to be a culprit in cardiac dysfunction. However, previous work demonstrated that myosin heavy-chain-mediated cardiac-specific overexpression of diacylglycerol transferase 1 (MHC-DGAT1), the primary enzyme for TAG synthesis, preserved cardiac function in two lipotoxic mouse models despite maintaining high TAG content. Therefore, we examined whether increased cardiomyocyte TAG levels due to DGAT1 overexpression led to changes in cardiac TAG turnover rates under normoxia and ischemia-reperfusion conditions. MHC-DGAT1 mice had elevated TAG content and synthesis rates, which did not alter cardiac function, substrate oxidation, or myocardial energetics. MHC-DGAT1 hearts had ischemia-induced lipolysis; however, when a physiologic mixture of long-chain fatty acids was provided, enhanced TAG turnover rates were associated with improved functional recovery from low-flow ischemia. Conversely, exogenous supply of palmitate during reperfusion suppressed elevated TAG turnover rates and impaired recovery from ischemia in MHC-DGAT1 hearts. Collectively, this study shows that elevated TAG content, accompanied by enhanced turnover, does not adversely affect cardiac function and, in fact, provides cardioprotection from ischemic stress. In addition, the results highlight the importance of exogenous supply of fatty acids when assessing cardiac lipid metabolism and its relationship with cardiac function.
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http://dx.doi.org/10.2337/db14-1943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512225PMC
August 2015

Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts.

Am J Physiol Heart Circ Physiol 2014 Nov 29;307(9):H1307-16. Epub 2014 Aug 29.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.
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http://dx.doi.org/10.1152/ajpheart.00280.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217009PMC
November 2014

Mutation in the γ2-subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage.

Circ Res 2014 Mar 6;114(6):966-75. Epub 2014 Feb 6.

From the Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle (M.K., L.G.-M., G.G., Y.-Y.Y., S.C.K., J.X., W.W., R.T.); and MRC Protein Phosphorylation unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom (R.W.H., K.S.). R.W.H. and K.S. are currently affiliated with Nestlé Institute of Health Sciences SA, Campus EPFL, Innovation Park, bâtiment G, Lausanne, Switzerland.

Rationale: AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase as a drug target.

Objective: We sought to identify the pro-growth-signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage.

Methods And Results: In a mouse model of N488I mutation of the Prkag2 gene (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate-stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth.

Conclusions: Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of γ2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.
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http://dx.doi.org/10.1161/CIRCRESAHA.114.302364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971100PMC
March 2014

Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.

Circ Res 2013 Aug;113(5):603-16

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.

The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.
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http://dx.doi.org/10.1161/CIRCRESAHA.113.302095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845521PMC
August 2013

Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure.

Cell Metab 2013 Aug;18(2):239-50

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, 98109, USA.

Mitochondrial respiratory dysfunction is linked to the pathogenesis of multiple diseases, including heart failure, but the specific mechanisms for this link remain largely elusive. We modeled the impairment of mitochondrial respiration by the inactivation of the Ndufs4 gene, a protein critical for complex I assembly, in the mouse heart (cKO). Although complex I-supported respiration decreased by >40%, the cKO mice maintained normal cardiac function in vivo and high-energy phosphate content in isolated perfused hearts. However, the cKO mice developed accelerated heart failure after pressure overload or repeated pregnancy. Decreased NAD(+)/NADH ratio by complex I deficiency inhibited Sirt3 activity, leading to an increase in protein acetylation and sensitization of the permeability transition in mitochondria (mPTP). NAD(+) precursor supplementation to cKO mice partially normalized the NAD(+)/NADH ratio, protein acetylation, and mPTP sensitivity. These findings describe a mechanism connecting mitochondrial dysfunction to the susceptibility to diseases and propose a potential therapeutic target.
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http://dx.doi.org/10.1016/j.cmet.2013.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779647PMC
August 2013

Sample preparation methodology for mouse heart metabolomics using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry.

Talanta 2013 Apr 13;108:123-30. Epub 2013 Mar 13.

Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195, USA.

The investigation of naturally volatile and derivatized metabolites in mammalian tissues by comprehensive two-dimensional (2D) gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS) can provide the data for a comprehensive analysis of the pathophysiology of disease processes. When relative quantification is needed for hypothesis testing, the preparation of sample tissue must provide clear evidence that a quantitative relationship exists between the final detected signal and the amount of metabolite in the tissue. Herein, we report the optimization of a metabolite extraction method for mouse heart tissue for GC × GC-TOFMS analysis. A recursive extraction experiment was initially performed to measure the extraction efficiency of representative target metabolites (sugars, tricarboxylic acid cycle metabolites, amino acids, lipid and signaling molecules) in the aqueous fraction of a three-phase extraction system involving tissue, methanol:water, and chloroform. Some metabolites suffered from incomplete extraction with a single extraction of ≈ 40 mg in 600 μl organic and 400 μl aqueous phases, possibly caused by saturation effects. Subsequent experiments, calibrating resulting metabolite signal to the mass of heart tissue extracted, demonstrated that doubling the solvent volumes and a lower tissue mass was needed to provide accurate relative quantification of the derivatized mouse heart metabolome. We demonstrate quantitative extraction of metabolites from ≈ 20 mg of heart tissue using 1200 μl organic phase (chloroform) and 800 μl aqueous phase (methanol:water in equal parts by volume).
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http://dx.doi.org/10.1016/j.talanta.2013.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638982PMC
April 2013

Transgenic overexpression of ribonucleotide reductase improves cardiac performance.

Proc Natl Acad Sci U S A 2013 Apr 25;110(15):6187-92. Epub 2013 Mar 25.

Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.

We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis. Hearts from TgRR mice had elevated left ventricular systolic function compared with wild-type (WT) mice, both in vivo and in vitro, without signs of hypertrophy or altered diastolic function. Isolated cardiomyocytes from TgRR mice had enhanced contraction and relaxation, with no change in Ca(2+) transients, suggesting targeted improvement of myofilament function. TgRR hearts had normal ATP and only slightly decreased phosphocreatine levels by (31)P NMR spectroscopy, and they maintained rate responsiveness to dobutamine challenge. These data demonstrate long-term (at least 5-mo) elevation of cardiac [dATP] results in sustained elevation of basal left ventricular performance, with maintained β-adrenergic responsiveness and energetic reserves. Combined with results from previous studies, we conclude that this occurs primarily via enhanced myofilament activation and contraction, with similar or faster ability to relax. The data are sufficiently compelling to consider elevated cardiac [dATP] as a therapeutic option to treat systolic dysfunction.
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http://dx.doi.org/10.1073/pnas.1220693110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625337PMC
April 2013

Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy.

Circ Res 2012 Aug 22;111(6):728-38. Epub 2012 Jun 22.

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican St, Seattle, WA 98109, USA.

Rationale: Decreased fatty acid oxidation (FAO) with increased reliance on glucose are hallmarks of metabolic remodeling that occurs in pathological cardiac hypertrophy and is associated with decreased myocardial energetics and impaired cardiac function. To date, it has not been tested whether prevention of the metabolic switch that occurs during the development of cardiac hypertrophy has unequivocal benefits on cardiac function and energetics.

Objective: Because malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits the entry of long chain fatty acids into the mitochondria, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H-/-) would maintain cardiac FAO and improve function and energetics during the development of pressure-overload hypertrophy.

Methods And Results: ACC2 deletion led to a significant reduction in cardiac malonyl CoA levels. In isolated perfused heart experiments, left ventricular function and oxygen consumption were similar in ACC2H-/- mice despite an ≈60% increase in FAO compared with controls (CON). After 8 weeks of pressure overload via transverse aortic constriction (TAC), ACC2H-/- mice exhibited a substrate utilization profile similar to sham animals, whereas CON-TAC hearts had decreased FAO with increased glycolysis and anaplerosis. Myocardial energetics, assessed by 31P nuclear magnetic resonance spectroscopy, and cardiac function were maintained in ACC2H-/- after 8 weeks of TAC. Furthermore, ACC2H-/--TAC demonstrated an attenuation of cardiac hypertrophy with a significant reduction in fibrosis relative to CON-TAC.

Conclusions: These data suggest that reversion to the fetal metabolic profile in chronic pathological hypertrophy is associated with impaired myocardial function and energetics and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity is a viable therapeutic strategy.
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http://dx.doi.org/10.1161/CIRCRESAHA.112.268128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434870PMC
August 2012

Acute exercise exacerbates ischemia-induced diastolic rigor in hypertensive myocardium.

Springerplus 2012 2;1:46. Epub 2012 Nov 2.

Department of Biokinetics, Eastern University, St. David's, Radnor Township, PA USA.

Previous studies have shown that acute exercise preconditions the myocardium from ischemic injury. The purpose of this study was to test whether acute exercise protects the hypertensive myocardium from ischemia-induced diastolic rigor, and to compare the response between normotensive and uncompensated hypertensive hearts. Hearts harvested from female Wistar-Kyoto (WKY; n = 24) and spontaneously hypertensive rats (SHR; n = 27) (age:10-12 weeks) were exposed to ischemia (Langendorff isovolumic preparation; 22 minutes of no flow ischemia and studied following prior conditions of: 1) no exercise (WKY-CON, n=8; SHR-CON, n=8); 2) ischemia initiated one hour post-acute exercise (WKY-1HR, n = 8; SHR-1HR, n = 11); and 3) ischemia initiated 24 hours post-acute exercise (WKY-24HR; n = 8; SHR-24HR, n = 8). Acute exercise consisted of one bout of treadmill running at 25 m/min for 60 minutes. Heart weight was similar between WKY and SHR despite elevated in vivo resting systolic blood pressure and rate pressure product in SHR (P<0.05). During normoxic perfusion, left ventricular (LV) Langendorff performance was similar between WKY and SHR over the post-exercise time course. However, during ischemia, LV diastolic rigor was less in WKY vs. SHR (P<0.05). Acute exercise augmented ischemia-induced LV dysfunction one hour post-exercise in SHR (P<0.05), with gradual recovery by 24 hours post-exercise. These data suggest that acute exercise promotes ischemic diastolic rigor in SHR, even prior to the development of cardiac hypertrophy.
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http://dx.doi.org/10.1186/2193-1801-1-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725917PMC
August 2013

Glucose metabolism and cardiac hypertrophy.

Cardiovasc Res 2011 May;90(2):194-201

Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 815 Mercer Street, Seattle, WA 98109, USA.

The most notable change in the metabolic profile of hypertrophied hearts is an increased reliance on glucose with an overall reduced oxidative metabolism, i.e. a reappearance of the foetal metabolic pattern. In animal models, this change is attributed to the down-regulation of the transcriptional cascades promoting gene expression for fatty acid oxidation and mitochondrial oxidative phosphorylation in adult hearts. Impaired myocardial energetics in cardiac hypertrophy also triggers AMP-activated protein kinase (AMPK), leading to increased glucose uptake and glycolysis. Aside from increased reliance on glucose as an energy source, changes in other glucose metabolism pathways, e.g. the pentose phosphate pathway, the glucosamine biosynthesis pathway, and anaplerosis, are also noted in the hypertrophied hearts. Studies using transgenic mouse models and pharmacological compounds to mimic or counter the switch of substrate preference in cardiac hypertrophy have demonstrated that increased glucose metabolism in adult heart is not harmful and can be beneficial when it provides sufficient fuel for oxidative metabolism. However, improvement in the oxidative capacity and efficiency rather than the selection of the substrate is likely the ultimate goal for metabolic therapies.
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http://dx.doi.org/10.1093/cvr/cvr071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078804PMC
May 2011