bims-hafaim 2023-03-05 papers

Issue of 2023–03–05
six papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2023 Feb 22. pii: 2023.02.22.529577. [Epub ahead of print]

High fat diet ameliorates the mitochondrial cardiomyopathy of CHCHD10 mutant mice.

Nneka Southwell, Dazhi Zhao, Nicole M Sayles, Jalia Dash, Keigo Fujita, Marilena Dâ Aurelio, Giovanni Manfredi, Hibiki Kawamata.

Mutations in CHCHD10, a mitochondrial protein with still undefined function, are associated with dominant multi-system mitochondrial diseases. CHCHD10 knock-in mice harboring a heterozygous S55L mutation (equivalent to the human pathogenic S59L mutation) develop a fatal mitochondrial cardiomyopathy. The heart of S55L knock-in mice shows extensive metabolic rewiring triggered by proteotoxic mitochondrial integrated stress response (mtISR). In the mutant heart, mtISR initiates well before the onset of mild bioenergetic impairments and is associated with a shift from fatty acid oxidation to glycolytic metabolism and widespread metabolic imbalance. We tested therapeutic interventions to counteract the metabolic rewiring and ameliorate the metabolic imbalance. Heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. Metabolomics and gene expression profiles demonstrated that HFD achieved an increase of fatty acid utilization in the heart accompanied by a decrease in cardiomyopathy markers. Surprisingly, HFD also decreased the accumulation of aggregated CHCHD10 in the S55L heart. Importantly, HFD increased the survival of mutant female mice exposed to acceleration of the mitochondrial cardiomyopathy associated with pregnancy. Our findings indicate that metabolic alterations can be effectively targeted for therapeutic intervention in mitochondrial cardiomyopathies associated with proteotoxic stress.

DOI: https://doi.org/10.1101/2023.02.22.529577

Circulation. 2023 Mar 01.

Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction.

Virginia S Hahn, Christopher Petucci, Min-Soo Kim, Kenneth C Bedi, Hanghang Wang, Sumita Mishra, Navid Koleini, Edwin J Yoo, Kenneth B Margulies, Zoltan Arany, Daniel P Kelly, David A Kass, Kavita Sharma.

BACKGROUND: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown.
METHODS: Plasma and endomyocardial biopsies were randomly selected from a 2-center derived biobank of HFpEF (n=38), HFrEF (n=30), and nonfailing donor control (n=20) tissue. Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning.
RESULTS: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups showed few differences in BCAA metabolites but little else.
CONCLUSIONS: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.

Keywords: HFpEF; branched chain amino acid; fatty acid oxidation; human; metabolism; metabolomics

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.061846

Am J Physiol Heart Circ Physiol. 2023 Mar 03.

Mitochondrial damage in a Takotsubo syndrome-like mouse model mediated by activation of b-adrenoceptor-Hippo signaling pathway.

Wei Wu, Qun Lu, Shan Ma, Jin-Chan Du, Kevin Huynh, Thy Duong, Zheng-Da Pang, Daniel Donner, Peter J Meikle, Xiu-Ling Deng, Xiao-Jun Du.

BACKGROUND: Takotsubo syndrome (TTS) is characterized by transient contractile dysfunction with its mechanism undefined. We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction, and that stimulation of β-adrenoceptors (βAR) activates Hippo pathway. Here we investigated the role of βAR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol-induced TTS-like mouse model.
METHODS: Elderly post-menopausal female mice were administered with isoproterenol (1.25 mg/kg/h for 23 hours). Cardiac function was determined by serially echocardiography. At day-1 and day-7 post-isoproterenol exposure, mitochondrial ultrastructure and function were examined by electron microscopy and various assays. Alterations in cardiac Hippo pathway and effects of genetic inactivation of Hippo kinase (Mst1) on mitochondrial damage and dysfunction in the acute phase of TTS were investigated.
RESULTS: Isoproterenol exposure induced transient increase in biomarkers of cardiac damage, and ventricular contractile dysfunction and dilation. At day-1 post-isoproterenol, we observed extensive abnormalities in mitochondrial ultrastructure, downregulation of mitochondrial marker proteins, and mitochondrial dysfunction evidenced by lower ATP content, increased lipid droplets, higher contents of lactate and augmented ROS. All changes were reversed by day-7. βAR stimulation led to activation of cardiac Hippo pathway with enhanced expression of Hippo kinase Mst1 and inhibitory YAP phosphorylation, as well as reduced nuclear YAP-TEAD1 interaction. In mice with cardiac expression of inactive mutant Mst1 gene, acute mitochondrial damage and dysfunction were mitigated.
CONCLUSION: Stimulation of cardiac βAR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS, promoting acute but transient ventricular dysfunction.

Keywords: Hippo pathway; Takotsubo syndrome; Yes-associated protein; beta-adrenoceptor; mitochondria

DOI: https://doi.org/10.1152/ajpheart.00459.2022

J Cardiovasc Transl Res. 2023 Feb 27.

Eicosapentaenoic Acid Preserves Mitochondrial Quality and Attenuates Cardiac Remodeling After Myocardial Infarction in Rats.

Miyuki Kobara, Tatsuya Shiraishi, Kazuki Noda, Hiroe Toba, Tetsuo Nakata.

Eicosapentaenoic acid (EPA) reduces the risk of ischemic heart diseases and is a component of mitochondria. We herein investigated whether dietary EPA mediated mitochondrial fatty acid compositions, dynamics, and functions, resulting in the attenuation of cardiac remodeling after myocardial infarction (MI). The coronary artery of male rats was ligated to induce MI, and they were then treated with or without EPA (1000 mg/kg/day) for 12 weeks. The EPA treatment improved left ventricular systolic function and increased the mitochondrial content of EPA in the non-infarct region 12 weeks after MI. The content of ATP and mitochondrial complex II, III, and IV activities decreased after MI but were maintained by the EPA treatment in association with the preservation of optic atrophy 1, a mitochondrial fusion protein. The present results suggest that dietary EPA increased the mitochondrial content of EPA and preserved the expression of mitochondrial fusion proteins and energy metabolism, which attenuated left ventricular remodeling after MI.

Keywords: Eicosapentaenoic acid; Energy metabolism; Mitochondria; Myocardial infarction; OPA1

DOI: https://doi.org/10.1007/s12265-023-10363-z

Nat Commun. 2023 Mar 02. 14(1): 1181

Retinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice.

Yandi Wu, Tongsheng Huang, Xinghui Li, Conghui Shen, Honglin Ren, Haiping Wang, Teng Wu, Xinlu Fu, Shijie Deng, Ziqi Feng, Shijie Xiong, Hui Li, Saifei Gao, Zhenyu Yang, Fei Gao, Lele Dong, Jianding Cheng, Weibin Cai.

Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.

DOI: https://doi.org/10.1038/s41467-023-36837-x

Front Cardiovasc Med. 2023 ;10 1105581

Fecal microbiome transplantation and tributyrin improves early cardiac dysfunction and modifies the BCAA metabolic pathway in a diet induced pre-HFpEF mouse model.

Jomana Hatahet, Tyler M Cook, Raiza R Bonomo, Nadia Elshareif, Chaitanya K Gavini, Chelsea R White, Jason Jesse, Virginie Mansuy-Aubert, Gregory Aubert.

More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement. Cardiac RNAseq analysis showed butyrate to significantly upregulate ppm1k gene that encodes protein phosphatase 2Cm (PP2Cm) which dephosphorylates and activates branched-chain α-keto acid dehydrogenase (BCKDH) enzyme, and in turn increases the catabolism of branched chain amino acids (BCAAs). Following both FMT and butyrate treatment, the level of inactive p-BCKDH in the heart was reduced. These findings show that gut microbiome modulation can alleviate early cardiac mechanics dysfunction seen in the development of obesity associated HFpEF.

Keywords: branched chain amino acids (BCAAs); gut microbiome; heart failure with preserved ejection fraction; obesity; short chain fatty acids

DOI: https://doi.org/10.3389/fcvm.2023.1105581