bims-mimcad 2024-03-10 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–03–10
nine papers selected by
Henver Brunetta, University of Guelph

Role of human Kallistatin in glucose and energy homeostasis in mice.
Adipose Tissue Peroxisomal Lipid Synthesis Orchestrates Obesity and Insulin Resistance through LXR-Dependent Lipogenesis.
Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology.
Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction.
Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.
Identification of molecular signatures in epicardial adipose tissue in heart failure with preserved ejection fraction.
N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration.
Childhood adverse life events and skeletal muscle mitochondrial function.
ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Mol Metab. 2024 Feb 29. pii: S2212-8778(24)00036-X. [Epub ahead of print]82 101905

Role of human Kallistatin in glucose and energy homeostasis in mice.

Leontine Sandforth, Sebastian Brachs, Julia Reinke, Diana Willmes, Gencer Sancar, Judith Seigner, David Juarez-Lopez, Arvid Sandforth, Jeffrey D McBride, Jian-Xing Ma, Sven Haufe, Jens Jordan, Andreas L Birkenfeld.

   OBJECTIVE: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown.
METHODS: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions.
RESULTS: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect.
CONCLUSIONS: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.

Keywords:  Diet-induced insulin resistance; Kallistatin; SERPIN A4; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.molmet.2024.101905
Mol Metab. 2024 Mar 06. pii: S2212-8778(24)00044-9. [Epub ahead of print] 101913

Adipose Tissue Peroxisomal Lipid Synthesis Orchestrates Obesity and Insulin Resistance through LXR-Dependent Lipogenesis.

Brian Kleiboeker, Anyuan He, Min Tan, Dongliang Lu, Donghua Hu, Xuejing Liu, Parniyan Goodarzi, Fong-Fu Hsu, Babak Razani, Clay F Semenkovich, Irfan J Lodhi.

Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here, we report that adipose-specific knockout of the peroxisomal lipid synthetic protein PexRAP promotes diet-induced obesity and insulin resistance through activation of de novo lipogenesis. PexRAP inactivation inhibits the flux of carbons to ethanolamine plasmalogens. This increases nuclear PC/PE ratio and promotes cholesterol mislocalization, resulting in the activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation leads to increased expression of the phospholipid remodeling enzyme LPCAT3 and induces fatty acid synthase-mediated lipogenesis, which promotes diet-induced obesity and insulin resistance. Treatment of PexRAP-deficient adipocytes with alkylglycerol, a plasmalogen precursor that enters the synthetic pathway downstream of PexRAP, rescues nuclear cholesterol mislocalization and LXR activation. These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.

DOI: https://doi.org/10.1016/j.molmet.2024.101913
Trends Mol Med. 2024 Mar 04. pii: S1471-4914(24)00027-3. [Epub ahead of print]

Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology.

Sevgi Döndü Özen, Serkan Kir.

  Skeletal muscle is essential in generating mechanical force and regulating energy metabolism and body temperature. Pathologies associated with muscle tissue often lead to impaired physical activity and imbalanced metabolism. Recently, ectodysplasin A2 receptor (EDA2R) signaling has been shown to promote muscle loss and glucose intolerance. Upregulated EDA2R expression in muscle tissue was associated with aging, denervation, cancer cachexia, and muscular dystrophies. Here, we describe the roles of EDA2R signaling in muscle pathophysiology, including muscle atrophy, insulin resistance, and aging-related sarcopenia. We also discuss the EDA2R pathway, which involves EDA-A2 as the ligand and nuclear factor (NF)κB-inducing kinase (NIK) as a downstream mediator, and the therapeutic potential of targeting these proteins in the treatment of muscle wasting and metabolic dysfunction.

Keywords:  NFκB-inducing kinase; aging-related sarcopenia; ectodysplasin A2 receptor signaling; insulin resistance in muscle; skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.molmed.2024.02.002
Acta Physiol (Oxf). 2024 Mar 04. e14124

Impairment of the adrenergic reserve associated with exercise intolerance in a murine model of heart failure with preserved ejection fraction.

Lukas Semmler, Tobias Jeising, Judith Huettemeister, Marc Bathe-Peters, Konstantina Georgoula, Rashin Roshanbin, Paulina Sander, Shu Fu, David Bode, Felix Hohendanner, Burkert Pieske, Paolo Annibale, Gabriele G Schiattarella, Christian U Oeing, Frank R Heinzel.

   AIM: Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve both in vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model.
METHODS: 12-week-old male C57BL/6J mice were fed regular chow (control) or a high-fat diet and L-NAME (HFpEF) for 15 weeks. At 27 weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes.
RESULTS: HFpEF mice (preserved left ventricular ejection fraction, increased E/e', pulmonary congestion [wet lung weight/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF.
CONCLUSION: In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro-oxidative signaling.

Keywords:  adrenergic signaling; cardiac output reserve; exercise intolerance; heart failure with preserved ejection fraction; nitro-oxidative signaling

DOI:  https://doi.org/10.1111/apha.14124
ESC Heart Fail. 2024 Mar 04.

Epicardial adipose tissue and pericardial constraint in heart failure with preserved ejection fraction.

Yoran Crum, Elke S Hoendermis, Dirk J van Veldhuisen, Gijs van Woerden, Michelle Lobeek, Michael G Dickinson, Laura M G Meems, Adriaan A Voors, Michiel Rienstra, Thomas M Gorter.

   AIMS: Obesity and epicardial adiposity play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF), and both are associated with increased filling pressures and reduced exercise capacity. The haemodynamic basis for these observations remains inaccurately defined. We hypothesize that an abundance of epicardial adipose tissue (EAT) within the pericardial sac is associated with haemodynamic signs of pericardial constraint.
METHODS AND RESULTS: HFpEF patients who underwent invasive heart catheterization with simultaneous echocardiography were included. Right atrial pressure (RAP), right ventricular end-diastolic pressure, and pulmonary capillary wedge pressure (PCWP) were invasively measured. The presence of a square root sign on the right ventricular pressure waveform and the RAP/PCWP ratio (surrogate parameters for pericardial constraint) were investigated. EAT thickness alongside the right ventricle was measured on echocardiography. Sixty-four patients were studied, with a mean age of 73 ± 10 years, 64% women, and a mean body mass index (BMI) of 28.6 ± 5.4 kg/m2 . In total, 47 patients (73%) had a square root sign. The presence of a square root sign was associated with higher BMI (29.3 vs. 26.7 kg/m2 , P = 0.02), higher EAT (4.0 vs. 3.4 mm, P = 0.03), and higher RAP (9 vs. 6 mmHg, P = 0.04). Women had more EAT than men (4.1 vs. 3.5 mm, P = 0.04), despite a comparable BMI. Women with a square root sign had significantly higher EAT (4.3 vs. 3.3 mm, P = 0.02), a higher mean RAP (9 vs. 5 mmHg, P = 0.02), and a higher RAP/PCWP ratio (0.52 vs. 0.26, P = 0.002). In men, such associations were not seen, although there was no significant interaction between men and women (P > 0.05 for all analyses).
CONCLUSIONS: Obesity and epicardial adiposity are associated with haemodynamic signs of pericardial constraint in patients with HFpEF. The pathophysiological and therapeutic implications of this finding need further study.

Keywords:  Epicardial adipose tissue; HFpEF; Invasive haemodynamics; Pericardial constraint

DOI:  https://doi.org/10.1002/ehf2.14739
ESC Heart Fail. 2024 Mar 08.

Identification of molecular signatures in epicardial adipose tissue in heart failure with preserved ejection fraction.

Shan He, Lei Zhao, Jianjun Zhang, Xinchun Yang, Huagang Zhu.

   AIMS: The molecular signatures in epicardial adipose tissue (EAT) that contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF) are poorly characterized. In this study, we sought to elucidate molecular signatures including genetic transcripts and long non-coding RNAs (lncRNAs) in EAT that might modulate HFpEF development.
METHODS: RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs and mRNAs in EAT samples from patients with HFpEF (n = 5) and without HF (control, n = 5) who underwent coronary artery bypass grafting. The sequencing results were validated using quantitative real-time PCR (qRT-PCR). Bioinformatics analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of differentially expressed RNAs was performed to predict enriched functions.
RESULTS: HFpEF patients had higher EAT thickness and NT-proBNP levels than the control group. A total of 64 471 transcripts were detected including 35 395 protein-coding sequences, corresponding to 16 854 genes in EAT. RNA-seq identified a total of 741 dysregulated mRNA transcripts (394 up-regulated and 347 down-regulated) and 334 differentially expressed lncRNA transcripts (222 up-regulated and 112 down-regulated) in the HFpEF group compared with the control group (P < 0.05). qRT-PCR analysis confirmed that two lncRNAs ENST00000561775 (P = 0.0194) and ENST00000519093 (P = 0.027) and an mRNA POSTN (P = 0.003) were differentially expressed. Functional enrichment analysis of the differentially expressed mRNAs suggested their potential roles in immune response involving cytokine interaction and chemokine signalling.
CONCLUSIONS: We are the first group to report on the lncRNA and mRNA landscape in EAT in HFpEF patients. Our study suggests the possible role of lncRNAs in EAT.

Keywords:  Epicardial adipose tissue; Genetic transcripts; Heart failure with preserved ejection fraction; Long non-coding RNA; RNA sequencing

DOI:  https://doi.org/10.1002/ehf2.14748
Nat Commun. 2024 Mar 08. 15(1): 2137

N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration.

Wenya Ma, Yanan Tian, Leping Shi, Jing Liang, Qimeng Ouyang, Jianglong Li, Hongyang Chen, Hongyue Sun, Haoyu Ji, Xu Liu, Wei Huang, Xinlu Gao, Xiaoyan Jin, Xiuxiu Wang, Yining Liu, Yang Yu, Xiaofei Guo, Ye Tian, Fan Yang, Faqian Li, Ning Wang, Benzhi Cai.

Translational control is crucial for protein production in various biological contexts. Here, we use Ribo-seq and RNA-seq to show that genes related to oxidative phosphorylation are translationally downregulated during heart regeneration. We find that Nat10 regulates the expression of Uqcr11 and Uqcrb mRNAs in mouse and human cardiomyocytes. In mice, overexpression of Nat10 in cardiomyocytes promotes cardiac regeneration and improves cardiac function after injury. Conversely, treating neonatal mice with Remodelin-a Nat10 pharmacological inhibitor-or genetically removing Nat10 from their cardiomyocytes both inhibit heart regeneration. Mechanistically, Nat10 suppresses the expression of Uqcr11 and Uqcrb independently of its ac4C enzyme activity. This suppression weakens mitochondrial respiration and enhances the glycolytic capacity of the cardiomyocytes, leading to metabolic reprogramming. We also observe that the expression of Nat10 is downregulated in the cardiomyocytes of P7 male pig hearts compared to P1 controls. The levels of Nat10 are also lower in female human failing hearts than non-failing hearts. We further identify the specific binding regions of Nat10, and validate the pro-proliferative effects of Nat10 in cardiomyocytes derived from human embryonic stem cells. Our findings indicate that Nat10 is an epigenetic regulator during heart regeneration and could potentially become a clinical target.

DOI: https://doi.org/10.1038/s41467-024-46458-7
Sci Adv. 2024 Mar 08. 10(10): eadj6411

Childhood adverse life events and skeletal muscle mitochondrial function.

Kate A Duchowny, David J Marcinek, Theresa Mau, L Grisell Diaz-Ramierz, Li-Yung Lui, Frederico G S Toledo, Peggy M Cawthon, Russell T Hepple, Philip A Kramer, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings, Paul M Coen, Anthony J A Molina.

Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events "get under the skin" to influence physical well-being. Using data from the Study of Muscle, Mobility, and Aging (n = 879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (i) maximal adenosine triphosphate production (ATPmax) and (ii) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing one or more adverse childhood events. After adjustment, each additional event was associated with -0.08 SD (95% confidence interval = -0.13, -0.02) lower ATPmax. No association was observed with Max OXPHOS. Adverse childhood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism for understanding how early social stress influences health in later life.

DOI: https://doi.org/10.1126/sciadv.adj6411
Nat Commun. 2024 Mar 05. 15(1): 1995

ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Tao Zhuang, Mei-Hua Chen, Ruo-Xi Wu, Jing Wang, Xi-De Hu, Ting Meng, Ai-Hua Wu, Yan Li, Yong-Feng Yang, Yu Lei, Dong-Hua Hu, Yan-Xiu Li, Li Zhang, Ai-Jun Sun, Wei Lu, Guan-Nan Zhang, Jun-Li Zuo, Cheng-Chao Ruan.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

DOI: https://doi.org/10.1038/s41467-024-46357-x