bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024‒06‒30
ten papers selected by
Henver Brunetta, University of Guelph
  1. A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.
  2. Mitochondria fission accentuates oxidative stress in hyperglycemia-induced H9c2 cardiomyoblasts in vitro by regulating fatty acid oxidation.
  3. Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.
  4. Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.
  5. Uncovering the Role of Epicardial Adipose Tissue in Heart Failure With Preserved Ejection Fraction.
  6. The DNA methyltransferase inhibitor decitabine blunts the response to a high animal fat and protein diet in mice.
  7. ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.
  8. Time-dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets.
  9. Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
  10. The extracellular matrix integrates mitochondrial homeostasis.
  1. Eur J Heart Fail. 2024 Jun 26.
    A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.
    Dalane W Kitzman, Gregory D Lewis, Ambarish Pandey, Barry A Borlaug, Andrew J Sauer, Sheldon E Litwin, Kavita Sharma, Diane K Jorkasky, Shaharyar Khan, Sanjiv J Shah.
      AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.
    CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.
    Keywords:  Controlled metabolic accelerator; HU6; Heart failure with preserved ejection fraction; Obesity; Protocol; Randomized clinical trial
    DOI:  https://doi.org/10.1002/ejhf.3305
  2. Cell Biol Int. 2024 Jun 23.
    Mitochondria fission accentuates oxidative stress in hyperglycemia-induced H9c2 cardiomyoblasts in vitro by regulating fatty acid oxidation.
    Xiaogang Song, Chongxi Fan, Chao Wei, Wuhan Yu, Jichao Tang, Feng Ma, Yongqing Chen, Bing Wu.
      Oxidative stress plays a pivotal role in the development of diabetic cardiomyopathy (DCM). Previous studies have revealed that inhibition of mitochondrial fission suppressed oxidative stress and alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. However, no research has confirmed whether mitochondria fission accentuates hyperglycemia-induced cardiomyoblast oxidative stress through regulating fatty acid oxidation (FAO). We used H9c2 cardiomyoblasts exposed to high glucose (HG) 33 mM to simulate DCM in vitro. Excessive mitochondrial fission, poor cell viability, and lipid accumulation were observed in hyperglycemia-induced H9c2 cardiomyoblasts. Also, the cells were led to oxidative stress injury, lower adenosine triphosphate (ATP) levels, and apoptosis. Dynamin-related protein 1 (Drp1) short interfering RNA (siRNA) decreased targeted marker expression, inhibited mitochondrial fragmentation and lipid accumulation, suppressed oxidative stress, reduced cardiomyoblast apoptosis, and improved cell viability and ATP levels in HG-exposed H9c2 cardiomyoblasts, but not in carnitine palmitoyltransferase 1 (CPT1) inhibitor etomoxir treatment cells. We also found subcellular localization of CPT1 on the mitochondrial membrane, FAO, and levels of nicotinamide adenine dinucleotide phosphate (NADPH) were suppressed after exposure to HG treatment, whereas Drp1 siRNA normalized mitochondrial CPT1, FAO, and NADPH. However, the blockade of FAO with etomoxir abolished the above effects of Drp1 siRNA in hyperglycemia-induced H9c2 cardiomyoblasts. The preservation of mitochondrial function through the Drp1/CPT1/FAO pathway is the potential mechanism of inhibited mitochondria fission in attenuating oxidative stress injury of hyperglycemia-induced H9c2 cardiomyoblasts.
    Keywords:  FAO; apoptosis; cardiomyoblasts; diabetes; mitochondrial fission; oxidative stress
    DOI:  https://doi.org/10.1002/cbin.12204
  3. J Am Coll Cardiol. 2024 Jun 12. pii: S0735-1097(24)07126-2. [Epub ahead of print]
    Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.
    STEP-HFpEF Trial Committees and Investigators
      BACKGROUND: In the Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) program, semaglutide improved heart failure (HF)-related symptoms, physical limitations, and exercise function, and reduced bodyweight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Whether semaglutide improves functional status, as assessed by NYHA functional class, is unknown.OBJECTIVES: The goal of this study was to examine the effects of semaglutide on change in NYHA functional class over time. We also investigated the effects of semaglutide on HF-related symptoms, physical limitations, and bodyweight and other trial endpoints across baseline NYHA functional class categories.
    METHODS: This was a prespecified analysis of pooled data from 2 international, double-blind, randomized trials (STEP-HFpEF and STEP-HFpEF type 2 diabetes [STEP-HFpEF DM], comprising the STEP-HFpEF program), which collectively randomized 1,145 participants with obesity-related HFpEF to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The outcome of interest for this analysis was the change in NYHA functional class (baseline to 52 weeks). We also investigated the effects of semaglutide on the dual primary, confirmatory secondary, and selected exploratory endpoints according to baseline NYHA functional class.
    RESULTS: More semaglutide-treated than placebo-treated patients had an improvement in NYHA functional class (32.6% vs 21.5%, respectively; OR: 2.20 [95% CI: 1.62-2.99; P < 0.001]) and fewer semaglutide-treated patients experienced deterioration in NYHA functional class (2.09% vs 5.24%, respectively; OR: 0.36 [95% CI: 0.19-0.70; P = 0.003]) at 52 weeks. Semaglutide (vs placebo) improved the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CCS) across NYHA functional class categories; this was especially pronounced in those in NYHA functional classes III/IV (10.5 points [95% CI: 6.6-14.4 points]) vs NYHA functional class II (6.0 points [95% CI: 3.4-8.6 points]) (P interaction = 0.06). By contrast, the degree of reduction in bodyweight was similar with semaglutide vs placebo regardless of baseline NYHA functional class category (NYHA functional class II, -8.4% [95% CI: -9.4% to -7.3%]; NYHA functional classes III/IV, -8.3% [95% CI: -9.9% to -6.8%]; P interaction = 0.96). Semaglutide consistently improved 6-minute walking distance (6MWD), the hierarchical composite endpoint (death, HF events, differences in KCCQ-CSS, and 6MWD changes), and reduced C-reactive protein and N-terminal prohormone of brain natriuretic peptide across NYHA functional class categories (all P interactions = NS).
    CONCLUSIONS: In patients with obesity-related HFpEF, fewer semaglutide-treated than placebo-treated patients had a deterioration, and more had an improvement, in NYHA functional class at 52 weeks. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories. Semaglutide-mediated improvements in health status were especially large in patients with NYHA functional classes III/IV. (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure and Obesity; NCT04788511) (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes; NCT04916470).
    Keywords:  New York Heart Association functional class; heart failure; left ventricular ejection fraction; obesity; semaglutide
    DOI:  https://doi.org/10.1016/j.jacc.2024.04.038
  4. J Am Coll Cardiol. 2024 Jun 19. pii: S0735-1097(24)07445-X. [Epub ahead of print]
    Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.
    STEP-HFpEF Trial Committees and Investigators
      BACKGROUND: More women than men have heart failure with preserved ejection fraction (HFpEF).OBJECTIVES: The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program.
    METHODS: In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes.
    RESULTS: Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo.
    CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).
    Keywords:  heart failure; obesity; semaglutide; sex
    DOI:  https://doi.org/10.1016/j.jacc.2024.06.001
  5. JACC Adv. 2023 Nov;2(9): 100657
    Uncovering the Role of Epicardial Adipose Tissue in Heart Failure With Preserved Ejection Fraction.
    Sarah A Goldman, Juan Antonio Requena-Ibanez, Ana Devesa, Carlos G Santos-Gallego, Juan José Badimon, Valentin Fuster.
      Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure. Obesity is a modifiable risk factor of HFpEF; however, body mass index provides limited information on visceral adiposity and patients with similar anthropometrics can present variable cardiovascular risk. Epicardial adipose tissue (EAT) is the closest fat deposit to the heart and has been proposed as a biomarker of visceral adiposity. EAT may be particularly important for cardiac function, because of its location (under the pericardium) and because it acts as a metabolically active endocrine organ (which can produce both beneficial and detrimental cytokines). In this paper, the authors review the role of EAT in normal and pathologic conditions and discuss the noninvasive imaging modalities that allow its identification. This review highlights EAT implications in HFpEF and discuss new therapies that act on EAT and might also exert beneficial effects on the cardiovascular system.
    Keywords:  atrial fibrillation; epicardial adipose tissue; heart failure with preserved ejection fraction; inflammation
    DOI:  https://doi.org/10.1016/j.jacadv.2023.100657
  6. J Lipid Res. 2024 Jun 26. pii: S0022-2275(24)00091-9. [Epub ahead of print] 100586
    The DNA methyltransferase inhibitor decitabine blunts the response to a high animal fat and protein diet in mice.
    José de Jesús Flores-Sierra, Magaly Del Rosario Muciño-Arellano, Gloria Del Carmen Romo-Morales, Jaime Eduardo Sánchez-Palafox, Viridiana Abigail Correa-Navarro, Dannia Colín-Castelán, Victoriano Pérez-Vázquez, Rubén Rangel-Salazar, Rafael Rivera-Bustamante, Carmen de la Rocha, Dalia Rodríguez-Ríos, Diana Lilia Trejo-Saavedra, Jorge Molina-Torres, Enrique Ramírez-Chávez, Nancy Shyrley García-Rojas, Robert Winkler, Gertrud Lund, Silvio Zaina.
      Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis, i.e., that the DNA methyltransferase inhibitor decitabine (Dec) ameliorates the metabolic profile of mice fed a moderately high-animal fat and protein diet (HAFPD), a proxy of cardiovascular risk-associated Western-type diet. HAFPD-fed mice were exposed to Dec or vehicle for eight weeks (8W set, 4-32/group). To assess any memory of past exposure to Dec, we surveyed a second mice set treated as 8W but HAFPD-fed for further eight weeks without any Dec (16W set, 4-20/group). In 8W, Dec markedly reduced HAFPD-induced body weight gain in females, but marginally in males. Characterization of females revealed that Dec augmented skeletal muscle lipid content, while decreasing liver fat content and increasing plasma non-esterified fatty acids, adipose insulin resistance, and -although marginally- whole blood acylcarnitines, compared to HAFPD alone. Skeletal muscle mitochondrial DNA copy number was higher in 8W mice exposed to HAFPD and Dec, or in 16W mice fed HAFPD only, relative to 8W mice fed HAFPD only, but Dec induced a transcriptional profile indicative of ameliorated mitochondrial function. Memory of past Dec exposure was tissue-specific and sensitive to both duration of exposure to HAFPD and age. In conclusion, Dec redirected HAFPD-induced lipid accumulation towards the skeletal muscle, likely due to augmented mitochondrial functionality and increased lipid demand. As caveat, Dec induced adipose insulin resistance. Our findings may help identifying strategies for prevention and treatment of lipid dysmetabolism.
    Keywords:  Dietary fat; liver; mitochondria; muscle; nutrition
    DOI:  https://doi.org/10.1016/j.jlr.2024.100586
  7. bioRxiv. 2024 Jun 10. pii: 2024.06.09.598152. [Epub ahead of print]
    ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.
    Mariam Meddeb, Navid Koleini, Seungho Jun, Mohammad Keykhaei, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Brian Lin, Gizem Keceli, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.
      BACKGROUND: ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found ACLY gene expression is reduced; however the impact this might have on cardiac function and/or metabolism has not been previously studied. As new ACLY inhibitors are in development for cancer and other disorders, such understanding has added importance.METHODS: Cardiomyocytes, ex-vivo beating hearts, and in vivo hearts with ACLY inhibited by selective pharmacologic (BMS303141, ACLYi) or genetic suppression, were studied. Regulation of ACLY gene/protein expression, and effects of ACLYi on function, cytotoxicity, tricarboxylic acid (TCA)-cycle metabolism, and redox and NAD+/NADH balance were assessed. Mice with cardiac ACLY knockdown induced by AAV9-acly-shRNA or cardiomyocyte tamoxifen-inducible Acly knockdown were studied.
    RESULTS: Acly gene expression was reduced more in obese patients with heart failure and preserved EF (HFpEF) than HF with reduced EF. In vivo pressure-overload and in vitro hormonal stress increased ACLY protein expression, whereas it declined upon fatty-acid exposure. Acute ACLYi (1-hr) dose-dependently induced cytotoxicity in adult and neonatal cardiomyocytes, and caused substantial reduction of systolic and diastolic function in myocytes and ex-vivo beating hearts. In the latter, ATP/ADP ratio also fell and lactate increased. U13C-glucose tracing revealed an ACLYdependent TCA-bypass circuit in myocytes, where citrate generated in mitochondria is transported to the cytosol, metabolized by ACLY and then converted to malate to re-enter mitochondria,bypassing several NADH-generating steps. ACLYi lowered NAD+/NADH ratio and restoring this balance ameliorated cardiomyocyte toxicity. Oxidative stress was undetected with ACLYi. Adult hearts following 8-weeks of reduced cardiac and/or cardiomyocyte ACLY downregulation exhibited ventricular dilation and reduced function that was prevented by NAD augmentation. Cardiac dysfunction from ACLY knockdown was worse in hearts subjected to sustained pressureoverload, supporting a role in stress responses.
    CONCLUSIONS: ACLY supports normal cardiac function through maintenance of the NAD+/NADH balance and is upregulated by hemodynamic and hormonal stress, but depressed by lipid excess. ACLY levels are most reduced in human HFpEF with obesity potentially worsening cardio-metabolic reserve.
    DOI:  https://doi.org/10.1101/2024.06.09.598152
  8. Obesity (Silver Spring). 2024 Jul;32(7): 1373-1388
    Time-dependent changes in feeding behavior and energy balance associated with weight gain in mice fed obesogenic diets.
    Payam A Fathi, Michelle B Bales, Julio E Ayala.
      OBJECTIVE: Obesity is characterized by dysregulated homeostatic mechanisms resulting in positive energy balance; however, when this dysregulation occurs is unknown. We assessed the time course of alterations to behaviors promoting weight gain in male and female mice switched to an obesogenic high-fat diet (HFD).METHODS: Male and female C57BL/6J mice were housed in metabolic chambers and were switched from chow to a 60% or 45% HFD for 4 and 3 weeks, respectively. Food intake, meal patterns, energy expenditure (EE), and body weight were continuously measured. A separate cohort of male mice was switched from chow to a 60% HFD and was given access to locked or unlocked running wheels.
    RESULTS: Switching mice to obesogenic diets promotes transient bouts of hyperphagia during the first 2 weeks followed by persistent caloric hyperphagia. EE increases but not sufficiently enough to offset increased caloric intake, resulting in a sustained net positive energy balance. Hyperphagia is associated with consumption of calorically larger meals (impaired satiation) more frequently (impaired satiety), particularly during the light cycle. Running wheel exercise delays weight gain in male mice fed a 60% HFD by enhancing satiation and increasing EE. However, exercise effects on satiation are no longer apparent after 2 weeks, coinciding with weight gain.
    CONCLUSIONS: Exposure to obesogenic diets engages homeostatic regulatory mechanisms for ~2 weeks that ultimately fail, and consequent weight gain is characterized by impaired satiation and satiety. Insights into the etiology of obesity can be obtained by investigating changes to satiation and satiety mechanisms during the initial ~2 weeks of HFD exposure.
    DOI:  https://doi.org/10.1002/oby.24052
  9. Nat Commun. 2024 Jun 25. 15(1): 5394
    Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.
    Bam D Paneru, Julia Chini, Sam J McCright, Nicole DeMarco, Jessica Miller, Leonel D Joannas, Jorge Henao-Mejia, Paul M Titchenell, David M Merrick, Hee-Woong Lim, Mitchell A Lazar, David A Hill.
      Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
    DOI:  https://doi.org/10.1038/s41467-024-49632-z
  10. Cell. 2024 Jun 24. pii: S0092-8674(24)00638-X. [Epub ahead of print]
    The extracellular matrix integrates mitochondrial homeostasis.
    Hanlin Zhang, C Kimberly Tsui, Gilberto Garcia, Larry K Joe, Haolun Wu, Ayane Maruichi, Wudi Fan, Sentibel Pandovski, Peter H Yoon, Brant M Webster, Jenni Durieux, Phillip A Frankino, Ryo Higuchi-Sanabria, Andrew Dillin.
      Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.
    Keywords:  TGF-β; TMEM2; extracellular matrix; hyaluronan; immunity; mitochondria
    DOI:  https://doi.org/10.1016/j.cell.2024.05.057
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