bims-mimcad 2024-07-28 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–07–28
seven papers selected by
Henver Brunetta, University of Guelph

Postprandial fatty acid-binding protein 4 is associated with muscle insulin resistance.
Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis.
Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.
Ryanodine receptor stabilization therapy suppresses Ca2+- based arrhythmias in a novel model of metabolic HFpEF.
Exercise mitigates reductive stress-induced cardiac remodeling in mice.
Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome.

Diabetologia. 2024 Jul 26.

Postprandial fatty acid-binding protein 4 is associated with muscle insulin resistance.

Tsuyoshi Okura, Yuichi Ito, Mari Anno, Satomi Endo, Sonoko Kitao, Risa Nakamura, Kazuhisa Matsumoto, Kyoko Shoji, Hiroko Okura, Kazuhiko Matsuzawa, Shoichiro Izawa, Yoshinori Ichihara, Etsuko Ueta, Masahiko Kato, Takeshi Imamura, Shin-Ichi Taniguchi, Kazuhiro Yamamoto.

   AIMS/HYPOTHESIS: Fatty acid-binding protein 4 (FABP4) has been reported to act as a hepatic insulin resistance factor. We previously reported that fasting FABP4 was correlated with insulin resistance measurements derived from the glucose clamp, and another study reported that postprandial FABP4 levels were decreased in healthy volunteers but were not reported (or known) in participants with type 2 diabetes. We have limited knowledge about the direct effect of FABP4 on muscle cells. We investigated the postprandial FABP4 levels in participants with type 2 diabetes, and the basic mechanism of muscle insulin resistance and FABP4.
METHODS: We performed a meal tolerance test and hyperinsulinaemic-euglycaemic clamp in 22 participants with type 2 diabetes and 26 participants without diabetes. We measured fasting and postprandial serum FABP4. We cultured mouse C2C12 muscle cells, and investigated the effect of FABP4 on glucose uptake. We analysed insulin signalling by western blot and insulin binding assay.
RESULTS: The postprandial FABP4 level in participants with type 2 diabetes was higher than that in participants without diabetes. Participants without diabetes had lower postprandial FABP4 than fasting except for one participant, whereas one-third of participants with type 2 diabetes had higher postprandial FABP4 than fasting. Postprandial FABP4 was correlated with the muscle insulin resistance M/I value from a glucose clamp in participants without diabetes (r=-0.42, p<0.05). The increase in FABP4 after a meal correlated with the muscle insulin resistance M/I value (r=-0.44, p<0.05) and the difference between fasting and postprandial glucagon in participants with type 2 diabetes (r=0.36, p<0.05). FABP4 alone appears to increase glucose uptake, and the combination of FABP4 and insulin decreases glucose uptake when compared with insulin alone. FABP4 inhibits insulin signalling of muscle cells through decreases in phosphorylation of insulin receptor substrate 1 and Akt. The physiological concentration of FABP4 did not inhibit insulin binding to muscle cells.
CONCLUSIONS/INTERPRETATION: These results suggested that the postprandial FABP4 level is associated with insulin resistance, and FABP4 may suppress insulin signals.

Keywords:  Fatty acid-binding protein; Glucose clamp; Insulin resistance; Muscle

DOI:  https://doi.org/10.1007/s00125-024-06222-4
Cardiovasc Diabetol. 2024 Jul 23. 23(1): 269

Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1-STING axis.

Ying Shi, Lili Zhao, Jing Wang, Xiankun Liu, Yiming Bai, Hongliang Cong, Ximing Li.

  Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed a high-fat diet (HFD) supplemented with L-NAME for 12 weeks and subsequently intraperitoneally injected with EMPA for another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes in the failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. HFpEF group) and 173 DEPs (HFpEF vs. EMPA group). The regulation of immune system processes was enriched in all groups and the interferon response genes (STAT1, Ifit1, Ifi35 and Ifi47) were upregulated in HFpEF mice but downregulated after EMPA administration. In addition, EMPA treatment suppressed the increase in the levels of aging markers (p16 and p21) in HFpEF hearts. Further bioinformatics analysis verified STAT1 as the hub transcription factor during pathological changes in HFpEF mice. We next treated H9C2 cells with IFN-γ, a primary agonist of STAT1 phosphorylation, to investigate whether EMPA plays a beneficial role by blocking STAT1 activation. Our results showed that IFN-γ treatment caused cardiomyocyte senescence and STAT1 activation, which were inhibited by EMPA administration. Notably, STAT1 inhibition significantly reduced cellular senescence possibly by regulating STING expression. Our findings revealed that EMPA mitigates cardiac inflammation and aging in HFpEF mice by inhibiting STAT1 activation. The STAT1-STING axis may act as a pivotal mechanism in the pathogenesis of HFpEF, especially under inflammatory and aging conditions.

Keywords:  Empagliflozin; Heart failure; STAT1; STING; Senescence

DOI:  https://doi.org/10.1186/s12933-024-02366-0
JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.

  The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

Keywords:  Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.180906
Circ Heart Fail. 2024 Jul 25. e011693

Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

Rachel J Skow, Satyam Sarma, James P MacNamara, Miles F Bartlett, Denis J Wakeham, Zachary T Martin, Mitchel Samels, Damsara Nandadeva, Tiffany L Brazile, Jimin Ren, Qi Fu, Tony G Babb, Bryce N Balmain, Michael D Nelson, Linda S Hynan, Benjamin D Levine, Paul J Fadel, Mark J Haykowsky, Christopher M Hearon.

   BACKGROUND: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation.
METHODS: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO2) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO2, and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity.
RESULTS: Peak VO2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P=0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO2/dL blood; P<0.001). During single leg knee extension, there was no difference in peak leg VO2 (P=0.306), but the peripherally limited group had greater blood flow/VO2 ratio (P=0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO2/dL blood; P=0.013), and lower muscle oxygen diffusive conductance (P=0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected (P=0.199).
CONCLUSIONS: Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O2 ratio and poor muscle diffusive capacity.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844.

Keywords:  exercise test; heart failure; magnetic resonance imaging; muscle, skeletal; stroke volume

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.123.011693
J Mol Cell Cardiol. 2024 Jul 23. pii: S0022-2828(24)00122-6. [Epub ahead of print]

Ryanodine receptor stabilization therapy suppresses Ca2+- based arrhythmias in a novel model of metabolic HFpEF.

Aaron D Kaplan, Liron Boyman, Christopher W Ward, W Jonathan Lederer, Maura Greiser.

  Heart Failure with preserved ejection fraction (HFpEF) has a high rate of sudden cardiac death (SCD) and empirical treatment is ineffective. We developed a novel preclinical model of metabolic HFpEF that presents with stress-induced ventricular tachycardia (VT). Mechanistically, we discovered arrhythmogenic changes in intracellular Ca2+ handling distinct from the changes pathognomonic for heart failure with reduced ejection fraction. We further show that dantrolene, a stabilizer of the ryanodine receptor Ca2+ channel, attenuates HFpEF-associated arrhythmogenic Ca2+ handling in vitro and suppresses stress-induced VT in vivo. We propose ryanodine receptor stabilization as a mechanistic approach to mitigation of malignant VT in metabolic HFpEF.

Keywords:  Arrhythmia; Calcium handling; Heart failure; Metabolic stress

DOI:  https://doi.org/10.1016/j.yjmcc.2024.07.006
Redox Biol. 2024 Jul 04. pii: S2213-2317(24)00241-6. [Epub ahead of print]75 103263

Exercise mitigates reductive stress-induced cardiac remodeling in mice.

Arun Jyothidasan, Sini Sunny, Asokan Devarajan, Aniqa Sayed, John Kofi Afortude, Brian Dalley, Vivek Nanda, Steven Pogwizd, Silvio H Litovsky, Joel D Trinity, Matthew Might, Namakkal S Rajasekaran.

  The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 μm2 to 280 μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.

Keywords:  Cardiac hypertrophy; ER stress; Exercise; Nrf2 signaling; Oxidative stress; Proteostasis; Reductive stress

DOI:  https://doi.org/10.1016/j.redox.2024.103263
Obesity (Silver Spring). 2024 Jul 22.

Proteomic biomarkers related to obesity in heart failure with reduced ejection fraction and their associations with outcome.

Teun B Petersen, Navin Suthahar, Folkert W Asselbergs, Marie de Bakker, K Martijn Akkerhuis, Alina A Constantinescu, Jan van Ramshorst, Peter D Katsikis, Peter J van der Spek, Victor A Umans, Rudolf A de Boer, Eric Boersma, Dimitris Rizopoulos, Isabella Kardys.

OBJECTIVE: Heart failure (HF) pathophysiology in patients with obesity may be distinct. To study these features, we identified obesity-related biomarkers from 4210 circulating proteins in patients with HF with reduced ejection fraction (HFrEF) and examined associations of these proteins with HF prognosis and biological mechanisms.
METHODS: In 373 patients with trimonthly blood sampling during a median follow-up of 2.1 (25th-75th percentile: 1.1-2.6) years, we applied an aptamer-based multiplex approach measuring 4210 proteins in baseline samples and the last two samples before study end. Associations between obesity (BMI > 30 kg/m2) and baseline protein levels were analyzed. Subsequently, associations of serially measured obesity-related proteins with biological mechanisms and the primary endpoint (PEP; composite of cardiovascular mortality, HF hospitalization, left ventricular assist device implantation, and heart transplantation) were examined.
RESULTS: Obesity was identified in 26% (96/373) of patients. A total of 30% (112/373) experienced a PEP (with obesity: 26% [25/96] vs. without obesity: 31% [87/277]). A total of 141/4210 proteins were linked to obesity, reflecting mechanisms of neuron projection development, cell adhesion, and muscle cell migration. A total of 50/141 proteins were associated with the PEP, of which 12 proteins related to atherosclerosis or hypertrophy provided prognostic information beyond clinical characteristics, N-terminal pro-B-type natriuretic peptide, and high-sensitivity troponin T.
CONCLUSIONS: Patients with HFrEF and obesity show distinct proteomic profiles compared to patients with HFrEF without obesity. Obesity-related proteins are independently associated with HF outcome. These proteins carry potential to improve management of obesity-related HF and could be leads for future research.

DOI: https://doi.org/10.1002/oby.24094