bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2025–04–20
twelve papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello



  1. J Cereb Blood Flow Metab. 2025 Apr 12. 271678X251334222
      Hyperglycemia in poorly controlled diabetes is widely recognized as detrimental to organ dysfunction. However, the acute effects of hyperglycemia on brain metabolism and function are not fully understood. The potential protective benefit of ketone bodies on mitochondrial function in the brain has also not been well characterized. Here, we evaluated the acute effects of hyperglycemia and β-hydroxybutyrate (BHB) on brain metabolism by employing a novel approach leveraging adenosine triphosphate (ATP)-dependence of bioluminescence originating from luciferin-luciferase activity. Oxygen consumption rate was measured in ex vivo live brain punches to further evaluate mitochondrial function. Our data demonstrate that brain metabolism in mice is affected by acute exposure to high glucose. This short-term effect of glucose exposure was reduced by co-administration with the ketone body BHB. Additionally, we investigated the functional relevance of BHB using an in vivo photothrombotic stroke model to assess its cerebroprotective effects in presence or absence of acute hyperglycemia. BHB significantly reduced infarct size in the brain stroke model, providing functional evidence for its protective role in the brain. These findings suggest that BHB may effectively mitigate the adverse effects of metabolic stress and ischemic events on brain metabolism and function.
    Keywords:  Acute hyperglycemia; brain metabolism; in vivo brain imaging; oxygen consumption rate; β-hydroxybutyrate
    DOI:  https://doi.org/10.1177/0271678X251334222
  2. Am J Physiol Endocrinol Metab. 2025 Apr 17.
      Ketone bodies are increasingly examined as an alternative fuel source for the known decreases in glucose utilization that occur with neurodegeneration. Here, we established a protocol to maximize ketone body respiration in isolated brain mitochondria, while quantifying acetyl-CoA and energy charge via liquid chromatography-tandem mass spectrometry in control mice compared to mice with neuron-specific deletion of succinyl- CoA-3-oxoacid-CoA transferase (SCOT), required for CoA transfer from succinyl-CoA to AcAc to support its oxidation. Maximal ADP-dependent AcAc respiration occurred at 1 mM; however, the percent increase above basal was minimal (~15%). Alpha- ketoglutarate (αKG) substantially increased AcAc-dependent respiration in isolated brain mitochondria, putatively through the generation of succinyl-CoA. Using mice with neuron- specific deletion of SCOT, we also examined brain mitochondrial respiration of AcAc and resulting acetyl CoA and energy charge (cellular energy availability via adenosine nucleotide ratios of ATP, ADP, and AMP). As expected, isolated brain mitochondria from SCOT-KO mice had lower AcAc State 3 respiration than control mice. Surprisingly, we did not find differences in mitochondrial energy charge between SCOT control and neuron SCOT-KO mice despite decreased acetyl-CoA level in SCOT-KO mice when AcAc was used as the substrate. In conclusion, we show that KG enhances ketone-supported respiration rate in isolated brain mitochondria, and ketone metabolism in neurons affects acetyl-CoA level in brain mitochondria but not energy charge. Future work will determine if diet, exercise, sex, or age impacts ketone-supported respiration rates in conjunction with differences in markers of brain health.
    Keywords:  Brain; Ketone; Mitochondria respiration; SCOT
    DOI:  https://doi.org/10.1152/ajpendo.00058.2025
  3. JACC Heart Fail. 2025 Mar 29. pii: S2213-1779(25)00237-9. [Epub ahead of print]
       BACKGROUND: The etiology of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) is multifactorial. Several contributing pathways may be improved by ketone ester (KE).
    OBJECTIVES: This study aims to determine whether KE improves exercise tolerance in HFpEF.
    METHODS: KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) is a randomized, crossover, placebo-controlled trial of acute KE dosing in 20 symptomatic HFpEF participants. Coprimary endpoints include peak oxygen consumption (VO2) during incremental cardiopulmonary exercise testing and time to exhaustion during an additional constant-intensity exercise (75% peak workload) bout.
    RESULTS: The average age was 71 ± 8 years, 60% were women, and 65% were White. KE did not improve peak VO2 (KE: 10.4 ± 3.6 vs placebo: 10.5 ± 4.0 mL/kg/min; P = 0.75). At rest, heart rate, biventricular systolic function, and cardiac output (0.6 L/min [95% CI: 0.3-1.0 L/min]) were greater with KE vs placebo, whereas total peripheral resistance (-3.2 WU [95% CI: -5.2 to -1.2 WU]) and the arteriovenous oxygen content difference (-0.7 mL of O2/dL blood [95% CI: -1.2 to -0.2 mL]) were lower. These differences mostly disappeared during incremental exercise. KE did not improve exercise endurance during the constant-intensity protocol (9.7 ± 7.3 minutes vs 8.7 ± 4.4 minutes; P = 0.51). In 6 participants receiving 6,6-2H2-glucose infusions during constant-intensity exercise, plasma glucose appearance rate before and during exercise was lower with KE (-0.24 mg/kg/min; P < 0.001). During both exercise protocols, KE lowered: 1) respiratory exchange ratios, demonstrating decreased systemic carbohydrate use; 2) nonesterified fatty acids and glucose; and 3) estimated left ventricular filling pressures (E/e').
    CONCLUSIONS: Despite robust ketosis, shifting substrate use away from carbohydrates, and decreasing estimated left ventricular filling pressures, acute KE supplementation did not improve peak VO2 or constant-intensity exercise in HFpEF. (Ketogenic Exogenous Therapies in HFpEF [KETO-HFpEF]; NCT04633460).
    Keywords:  echocardiography; exercise; heart failure with preserved ejection fraction; ketones; metabolism; skeletal muscle; vascular stiffness
    DOI:  https://doi.org/10.1016/j.jchf.2025.03.002
  4. Basic Res Cardiol. 2025 Apr 12.
      Cardiogenic shock (CS) is characterized by reduced cardiac output (CO), reduced end-organ perfusion, and high mortality. Medical therapies have failed to improve survival. The ketone body 3-hydroxybutyrate (3-OHB) enhances cardiac function in heart failure and CS. We aimed to elucidate the cardiovascular and cardiometabolic effects of 3-OHB treatment during CS. In a randomized, assessor-blinded crossover design, we studied 16 female pigs (60 kg, 5 months of age). CS was induced by left main coronary artery microsphere injections. Predefined criteria for CS were a 30% reduction in CO or mixed venous saturation (SvO2). Intravenous 3-OHB infusion and a matching control solution were administered for 120 min in random order. Hemodynamic measurements were obtained by pulmonary artery catheterization and a left ventricular (LV) pressure-volume catheter. Myocardial mitochondrial function was assessed using high resolution respirometry. During CS, infusion with 3-OHB increased CO by 0.9 L/min (95%CI 0.4-1.3 L/min) compared with control infusion. SvO2 (P = 0.026) and heart rate (P < 0.001) increased. Stroke volume (P = 0.6) was not altered. LV contractile function as determined by LV end-systolic elastance improved during 3-OHB infusion compared with control infusion (P = 0.004). Systemic and pulmonary vascular resistance decreased, and diuresis increased. LV mitochondrial function was higher after 3-OHB infusion compared with control. We conclude that 3-OHB infusion enhances cardiac function by increasing contractility and reducing vascular resistance, while also preserving myocardial mitochondrial respiratory function in a large animal model of ischemic CS. These novel findings support the therapeutic potential of exogenous ketone supplementation in CS management.
    Keywords:  3-Hydroxy butyrate; Cardiac output; Cardiogenic shock; Cardiometabolic; Hemodynamics; Mitochondrial function
    DOI:  https://doi.org/10.1007/s00395-025-01103-2
  5. Am J Physiol Heart Circ Physiol. 2025 Apr 15.
      XXXX.
    Keywords:  Mitochondria; cholesterol; metabolism; physiology; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpheart.00219.2025
  6. J Orthop Surg Res. 2025 Apr 19. 20(1): 395
       BACKGROUND: Mitochondrial fission and fusion both contribute to maintaining mitochondrial function and optimizing bioenergetic capacity.
    OBJECTIVE: The aim of this study was to compare the effect of aerobic and resistance training on mitochondrial fission and fusion markers in skeletal and cardiac muscles of Wistar rats.
    METHOD: 24 male Wistar rats were randomly divided into four groups of moderate-intensity interval training (MIIT), high-intensity interval training (HIIT), resistance training (RT) and control (CON). The MIIT and HIIT groups performed treadmill exercises with an intensity of 60-65% and 80-85% of the maximum speed, respectively, while the RT group performed resistance training with an intensity of 30-60% of the rat's body weight for 8 weeks. The soleus (SOL), extensor digitorum longus (EDL) and left ventricular tissues were used to evaluate markers of mitochondrial fission and fusion PGC-1α (fusion/fission), Opa-1 (fusion), Fis-1 (fission), Drp-1 (fission), Mfn-1 and Mfn-2 (fusion) genes expression.
    RESULTS: In all three tissues, a significant increase in some mitochondrial fusion markers was observed after 8 weeks of training (p = < 0.0001-0.0452). Furthermore, a significant decrease in cardiac mitochondrial fission markers was observed in all three groups (p = < 0.0001-0.0156). This reduction in some markers was evident in the SOL tissue of the HIIT group (p < 0.0001 for Drp-1 and p = 0.0007 for Fis-1) and in the EDL tissue of the RT group (p = 0.0005 for Fis-1 and p = 0.0012 for Drp-1). The mitochondrial fission/fusion markers in the heart (p = 0.0007-0.0449) and SOL (p = 0.0050-0.0258) tissues of the HIIT group had more changes than the RT group, while the mitochondrial fission markers in the EDL tissue of the RT group had a lower level than the HIIT (p = 0.0087 for Drp-1) and MIIT (p = 0.0130 for Fis-1 and p = 0.0010 for Drp-1) groups.
    CONCLUSION: Our study demonstrated that HIIT, through better regulation of mitochondrial fusion and fission than RT, improves mitochondrial dynamics in cardiac and SOL tissues.
    Keywords:  Exercise; Mitochondrial dynamics; Muscles; Myocardium; Rats
    DOI:  https://doi.org/10.1186/s13018-025-05809-w
  7. BMC Nutr. 2025 Apr 14. 11(1): 76
       BACKGROUND: Low-carbohydrate diets (LCDs) have been associated with inflammation while there is still conflicting evidence regarding the effects of this type of diet on inflammatory markers and the clinical benefit of them remains uncertain. So, we aimed to ascertain the effects of LCDs on serum concentrations of tumor necrosis factor alpha (TNF-α) and interleukin- 6 (IL- 6) by performing a systematic review and meta-analysis of randomized clinical trials (RCTs).
    METHODS: The online databases PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, and Scopus were comprehensively searched up to February 2024, to find pertinent RCTs. Pooled weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using the random-effects model.
    RESULTS: This meta-analysis of 33 studies assessed a total of 2106 adults irrespective of their health status. Compared with control group, participants on LCDs experienced a decline in IL- 6 levels (WMD: - 0.31 pg/mL; 95% CI: - 0.49 to - 0.12; P = 0.001). However, no significant effect was revealed for TNF-α (WMD: - 0.02 pg/mL; 95% CI: - 0.08 to - 0.03; P = 0.449). Stratification analyses indicated that beneficial effects of LCDs on inflammatory cytokines (WMD: - 0.28 pg/mL; 95% CI: - 0.47 to - 0.10; P = 0.003, WMD: - 0.26 pg/mL; 95% CI: - 0.48 to - 0.03; P = 0.027, for TNF-α and IL- 6, respectively) were stronger when carbohydrate intake was < 10%. The results of Meta-regression analyses suggested that baseline level of both markers remained as a strong predictor of the effect size (P = 0.038 and P = 0.001 for TNF-α and IL- 6, respectively).
    CONCLUSION: Adherence to LCDs appeared to be effective at improving inflammatory cytokines particularly, when carbohydrate intake was restricted to less than 10% of total energy. Nevertheless, further rigorously designed clinical trials considering factors such as race and genetic, the sources and quality of dietary carbohydrates, protein, and fat are required to gain a deeper understanding of the impact of LCDs on inflammatory markers.
    TRIAL REGISTRATION: PROSPERO, registration no: CRD42023387452.
    Keywords:  Carbohydrate restriction; Inflammation; Interleukin- 6; Low-carbohydrate diet; Meta-analysis; TNF-α
    DOI:  https://doi.org/10.1186/s40795-025-01062-w
  8. Sci Adv. 2025 Apr 18. 11(16): eads1842
      Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.
    DOI:  https://doi.org/10.1126/sciadv.ads1842
  9. Bio Protoc. 2025 Apr 05. 15(7): e5257
      With the advancement of liquid chromatography-mass spectrometry (LC-MS/MS), the quantification of glycerophospholipid (PL) molecules has become more accessible, leading to the discovery of numerous enzymes responsible for determining the acyl groups attached to these molecules. Metabolic tracer experiments using radioisotopes and stable isotopes are powerful tools for defining the function of metabolic enzymes and metabolic flux. We have established an ex vivo muscle experimental system using stable isotope-labeled fatty acids to evaluate fatty acid incorporation into PL molecules. Here, we describe a method to incorporate fatty acids with stable isotope labels into excised skeletal muscle and detect the PL molecules containing labeled acyl chains by LC-MS/MS. Key features • Quantify the metabolism of fatty acids into phospholipid acyl chains. • Enable measurements in excised muscle samples. • Assess the effects of genetic recombination of acyltransferases.
    Keywords:  Acyl chain; Free-fatty acid; Liquid chromatography–mass spectrometry; Phospholipid; Skeletal muscle; Stable isotope tracer
    DOI:  https://doi.org/10.21769/BioProtoc.5257
  10. Exp Gerontol. 2025 Apr 16. pii: S0531-5565(25)00078-6. [Epub ahead of print] 112749
      Muscle atrophy is characterized by a decrease in muscle mass, strength, and activity. Recently, it was determined that microRNAs (miRNAs) can regulate muscle atrophy and that dexamethasone (Dex), an allergy and autoimmune disorder treatment that can induce muscle atrophy. Therefore, this study was designed to identify miRNAs expressed in Dex-induced muscle atrophy in mice using small RNA sequencing. A total of 820 miRNAs were identified, with 58 miRNAs expressed explicitly in atrophic muscles. Dex-induced muscle atrophy miRNAs clustered separately from the differential miRNAs in aging, disuse, and cancer-induced muscle atrophy models. The target genes of Dex-induced muscle atrophy miRNAs were independently enriched in inositol phosphate metabolism, hypoxia-inducible factor-1 signaling pathway, etc. Of note, there was a significant increase in the volume of fat cells and adipose weight in the Dex group, suggesting that fat deposition during Dex-induced skeletal muscle atrophy is a unique and typical feature. SIMPLE SUMMARY: Dexamethasone (Dex) is a glucocorticoid used to treat allergic and autoimmune diseases, but excessive use can lead to skeletal muscle atrophy. We used dexamethasone (Dex) to build a muscle atrophy model in mice, and obvious changes had taken place in mouse body weight, muscle tissue morphology and related genes. A large number of microRNAs were found to be differentially expressed, and their functions were enriched in pathways related to muscle development. At the same time, we compared the similarities and differences of microRNAs and their functions between Dex induced muscle atrophy model and other muscle atrophy models. Finally, we were surprised to find that Dex induced muscle atrophy is specifically accompanied by the accumulation of body fat.
    Keywords:  Dexamethasone; Lipid deposition; Muscle atrophy; microRNAs
    DOI:  https://doi.org/10.1016/j.exger.2025.112749
  11. J Biomech. 2025 Apr 12. pii: S0021-9290(25)00200-3. [Epub ahead of print]185 112688
      Most research involving rodents has analyzed biomechanical gait parameters under pathological conditions, with some studies exploring the effects of moderate-intensity training on these variables in the context of aging and disease. Additionally, aging and obesity in humans cause morphological changes in the musculoskeletal system, while physical exercise helps mitigate muscle deterioration. This study aimed to investigate linear gait kinematics and muscle tissue morphometry in Wistar rats of different ages, fed a high-fat diet (HFD), and subjected to a HIIT protocol. Thus, the aim of this study was to analyze linear kinematic gait parameters, as well as morphometric aspects of muscle tissue in Wistar rats of different ages fed with an HFD diet and subjected to a high-intensity interval training (HIIT) protocol. Seven-, nine-, 12- and 18-month-old male Wistar rats divided in 16 groups (n = 7): T-SD and S-SD (trained and sedentary fed with standard diet), S-HFD and T-HFD (trained and sedentary fed with high-fat diet) were subjected to a HIIT protocol, 3x a week, for 8 weeks. After the training period, the gait cycles of all groups were recorded. The cross-sectional area of the muscle fibers of the soleus and extensor digitorum longus was assessed. The practice of HIIT body mass and causing muscle fiber hypertrophy regardless of diet and age (p < 0.001), increased maximum running capacity, reduced stride length, stride and support time, and increased stride frequency, even under the influence of age (p < 0.001). As a conclusion, HIIT promoted greater linear locomotor efficiency, resulting in a more efficient and dynamic gait. Obesity condition did not directly affect the linear variables analyzed.
    Keywords:  Gait analysis; Motion capture; Obesity; Skeletal muscle; Training
    DOI:  https://doi.org/10.1016/j.jbiomech.2025.112688
  12. Nutrients. 2025 Apr 04. pii: 1265. [Epub ahead of print]17(7):
      Background/Objectives: This study piloted a 24-week bodybuilding program combining resistance training (RT) with a dietary bulk-and-cut protocol in middle-aged adult males. Methods: Seven untrained males (33 ± 3.0 years; BMI = 35.0 ± 4.6 kg/m2; body fat = 36 ± 5%) completed a 24-week intervention combining RT with a dietary protocol consisting of 12-week cycles of caloric bulking (0-12 weeks) and cutting (12-24 weeks). The participant retention rate was 64%, while compliance with training was 96.7%, and adherence to dietary cycles was over 93%. To assess the preliminary efficacy of the intervention, venous blood samples and measurements of body composition (BodPod), muscle strength, and VO2max (cycle ergometer) were collected at baseline (week 0) and following the bulking (week 12) and cutting (week 24) cycles. Circulating lipids (triglycerides, total, low-density, and high-density cholesterol), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured in serum. Results: The training led to significant increases in muscle strength, especially in the deadlift (+46%, p < 0.001) and squat (+65%, p < 0.001). Improvements in body composition were characterized by an increase in fat-free mass and a decrease in body fat percentage over the 24-week intervention (+3% and -6%, respectively, p < 0.05). Lipids, CRP, IL-6, and IL-10 did not change significantly, but there was a notable reduction in TNF-α (time effect p = 0.05, pη2 = 0.39), with 15% lower concentrations at week 24 compared to baseline, indicating reduced inflammation. Conclusions: Overall, the pilot intervention achieved high compliance and adherence rates, leading to improvements in body composition and lower resting TNF-α concentrations in a group of middle-aged males with obesity.
    Keywords:  blood lipids; exercise and diet intervention; inflammation; obesity
    DOI:  https://doi.org/10.3390/nu17071265