bims-kimdis 2025-03-23 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–03–23
33 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.
Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions.
Perspectives on the Ketogenic Diet as a Non-pharmacological Intervention For Major Depressive Disorder.
Heart ketone metabolism under acute ketone supplementation in ZDF rats, a type 2 diabetes heart failure model.
Fasting and Headache.
The cyclic metabolic switching theory of intermittent fasting.
Isolating the acute metabolic effects of carbohydrate restriction on postprandial metabolism with or without energy restriction: a crossover study.
Ketone body metabolism and cardiometabolic implications for cognitive health.
A Systematic Review of the Effects of Low-Carbohydrate Diet on Athletic Physical Performance Parameters.
Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.
Integrating Ketone Bodies in Multi-Marker Risk Prediction of Incident Heart Failure in the Multi-Ethnic Study of Atherosclerosis (MESA).
A ketogenic-promoting beverage acutely elevates cardiac function and myocardial blood flow compared to placebo in adults: A cardiac MRI investigation.
Macrophage and cardiomyocyte roles in cardioprotection: Exploiting the NLRP3 Inflammasome inhibitor INF150.
Targeting the NLRP3 by Natural Compounds: Therapeutic Strategies to Mitigate Doxorubicin-Induced Cardiotoxicity.
Skeletal muscle atrophy induced by aging and disuse atrophy are strongly associated with the upregulation of the endoplasmic stress protein CHOP in rats.
PoWeR elicits intracellular signaling, mitochondrial adaptations, and hypertrophy in multiple muscles consistent with endurance and resistance exercise training.
Effect of acipimox on skeletal muscle biochemistry, structure and function in older people with probable sarcopenia: an experimental medicine study.
NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.
Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, as potential (off-label) anti-obesity agents and effects on cardiovascular risk: A systematic review and meta-analysis.
Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.
Lactic acidosis: implications for human exercise performance.
The Role and Regulation of Intramuscular Sex Hormones in Skeletal Muscle: A Systematic Review.
The efficacy of resistance exercise training on metabolic health, body composition, and muscle strength in older adults with type 2 diabetes: A systematic review and Meta-Analysis.
BEETter AGING: Short-Term Dietary Nitrate Supplementation Enhances Muscle Contractile Properties in Older But Not in Young Adults.
A deep dive into oxygen sensing.
Exercise Training for Patients With Heart Failure: The Details Matter.
Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.
3-Hydroxybutyrate Promotes Myoblast Proliferation and Differentiation through Energy Metabolism and GPR109a-Mediated Ca2+-NFAT Signaling Pathways.
Mitochondrial fission - changing perspectives for future progress.
Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.
DNA methylation entropy is a biomarker for aging.
Nutritional Approach to Diabetic Sarcopenia: A Comprehensive Review.

Front Cell Neurosci. 2025 ;19 1551700

Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.

Hao Wen, Nagisa Sada, Tsuyoshi Inoue.

  The ketogenic diet increases ketone bodies (β-hydroxybutyrate and acetoacetate) in the brain, and ameliorates epileptic seizures in vivo. However, ketone bodies exert weak or no effects on electrical activity in rodent hippocampal slices. Especially, it remains unclear what kinds of conditions are required to strengthen the actions of ketone bodies in hippocampal slices. In the present study, we examined the effects of acetoacetate on hippocampal pyramidal cells in normal slices and epileptiform slices of mice. By using patch-clamp recordings from CA1 pyramidal cells, we first confirmed that acetoacetate did not change the membrane potentials and intrinsic properties of pyramidal cells in normal slices. However, we found that acetoacetate weakened spontaneous epileptiform bursts in pyramidal cells of epileptiform slices, which were acutely induced by applying convulsants to normal slices. Interestingly, acetoacetate did not change the frequency of the epileptiform bursts, but attenuated individual epileptiform bursts. We finally examined the effects of acetoacetate on excitatory synaptic barrages during epileptiform activity, and found that acetoacetate weakened epileptiform bursts by reducing synchronous synaptic inputs. These results show that acetoacetate attenuated neuronal bursts in epileptiform slices, but did not affect neuronal activity in normal slices, which leads to seizure-selective actions of ketone bodies.

Keywords:  epilepsy; hippocampus; ketogenic diet; ketone body; patch-clamp recording; slice physiology

DOI:  https://doi.org/10.3389/fncel.2025.1551700
AAPS J. 2025 Mar 14. 27(2): 65

Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions.

N Panse, P M Gerk.

  Although exogenous ketogenic dietary supplements continue to grow in popularity, their pharmacokinetic properties have not been adequately studied, thus hindering their optimal use and benefits. Here, the metabolic characteristics of one such supplement (Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate) (KE)) were studied along with its metabolite- (R)-1,3-butanediol ((R)-1,3-BD), both of which are precursors and undergo metabolic conversion to (R)-beta-hydroxybutyrate (BHB). The metabolism of aldol (an aldehyde intermediate between the conversion of (R)-1,3-BD to (R)-BHB was also evaluated, as it is frequently not considered in any scientific discussion. The metabolic parameters were calculated using pooled human (mixed gender) and pooled rat (male and female) liver fractions. These were later used to estimate the hepatic extraction ratio and the hepatic clearance of these molecules. KE showed rapid and non-saturable clearance in human and rat liver fractions, even at concentrations as high as 15,000 μM. In the case of (R)-1,3-BD, there was saturable metabolism in rats and humans with Km and Vmax values of 8,000 μM and 27.1 nmol/min/mg of protein (humans), 19,300 μM and 113.5 nmol/min/mg of protein (male rats), and 11,910 μM and 75.8 nmol/min/mg of protein (female rats). The metabolism of aldol showed rapid and non-saturable hepatic clearance in human liver fractions.

Keywords:  Veech ketone ester; beta-hydroxybutyrate; clearance; hepatic metabolism; ketone bodies

DOI:  https://doi.org/10.1208/s12248-025-01044-7
Trends Psychiatry Psychother. 2025 Mar 21.

Perspectives on the Ketogenic Diet as a Non-pharmacological Intervention For Major Depressive Disorder.

Jade Shelp, Cristiano Chaves, Alexander Terpstra, Elena Koning, Fabiano A Gomes, Jennifer Fabe, Vitor Breda, Nicole Laurent, Christopher Palmer, Elisa Brietzke.

   BACKGROUND: Major Depressive Disorder (MDD) is a prevalent mood disorder characterized by persistent low mood and anhedonia, significantly impacting cognitive function and daily living. Despite available pharmacological treatments, nearly one-third of individuals with MDD do not achieve adequate symptom relief with conventional treatments. The ketogenic diet (KD), a high-fat, low-carbohydrate diet that induces ketosis, has emerged as a potential non-pharmacological intervention for MDD.
OBJECTIVE: To provide a comprehensive perspective on the current knowledge and gaps regarding the potential antidepressant effect of the KD, emphasizing its safety, efficacy, and mechanistic pathways.
METHODS: This narrative review synthesizes data from preclinical and clinical studies on the effects of KD on mood, cognitive function, and its potential as an antidepressant. Mechanistic insights from animal and human studies are explored to elucidate possible pathways through which KD may exert its effects on MDD.
RESULTS: Evidence from animal models suggests that KD may reduce depressive-like behaviors and improve cognitive function. Preliminary human studies, including case reports and observational studies, indicate potential benefits such as mood stabilization, increased energy, and reduced depression severity. Proposed mechanisms include immune-inflammatory regulation, correction of mitochondrial dysfunction, and neurotransmitter modulation. However, key gaps remain, particularly regarding the therapeutic window, long-term efficacy, and specific mechanisms of action in MDD.
CONCLUSION: KD represents a promising avenue for further investigation as a non-pharmacological treatment of MDD. Further research is needed to establish its clinical utility, identify predictors of response, and assess its feasibility as a treatment option for MDD.

Keywords:  Major depressive disorder; ketogenic diet; ketosis; metabolism; nutrition

DOI:  https://doi.org/10.47626/2237-6089-2024-0932
EJNMMI Res. 2025 Mar 14. 15(1): 23

Heart ketone metabolism under acute ketone supplementation in ZDF rats, a type 2 diabetes heart failure model.

Etienne Croteau, Gabriel Richard, Patrick Prud'Homme, Etienne Rousseau, Stephen C Cunnane, Véronique Dumulon-Perreault, Otman Sarrhini, Serge Phoenix, Sébastien Tremblay, Brigitte Guérin, Roger Lecomte.

   BACKGROUND: In non-insulin-dependent, type 2, diabetes mellitus (T2D), glucose metabolism is compromised, and the heart loses its metabolic flexibility. The Zucker Diabetic Fatty rat (ZDF) model, which replicates the pathophysiology of T2D in patients, shows that as T2D progresses so does heart failure. Heart ketone metabolism seems to play a role in mitigating the heart failure process. This study assesses ketone metabolism in a ZDF heart failure model using cardiac PET imaging.
METHODS: Six lean ZDF rats (CTRL) and six diabetic obese ZDF rats (T2D) were evaluated for coronary flow reserve (CFR) using [13N]ammonia ([13N]NH3) cardiac PET. In addition, rats were evaluated with [11C]acetoacetate ([11C]AcAc) PET during rest and stress conditions to assess ketone metabolism, both at baseline and under an acute exogenous ketone ester oral supplementation. Blood chemistry, cardiac function and hemodynamic parameters were also evaluated under these conditions.
RESULTS: CFR was impaired in the T2D model (CTRL: 1.8 ± 0.5; T2D: 1.4 ± 0.2, p < 0.05) suggesting the development of heart failure in the T2D model. Blood ketones increased more than 2-fold after supplementation. The [11C]AcAc heart ketone uptake values with and without ketone supplementation were similar for the CTRL group, and these values were higher than for T2D rats. For the T2D group, the uptake decreased by 20% at rest under ketone supplementation vs. no supplementation (p < 0.05) and remained unchanged under stress with and without supplementation. Because of this decrease at rest, the stress/rest ratio after supplementation increases to the level observed in CTRL. [11C]AcAc heart ketone metabolism showed a slight decrease under stress for the CTRL group, but not for the T2D. Under ketone supplementation, the metabolism stress/rest ratio increased only in T2D (1.25 ± 0.29, p = 0.03 compared to baseline).
CONCLUSION: In a rat model of T2D and CFR impairment, we were able to measure changes in ketone metabolism using [11C]AcAc PET at rest and under stress with and without acute ketone supplementation. Our findings suggest that the heart ketone metabolism of T2D rats is impaired during the heart failure process. Ketone supplementation may have the potential to restore this cardiac reserve.

Keywords:  Acetoacetate; Beta-hydroxybutyrate; Heart failure; Ketone bodies; Myocardial blood flow; Positron emission tomography; Type II diabetes

DOI:  https://doi.org/10.1186/s13550-025-01215-9
Curr Pain Headache Rep. 2025 Mar 21. 29(1): 67

Fasting and Headache.

Patrick T Ebbert, Lauren R Natbony.

   PURPOSE OF REVIEW: This review synthesizes the latest updates in the literature on the connection between fasting and migraine, examining both clinical outcomes and underlying pathophysiological mechanisms.
RECENT FINDINGS: Although no studies have specifically explored fasting as a therapeutic intervention for migraine, various retrospective analyses suggest that fasting might worsen migraine symptoms in the short term. On the other hand, recent investigations, including several randomized controlled trials, have shown that ketogenic diets significantly reduce the number of migraine days and decrease inflammation markers. Additional research has shown improvements in disability assessments, as indicated by VAS, MIDAS, and HIT-6 scores. These benefits are not replicated by merely administering ketone bodies. Furthermore, genetic studies have found a link between glycemic processing and the occurrence of migraine. There is accumulating evidence that ketogenesis can reduce both the frequency and disability associated with migraine, likely through the reduction of systemic inflammatory markers and diminished cortical excitability. However, the potential benefits of intermittent fasting on migraine prevention remain underexplored and warrant further investigation.

Keywords:  Fasting headache; Fasting-induced migraine; Intermittent fasting and headache; Ketogenic diet for headache; Migraine diet; Nutritional approaches to migraine

DOI:  https://doi.org/10.1007/s11916-024-01326-3
Nat Metab. 2025 Mar 14.

The cyclic metabolic switching theory of intermittent fasting.

Mark P Mattson.

Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices.

DOI: https://doi.org/10.1038/s42255-025-01254-5
Eur J Nutr. 2025 Mar 20. 64(3): 133

Isolating the acute metabolic effects of carbohydrate restriction on postprandial metabolism with or without energy restriction: a crossover study.

Hayriye Biyikoglu, M Denise Robertson, Adam L Collins.

  Low-carbohydrate diets and intermittent energy restriction may offer metabolic advantages in fuel utilisation, that are independent of weight loss. The underlying mechanisms for these effects are unclear but may involve extensions of the catabolic phase and/or attenuation of insulin secretion. To address this gap, we aimed to investigate the independent acute metabolic effect of carbohydrate restriction at varying energy levels. Twelve, (six female) healthy overweight/obese participants (27.3 ± 1.8 years; 25.2 ± 1.6 kg/m2) completed this three-way study. Volunteers followed three diets for one day (36 h, covering the intervention day and overnight fasting), separated by 5-day washout: a normal carbohydrate, energy-balanced diet (nEB, 55% CHO), a low-carbohydrate, energy-balanced diet (LCEB, 50 g/day CHO), and a low-carbohydrate, energy-restricted diet (LC25, 50 g/day CHO with 75% energy restriction). Fasting and serial postprandial (360 min) measurements to a mixed test meal were collected the following morning. Additionally, subjective appetite responses and two-day subsequent ad libitum food intake was assessed. Both low-carbohydrate with and without energy restriction diets induced comparable decrease in triacylglycerol iAUC (p = 0.02, p = 0.04, respectively), and respiratory quotient (both p < 0.01) along with increase in non-esterified fatty acids (both p < 0.01) and 3-hydroxybutyrate (p = 0.001, p = 0.01, respectively) levels. Compared to a non-restricted carbohydrate, energy-balanced diet, postprandial glucose levels significantly increased in the LCEB arm (p = 0.024) and showed a rising trend in the LC25 arm (p = 0.07). Neither insulin responses nor resting, and diet-induced thermogenesis were significantly altered by variations in energy or carbohydrate content. These findings demonstrate that carbohydrate restriction, without altering energy intake, can elicit effects similar to those observed in short-term fasting. As such we propose a strategy of repeated carbohydrate restriction cycles alone may be an emerging alternative approach for the enhancement of cardiometabolic health, warranting further investigation.

Keywords:  Cross-over; Intermittent energy restriction; Low-carbohydrate; Postprandial

DOI:  https://doi.org/10.1007/s00394-025-03646-5
NPJ Metab Health Dis. 2024 ;pii: 29. [Epub ahead of print]2

Ketone body metabolism and cardiometabolic implications for cognitive health.

Kyle Fulghum, Sebastian F Salathe, Xin Davis, John P Thyfault, Patrycja Puchalska, Peter A Crawford.

Cardiometabolic complications of obesity present a growing public health concern and are associated with poor outcomes, mediated in part by an increased risk for cardiovascular disease, metabolic dysfunction-associated fatty liver disease, and systemic insulin resistance. Recent studies support that both insulin resistance and obesity are also associated with aberrant brain metabolism and cognitive impairment similar to what is observed in neurodegenerative diseases. Central to these pathological outcomes are adverse changes in tissue glucose and ketone body metabolism, suggesting that regulation of substrate utilization could be a mechanistic link between the cardiometabolic outcomes of obesity and the progression of cognitive decline. Here, we review ketone body metabolism in physiological and pathological conditions with an emphasis on the therapeutic potential of ketone bodies in treating cardiometabolic diseases and neurodegenerative diseases that lead to cognitive decline. We highlight recent findings in the associations among cardiometabolic disease, ketone body metabolism, and cognitive health while providing a theoretical framework by which ketone bodies may promote positive health outcomes and preserve cognitive function.

DOI: https://doi.org/10.1038/s44324-024-00029-y
Cureus. 2025 Feb;17(2): e79166

A Systematic Review of the Effects of Low-Carbohydrate Diet on Athletic Physical Performance Parameters.

Zeeshaan H Sultan, Diana Speelman.

  A low-carbohydrate diet (LCD) or ketogenic diet is commonly used by individuals who want to achieve ketosis, which can boost fat metabolism, increase insulin sensitivity, and reduce blood sugar spikes. However, many athletes are hesitant to utilize a diet that specifically restricts the intake of carbohydrates, an important source of energy for physical activity. Athletes usually adopt a high-carbohydrate or high-protein diet, depending on their goals. This review aims to examine the evidence for the impact of an LCD on athletes' aerobic, anaerobic, and upper and lower body strength performance. A systematic review of original studies was conducted for articles indexed in PubMed that utilized an LCD in athletes and reported athletic performance values. A total of 19 studies were included in the final synthesis. An LCD may aid in maintaining or increasing upper and lower body strength. However, this type of diet provides no consistent benefit and may even negatively impact some measures of aerobic and anaerobic performance. Taken together, no strong evidence indicates the benefit of an LCD on athletic performance. Athletes wishing to modify their diet for improved performance should consider possible diets with specific training and performance goals in mind.

Keywords:  aerobic performance; athletic performance; ketogenic diet; low-carbohydrate high-fat diet; lower body strength; strength

DOI:  https://doi.org/10.7759/cureus.79166
Am J Physiol Cell Physiol. 2025 Mar 19.

Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.

Joachim Nielsen, Kristine Grøsfjeld Petersen, Martin Eisemann de Almeida, Sam O Shepherd, Britt Christensen, Maria Houborg Petersen, Kurt Højlund, Niels Ørtenblad, Kasper Degn Gejl.

  Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles' size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria total contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria (+30%) and LDs (+100%) in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater total LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (r=0.72) with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibers rich in mitochondria.

Keywords:  PLIN5; endurance performance; fat oxidation; lipid droplets; metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpcell.00123.2025
Eur J Prev Cardiol. 2025 Mar 21. pii: zwaf168. [Epub ahead of print]

Integrating Ketone Bodies in Multi-Marker Risk Prediction of Incident Heart Failure in the Multi-Ethnic Study of Atherosclerosis (MESA).

Parag Anilkumar Chevli, Senthil Selvaraj, Byron C Jaeger, Aziz Hammoud, Margery A Connelly, Christopher deFilippi, Joao A C Lima, Sadiya S Khan, David M Herrington, Michael D Shapiro, Muthiah Vaduganathan.

   AIMS: Circulating ketone bodies (KB) have emerged as a potential adjunctive biomarker for incident heart failure (HF) risk and might provide incremental information beyond established biomarkers. A multi-marker risk score may improve risk stratification of incident HF in the community. The authors aim to develop a risk score using N-terminal proB-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin (hs-cTnT) and a unique systemic biomarker of KB to predict HF among participants without cardiovascular disease.
METHODS: A multi-marker score was developed incorporating NT-proBNP ≥ 125 pg/mL, hs-cTnT ≥ 14 ng/L, and total KB ≥ 75th percentile (316 μmol/L), with 1 point allocated for each abnormal marker among Multi-Ethnic Study of Atherosclerosis (MESA) participants. Multivariable Cox model was used to assess the association between multi-marker risk score and the risk of incident HF.
RESULTS: Among 6,748 participants, there were 383 incident HF events over a median follow-up of 15.7 years. The three biomarkers exhibited poor correlation with one another (r<0.06 for all). The addition of KB to NT-proBNP and hs-cTnT to identify incident HF improved 5- and 10-year risk prediction (C-statistic 0.74 vs. 0.77, p=0.02 and 0.70 vs. 0.73, p=0.02 respectively). There was no evidence of miscalibration using the multi-marker score for predicting 5- and 10-year HF risk (p>0.05). A graded association was observed between the multi-marker score and risk of HF independent of established clinical factors.
CONCLUSIONS: The addition of plasma KB to a clinical risk score using biomarkers of cardiac injury and stress may further improve the prediction of incident HF.

Keywords:  Cardiovascular Disease; Heart Failure; Ketone Bodies; Risk Prediction

DOI:  https://doi.org/10.1093/eurjpc/zwaf168
Physiol Rep. 2025 Mar;13(6): e70208

A ketogenic-promoting beverage acutely elevates cardiac function and myocardial blood flow compared to placebo in adults: A cardiac MRI investigation.

Christopher D Crabtree, Yue Pan, Preethi Chandrasekaran, Yuwei Wang, Debbie Scandling, Teryn Bedell, Justen Stoner, Drew Decker, Madison Kackley, Bradley Robinson, Alex Buga, Yuchi Han, Jeff Volek, Orlando P Simonetti.

  Increasing evidence suggests cardiac function improves in healthy and failing hearts alongside circulating ketones (1-4 mM). This study characterized cardiac function and blood flow responses to a ketogenic beverage compared to a volume/calorie matched placebo with repeated imaging over 120 min. This was a two-group, placebo-controlled, acute cardiac imaging study. Adults without cardiac abnormalities underwent baseline cardiac MRI including quantitative myocardial perfusion to measure myocardial blood flow (MBF). Subjects consumed 50 g of a ketogenic-promoting beverage [bis-hexanoyl R-1-3-butanediol (BH-BD)] (BH-BD; n = 11) or a calorically/volume-matched lipid-based placebo (PL; n = 10) with cardiac MRI every 15-30 min. Following 120 min, subjects underwent a final scan including MBF measurement. R-BHB and glucose were measured at every timepoint. 120 min following BH-BD consumption, R-BHB reached 2.1 mM. Cardiac output (CO) was elevated compared to PL (p < 0.05) and increased +31% 120 min after BH-BD ingestion (p < 0.001). CO elevation was due to increased stroke volume (+11%; p = 0.02) and heart rate (+22%; p < 0.001). MBF increased 29% from baseline (p < 0.001). PL did not induce differences in cardiac parameters. 50 g BH-BD ingestion achieves exogenous ketosis and is associated with elevated MBF and CO providing evidence supporting their use as a therapeutic clinical agent.

Keywords:  cardiac MRI; cardiac function; ketones; metabolic imaging; myocardial perfusion

DOI:  https://doi.org/10.14814/phy2.70208
Vascul Pharmacol. 2025 Mar 15. pii: S1537-1891(25)00026-6. [Epub ahead of print] 107487

Macrophage and cardiomyocyte roles in cardioprotection: Exploiting the NLRP3 Inflammasome inhibitor INF150.

Magalì Giordano, Saveria Femminò, Federica Blua, Francesca Boccato, Chiara Rubeo, Beatrice Mantuano, Francesca Cioffi, Stefano Comità, Arianna Brovero, Rosa Ciullo, Massimo Bertinaria, Claudia Penna, Pasquale Pagliaro.

   BACKGROUND: Cardiovascular diseases remain the leading cause of disability and death in the Western world. Effective cardioprotection involves limiting ischemia/reperfusion injury (IRI), including cell death (pyroptosis) driven by the NLRP3 inflammasome. While various cardiac resident cellular populations contribute to cardioprotection, it remains unclear whether targeting resident macrophages is inherently cardioprotective. Given that INF150, an NLRP3 inhibitor, exhibits varying abilities to penetrate cardiomyocytes and macrophages, we sought to address this question.
METHODS: We studied the cardioprotective potential of INF150, the potent metabolite of the NLRP3 inhibitor INF195, in isolated hearts or cells. In isolated hearts, we measured infarct size, caspase-1 cleavage, and interleukins (IL) release, while in macrophages, H9c2 cells and differentiated H9c2, we analyzed cell viability, and pyroptosis markers, including IL-1β release and Gasdermin D cleavage, following hypoxia/reoxygenation (H/R).
RESULTS AND CONCLUSION: While INF150 effectively shielded macrophages from LPS/ATP challenges, it failed to penetrate H9c2 and differentiated H9c2, even at high concentrations (no changes in pyroptosis markers induced by H/R). In the isolated mice heart model, INF150 did not demonstrate cardioprotective effects: infarct size, IL-1β, cleaved caspase-1 levels did not change significantly across tested concentrations of INF150. These findings suggest that while INF150 shows promise in macrophage/phagocytic models, its inability to penetrate cardiomyocytes limits its effectiveness in the whole cardiac tissue. Our results underscore the importance of cardiomyocyte uptake for effective cardioprotection, highlighting the need for NLRP3 inhibitors capable of targeting these cells directly. Future research should focus on enhancing the delivery and cardiomyocyte uptake of NLRP3 inhibitors to achieve cardioprotection. Unlike its precursor, INF195, which penetrates H9c2 cells, INF150 does not appear to offer cardioprotection in the whole organ.

Keywords:  Cardiomyocytes; Cardioprotection; Cellular uptake; Ischemia/reperfusion injury (IRI); Macrophages; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.vph.2025.107487
Cell Biochem Biophys. 2025 Mar 18.

Targeting the NLRP3 by Natural Compounds: Therapeutic Strategies to Mitigate Doxorubicin-Induced Cardiotoxicity.

Dareuosh Shackebaei, Kheirollah Yari, Nader Rahimi, Sara Gorgani, Fatemeh Yarmohammadi.

  Doxorubicin (DOX), a widely utilized anthracycline chemotherapy agent, is known for its potent anticancer efficacy across various malignancies. However, its clinical use is considerably restricted due to the risk of dose-dependent cardiotoxicity, which can lead to long-term heart dysfunction. The underlying mechanism of DOX-induced cardiotoxicity has been associated with the formation of reactive oxygen species (ROS) and disrupting cellular signaling pathways. This is particularly relevant to the activation of the NLRP3 inflammasome, which triggers inflammation and pyroptosis in cardiac cells. In recent years, there has been growing interest in natural compounds that exhibit potential cardioprotective effects against the adverse cardiac effects of DOX. The present study showed that specific natural compounds, such as honokiol, resveratrol, cynaroside, and curcumin, can confer significant protection against DOX-induced cardiotoxicity through the modulation of NLRP3 inflammasome signaling pathways. In summary, incorporating natural compounds into treatment plans could be a practical approach to improve the safety profile of DOX, thereby protecting cardiac health through the regulation of the NLRP3 pathway.

Keywords:  Cardiomyopathy; Chemotherapy; Herbal medicine; Inflammasome; Pyroptosis

DOI:  https://doi.org/10.1007/s12013-025-01723-4
Mol Biol Rep. 2025 Mar 18. 52(1): 322

Skeletal muscle atrophy induced by aging and disuse atrophy are strongly associated with the upregulation of the endoplasmic stress protein CHOP in rats.

J Max Michel, Joshua S Godwin, Nathan R Kerr, Thomas E Childs, Frank W Booth, C Brooks Mobley, David C Hughes, Michael D Roberts.

   BACKGROUND: While canonical anabolic and proteolytic pathways have been well examined in the context of skeletal muscle proteostasis, the roles of endoplasmic reticulum stress (ERS) and the induced unfolded protein response (UPR) are underappreciated. Thus, we aimed to determine whether aging and/or disuse atrophy in rats altered skeletal muscle ERS/UPR markers.
METHODS AND RESULTS: Soleus (SOL) and plantaris (PLT) muscles of 3-month-old (mo), 6 mo, 12 mo, 18 mo, and 24 mo rats (9-10 per group, 48 in total) were analyzed for UPR proteins with further analysis performed on the protein CHOP. The gastrocnemius muscles of 4 mo rats that had undergone hindlimb immobilization (HLI, n = 12) or sham casting (CTL, n = 12) were analyzed for similar targets as well as more extensive CHOP-related targets. CHOP protein was greater in the PLT and SOL of 18 and 24 mo rats versus other age groups (P < 0.05). Moreover, negative correlations existed between CHOP expression and normalized PLT (R=-0.702, P < 0.001) and SOL (R=-0.658, P < 0.001) muscle weights in all rats analyzed at different ages. CHOP protein expression was also greater in the gastrocnemius of HLI versus CTL rats (P < 0.001), and a negative correlation existed between CHOP protein expression and normalized muscle weights in these rats (R=-0.814, P < 0.001). Nuclear CHOP protein levels (P < 0.010) and genes transcriptionally regulated by CHOP were also greater in HLI versus CTL rats (P < 0.001) implicating transcriptional activity of CHOP is elevated during disuse atrophy.
CONCLUSIONS: CHOP is operative during aging- and disuse-induced skeletal muscle atrophy in rodents, and more research is needed to determine if CHOP is a key mechanistic driver of these processes.

Keywords:  Aging; CHOP; Disuse; Endoplasmic reticulum stress; Unfolded protein response

DOI:  https://doi.org/10.1007/s11033-025-10415-4
J Appl Physiol (1985). 2025 Mar 18.

PoWeR elicits intracellular signaling, mitochondrial adaptations, and hypertrophy in multiple muscles consistent with endurance and resistance exercise training.

Christian J Elliehausen, Szczepan S Olszewski, Dennis M Minton, Audrey L Spiegelhoff, Carolyn G Shult, Wenyuan G Zhu, Troy A Hornberger, Adam R Konopka.

  Physical activity guidelines recommend both endurance and resistance exercise to improve and maintain overall health. Recently, progressive weighted wheel running (PoWeR), a voluntary, progressive, and high-volume exercise paradigm, was posited as a singular prototype of combined endurance and resistance exercise in mice as evident by enhanced capillarization and hypertrophy of select plantar flexor muscles. Despite growing interest in this model, it remains incompletely characterized if PoWeR resembles the acute and chronic responses to resistance and/or endurance exercise in humans. Therefore, the purpose of this study was to assess canonical signaling events, mitochondrial bioenergetics, and cellular adaptations across multiple extensor and flexor muscles of the fore- and hindlimbs that may be conducive for whole-body functional improvements as traditionally observed in humans. 8-weeks of PoWeR (~8km/day) improved glucose metabolism, exercise capacity, body composition, and bone mineral density as well as increased mass, myofiber CSA, and oxidative myofiber type distribution in the soleus, plantaris, and FDL. Using two ex-vivo high-resolution flourorespirometry protocols that model in vivo physiological conditions, PoWeR decreased mitochondrial ADP sensitivity which was accompanied by greater mitochondrial H2O2 emissions, respiration, conductance, and protein content in the vastus lateralis, gastrocnemius, and triceps in muscle-specific fashion. Three days of short-term PoWeR stimulated mTORC1 and AMPK signaling in soleus, plantaris and/or FDL in line with the hypertrophic and metabolic adaptations observed with long-term training. Collectively, these data support PoWeR as a suitable paradigm in mice to model the acute signaling and chronic adaptations associated with endurance and resistance exercise in humans.

Keywords:  Hypertrophy; mTOR; metabolism; mitochondria; reactive oxygen species

DOI:  https://doi.org/10.1152/japplphysiol.00872.2024
Geroscience. 2025 Mar 18.

Effect of acipimox on skeletal muscle biochemistry, structure and function in older people with probable sarcopenia: an experimental medicine study.

Claire McDonald, Craig Alderson, Matthew G Birkbeck, Silvia Del Din, Gráinne S Gorman, Kieren G Hollingsworth, Cameron Kirk, Clare Massarella, Lynn Rochester, Helen A L Tuppen, Charlotte Warren, Avan A Sayer, Miles D Witham.

   BACKGROUND: Skeletal muscle nicotinamide adenine dinucleotide (NAD) concentrations are low in people with sarcopenia. Increasing NAD concentrations may offer a novel therapy. This study tested if acipimox (a NAD precursor) improves skeletal muscle NAD concentration and function in people with probable sarcopenia. Participants aged 65 and over with low walk speed (< 0.8 m/s) and low muscle strength (by 2019 European Working Group criteria) were recruited to this before and after, proof-of-concept study. Participants received acipimox 250 mg orally (twice or thrice daily according to creatinine clearance) + aspirin 75 mg daily (to prevent facial flushing) for 4 weeks. Muscle biopsy of the vastus lateralis, 31P magnetic resonance spectroscopy and a 7-digital mobility assessment were performed before starting acipimox and after 3 weeks of treatment. The primary outcome was change in skeletal muscle NAD concentration. Secondary outcomes included change in phosphocreatine recovery rate and measures of physical performance. Eleven participants (8 women), mean age 78.9 years (SD 4.3), were recruited. Mean walk speed at baseline was 0.69 m/s (SD 0.07). All completed baseline and follow-up visits. Median medication adherence was 95% (range 91-104%). There was no statistically significant difference in the primary outcome of change in NAD concentrations in skeletal muscle between baseline and follow-up [median difference: - 0.003 umol/g (IQR - 0.058 to 0.210); P = 0.26] or secondary outcomes. Nineteen none-serious adverse events were reported. Although the study protocol was feasible and well tolerated, acipimox did not improve skeletal muscle NAD concentration, biochemical markers or physical function in people with probable sarcopenia.
CLINICALTRIALS: gov Identifier: ISRCTN (ISRCTN87404878).

Keywords:  Acipimox; Clinical trial; Nicotinamide adenine dinucleotide; Sarcopenia

DOI:  https://doi.org/10.1007/s11357-025-01606-9
bioRxiv. 2025 Mar 07. pii: 2024.12.11.627830. [Epub ahead of print]

NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.

Mateusz Szczerba, Akshaya Ganesh, Maria Luisa Gil-Marques, Volker Briken, Marcia B Goldberg.

The NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and non-canonical NLRP3 inflammasome activation after infection with gram-negative bacteria. Here, we generated a series of defined NLRP11 deletion mutants to further analyze the role of NLRP11 in NLRP3 inflammasome activation. Like the complete NLRP11 deletion mutant ( NLRP11 -/- ), the NLRP11 mutant lacking the NACHT and LRR domains ( NLRP11 ∆ N_LRR ) showed reduced activation of the canonical NLRP3 inflammasome, whereas a pyrin domain mutant ( NLRP11 ∆ PYD ) had no effect on NLRP3 activation. The NLRP11 -/- and NLRP11 ∆ N_LRR mutants but not the NLRP11 ∆ PYD mutant also displayed reduced activation of caspase-4 during infection with the intracytosolic, gram-negative pathogen Shigella flexneri . We found that the human adapted, acid-fast pathogen Mycobacterium tuberculosis and the opportunistic pathogen M. kansasii both activate the non-canonical NLRP11 inflammasome in a caspase-4/5-dependent pathway. In conclusion, we show that NLRP11 functions in the non-canonical caspase-4/5 inflammasome activation pathway and the canonical NRLP3 inflammasome pathway, and that NLRP11 is required for full recognition of mycobacteria by each of these pathways. Our work extends the spectrum of bacterial pathogen recognition by the non-canonical NLRP11-caspase4/5 pathway beyond gram-negative bacteria.

DOI: https://doi.org/10.1101/2024.12.11.627830
Nat Rev Cardiol. 2025 Mar 20.

Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.

Rishith Ravindran, Åsa B Gustafsson.

Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.

DOI: https://doi.org/10.1038/s41569-025-01142-1
Int J Clin Pharmacol Ther. 2025 Mar 21.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, as potential (off-label) anti-obesity agents and effects on cardiovascular risk: A systematic review and meta-analysis.

Hye Duck Choi, Hyeon Kyeong Kim.

OBJECTIVES: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are primarily used for the treatment of type 2 diabetes; however, they have also been reported to be effective in weight loss. We conducted a meta-analysis to consolidate evidence from randomized clinical trials assessing the effects of SGLT2 inhibitors, as potential anti-obesity agents, on cardiovascular risk in overweight and obese participants.
MATERIALS AND METHODS: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane Library for randomized controlled trials involving SGLT2 inhibitors that reported cardiovascular outcomes in overweight and obese individuals. Random-effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals (CI).
RESULTS: We extracted and analyzed the data from 7 studies, representing 17,810 participants treated with SGLT2 inhibitors and 14,876 participants treated with placebo. The risk of cardiovascular events, including cardiovascular death, myocardial infarction, ischemic stroke, and hospitalization for heart failure, significantly decreased by ~ 27.8% in participants treated with SGLT2 inhibitors, compared to the placebo group (relative risk = 0.722; 95% CI 0.639 - 0.821).
CONCLUSION: Significant improvements in cardiovascular outcomes can be expected when SGLT2 inhibitors are used to treat diabetes, chronic kidney disease, or heart failure in overweight and obese individuals.

DOI: https://doi.org/10.5414/CP204749
Acta Neuropathol Commun. 2025 Mar 15. 13(1): 61

Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.

Vladislav O Sviderskiy, Varshini Vasudevaraja, Luiz Gustavo Dubois, James Stafford, Elisa K Liu, Jonathan Serrano, Richard Possemato, Matija Snuderl.

  Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.

Keywords:  Adult glioma; Fatty acid oxidation; Glucose; H3 mutant; Metabolic profiling; Pediatric glioma

DOI:  https://doi.org/10.1186/s40478-025-01961-w
Eur J Appl Physiol. 2025 Mar 15.

Lactic acidosis: implications for human exercise performance.

Simeon P Cairns, Michael I Lindinger.

  During high-intensity exercise a lactic-acidosis occurs with raised myoplasmic and plasma concentrations of lactate- and protons ([lactate-], [H+] or pH). We critically evaluate whether this causes/contributes to fatigue during human exercise. Increases of [lactate-] per se (to 25 mM in plasma, 50 mM intracellularly) exert little detrimental effect on muscle performance while ingestion/infusion of lactate- can be ergogenic. An exercise-induced intracellular acidosis at the whole-muscle level (pHi falls from 7.1-7.0 to 6.9-6.3), incorporates small changes in slow-twitch fibres (pHi ~ 6.9) and large changes in fast-twitch fibres (pHi ~ 6.2). The relationship between peak force/power and acidosis during fatiguing contractions varies across exercise regimes implying that acidosis is not the sole cause of fatigue. Concomitant changes of other putative fatigue factors include phosphate metabolites, glycogen, ions and reactive oxygen species. Acidosis to pHi 6.7-6.6 at physiological temperatures (during recovery from exercise or induced in non-fatigued muscle), has minimal effect on force/power. Acidosis to pHi ~ 6.5-6.2 per se reduces maximum force (~12%), slows shortening velocity (~5%), and lowers peak power (~22%) in non-fatigued muscles/individuals. A pre-exercise induced-acidosis with ammonium chloride impairs exercise performance in humans and accelerates the decline of force/power (15-40% initial) in animal muscles stimulated repeatedly in situ. Raised [H+]i and diprotonated inorganic phosphate ([H2PO4-]i) act on myofilament proteins to reduce maximum cross-bridge activity, Ca2+-sensitivity, and myosin ATPase activity. Acidosis/[lactate-]o attenuates detrimental effects of large K+-disturbances on action potentials and force in non-fatigued muscle. We propose that depressive effects of acidosis and [H2PO4-]i on myofilament function dominate over the protective effects of acidosis/lactate- on action potentials during fatigue. Raised extracellular [H+]/[lactate-] do not usually cause central fatigue but do contribute to elevated perceived exertion and fatigue sensations by activating group III/IV muscle afferents. Modulation of H+/lactate- regulation (via extracellular H+-buffers, monocarboxylate transporters, carbonic anhydrase, carnosine) supports a role for intracellular acidosis in fatigue. In conclusion, current evidence advocates that severe acidosis in fast-twitch fibres can contribute to force/power fatigue during intense human exercise.

Keywords:  Acidosis; Exercise performance; Inorganic phosphate; Lactate; Potassium; Skeletal muscle fatigue

DOI:  https://doi.org/10.1007/s00421-025-05750-0
J Clin Endocrinol Metab. 2025 Mar 18. pii: dgaf174. [Epub ahead of print]

The Role and Regulation of Intramuscular Sex Hormones in Skeletal Muscle: A Systematic Review.

Viktor Engman, Annabel J Critchlow, Eija K Laakkonen, Mette Hansen, Shaun Mason, Séverine Lamon.

   INTRODUCTION: Serum concentrations of androgens and oestrogens, the main male and female sex hormones, respectively, naturally fluctuate across the lifespan. Sex hormones are mainly produced in the gonads, but evidence suggests that they can also be locally synthesised in skeletal muscle. However, little is known about the purpose of intramuscular sex hormones and their role in skeletal muscle. This systematic review aimed to investigate 1) how intramuscular sex hormone concentrations vary across the lifespan, 2) whether exercise affects intramuscular sex hormone concentrations, and 3) whether intramuscular sex hormones are associated with skeletal muscle mass and function.
METHODS: Four databases were searched, and studies were included if they contained measurements of intramuscular sex hormones from healthy males and females free from any hormonal treatment or from rodents.
RESULTS: Thirteen studies were included. Intramuscular testosterone was reduced in older males compared to their younger counterparts, but comparison of intramuscular sex hormone concentrations between pre- and post-menopausal females yielded inconclusive findings. Chronic exercise decreased androgens and oestradiol in females, but increased androgens in males. Acute exercise did not change intramuscular hormone concentrations in humans but increased them in rodents. Intramuscular androgens were positively associated with muscle mass and strength in males. In females, conflicting findings were reported for both oestradiol and androgens, and measures of muscle mass and function.
CONCLUSION: Current evidence suggests that ageing and exercise differentially modulate intramuscular sex hormone concentrations, and their association with muscle mass and function, between males and females, and model systems.

Keywords:  Oestrogen; Sex hormones; Skeletal muscle; Testosterone

DOI:  https://doi.org/10.1210/clinem/dgaf174
Diabetes Res Clin Pract. 2025 Mar 14. pii: S0168-8227(25)00093-2. [Epub ahead of print]222 112079

The efficacy of resistance exercise training on metabolic health, body composition, and muscle strength in older adults with type 2 diabetes: A systematic review and Meta-Analysis.

Mingxing Feng, Luyan Gu, Yan Zeng, Wenjing Gao, Chongyu Cai, Yingqiu Chen, Xiuying Guo.

  This systematic review and meta-analysis evaluated the efficacy of Resistance Exercise Training (RET) on metabolic health, body composition, and muscle strength in older adults with type 2 diabetes (T2DM). Electronic databases were systematically searched and meta-analyses were conducted using random-effects models. Meta-regression analyses were also performed to explore potential sources of heterogeneity. Nineteen randomized controlled trials (RCTs) met the inclusion criteria. RET significantly improved hemoglobin A1c (MD: -0.51, P < 0.0001) and fasting blood glucose (mean differences: MD: -1.43 mg/dl, P = 0.04), though insulin levels remained unchanged. Lipid profile analysis revealed significant reductions in triglycerides (MD: -0.32, P = 0.03), total cholesterol (MD: -7.08, P = 0.005), and low-density lipoprotein (MD: -1.91, P = 0.05), without significant changes in high-density lipoprotein. RET increased lean mass and reduced waist circumference but had no effect on body weight and fat mass. Muscle strength improved significantly, but there was no impact on blood pressure or heart rate. These findings suggest that RET is beneficial for enhancing glycemic control, lipid profiles, lean mass, and muscle strength in older adults with T2DM, while its effects on body weight, fat mass, and cardiovascular health remain inconclusive. Further studies are needed to explore long-term effects.

Keywords:  Elderly; Glycemic control; Insulin sensitivity; Resistance training; Systematic review

DOI:  https://doi.org/10.1016/j.diabres.2025.112079
Med Sci Sports Exerc. 2025 Mar 18.

BEETter AGING: Short-Term Dietary Nitrate Supplementation Enhances Muscle Contractile Properties in Older But Not in Young Adults.

Letizia Rasica, Marta Colosio, Alessandra Ferri, Giovanni Baldassarre, Chris Easton, Mia Burleigh, Gianluca Vernillo, Roberto Bottinelli, Mauro Marzorati, Simone Porcelli.

PURPOSE: Dietary nitrate (NO3-) supplementation has been shown to improve skeletal muscle contractile function and reduce fatigue, potentially due to alterations in skeletal muscle Ca2+ handling/sensitivity. Since aging muscle can have impaired Ca2+ handling, the aim of the study was to evaluate the effects of dietary NO3- supplementation on muscle contractile properties in young and older adults.
METHODS: Eleven older (69 ± 4 yrs, O) and 11 young (26 ± 2 yrs, YG) adults consumed either NO3--rich beetroot juice (BR) or placebo (PLA), for 7 days. After supplementations, plantar flexors of dominant leg were evaluated as follow: a) maximal voluntary isometric contraction (MVIC); b) potentiated single twitches (Twpot) and double twitches electrical stimulations at the frequency of 100 Hz (Db100) on the tibial posterior nerve; c) a fatigue isometric (70% of MVIC) test until exhaustion. The force-frequency relationship was assessed with trains of electrical pulses across a wide range of frequencies on the muscle belly of the non-dominant leg.
RESULTS: BR supplementation increased plasma [NO3-] and nitrite [NO2-] in both O and YG compared to PLA (more than 7-fold; all P ≤ 0.02). No changes were observed in MVC, Twpot, and Db100 force after BR compared to PLA in both YG and O. Only in O, Db100 area under the curve (-7 ± 6 N·s change from PLA) and half relaxation time (-0.05 ± 0.06 s change from PLA) were significantly reduced. and time to exhaustion (+32 ± 43 s change from PLA) was significantly longer (all P < 0.02) after BR. In O, BR also significantly increased submaximal force produced by trains of electrical pulses (P < 0.001).
CONCLUSIONS: NO3- supplementation positively affects muscle contractile proprieties, submaximal electrically evoked force production and fatigue resistance in older adults while these positive results were not found in young.

DOI: https://doi.org/10.1249/MSS.0000000000003708
Science. 2025 Mar 21. 387(6740): 1256-1257

A deep dive into oxygen sensing.

Lucy Hawkes, Jessica Kendall-Bar.

Seals directly detect blood oxygen to adjust time underwater.

DOI: https://doi.org/10.1126/science.adw1936
JACC Heart Fail. 2025 Mar 11. pii: S2213-1779(25)00075-7. [Epub ahead of print]

Exercise Training for Patients With Heart Failure: The Details Matter.

Gordon R Reeves, Dalane W Kitzman.



Keywords:  cardiac rehabilitation; exercise training; frailty; heart failure; physical rehabilitation

DOI:  https://doi.org/10.1016/j.jchf.2024.11.019
Cell Rep. 2025 Mar 13. pii: S2211-1247(25)00201-3. [Epub ahead of print]44(3): 115430

Mitochondrial reactive oxygen species regulate acetyl-CoA flux between cytokine production and fatty acid synthesis in effector T cells.

Beibei Wu, Jin Seok Woo, Spyridon Hasiakos, Calvin Pan, Shawn Cokus, Cristiane Benincá, Linsey Stiles, Zuoming Sun, Matteo Pellegrini, Orian S Shirihai, Aldon J Lusis, Sonal Srikanth, Yousang Gwack.

  Genetic and environmental factors shape an individual's susceptibility to autoimmunity. To identify genetic variations regulating effector T cell functions, we used a forward genetics screen of inbred mouse strains and uncovered genomic loci linked to cytokine expression. Among the candidate genes, we characterized a mitochondrial inner membrane protein, TMEM11, as an important determinant of Th1 responses. Loss of TMEM11 selectively impairs Th1 cell functions, reducing autoimmune symptoms in mice. Mechanistically, Tmem11-/- Th1 cells exhibit altered cristae architecture, impaired respiration, and increased mitochondrial reactive oxygen species (mtROS) production. Elevated mtROS hindered histone acetylation while promoting neutral lipid accumulation. Further experiments using genetic, biochemical, and pharmacological tools revealed that mtROS regulate acetyl-CoA flux between histone acetylation and fatty acid synthesis. Our findings highlight the role of mitochondrial cristae integrity in directing metabolic pathways that influence chromatin modifications and lipid biosynthesis in Th1 cells, providing new insights into immune cell metabolism.

Keywords:  CP: Immunology; CP: Metabolism; EAE; MICOS complex; Th1 cells; cytokine production; histone acetylation; mitochondria; mitochondrial cristae architecture; neutral lipids; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2025.115430
J Proteome Res. 2025 Mar 18.

3-Hydroxybutyrate Promotes Myoblast Proliferation and Differentiation through Energy Metabolism and GPR109a-Mediated Ca2+-NFAT Signaling Pathways.

Xu Qiu, Wenfang Wu, Shuya Zhang, Caihua Huang, Donghai Lin.

  Skeletal muscle wasting is a critical clinical problem associated with several diseases that significantly impair patient outcomes due to the progressive loss of muscle mass and function. This study explores the potential of 3-hydroxybutyrate (3-HB) as a therapeutic agent to counteract muscle atrophy by promoting the proliferation and differentiation of C2C12 myoblasts. Using nuclear magnetic resonance (NMR)-based metabolomics analysis, we uncover the underlying mechanisms by which 3-HB exerts its effects. Our findings demonstrate that 3-HB exerts its effects through two distinct mechanisms: as a metabolic substrate and as a signaling molecule. As a metabolic substrate, 3-HB enhances myoblast energy efficiency by stimulating the expression of G protein-coupled receptor 109a (GPR109a), which subsequently upregulates the 3-HB transporters MCT1 and CD147, the utilization enzyme OXCT1, and phosphorylated AMPK, thereby increasing ATP production. As a signaling molecule, 3-HB activates GPR109a, promoting calcium influx, improving calcium homeostasis, and increasing the expression of Ca2+-related proteins such as CAMKK2. This signaling cascade activates calcineurin (CaN), facilitating NFAT translocation to the nucleus and gene expression that drives myoblast proliferation and differentiation. By elucidating the dual regulatory roles of 3-HB in energy metabolism and cellular signaling, this study not only advances our understanding of muscle physiology but also highlights the potential of 3-HB as a novel therapeutic approach for the prevention or treatment of skeletal muscle atrophy.

Keywords:  GPR109a receptor; cellular signaling; metabolic fuel; metabolomic profiling; myoblast proliferation

DOI:  https://doi.org/10.1021/acs.jproteome.4c01150
J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):

Mitochondrial fission - changing perspectives for future progress.

Sukrut C Kamerkar, Ao Liu, Henry N Higgs.

  Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.

Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission

DOI:  https://doi.org/10.1242/jcs.263640
Mol Neurobiol. 2025 Mar 17.

Nutritional Interventions in Amyotrophic Lateral Sclerosis: From Ketogenic Diet and Neuroprotective Nutrients to the Microbiota-Gut-Brain Axis Regulation.

Samira Nabakhteh, Anahita Lotfi, Arman Afsartaha, Elaheh Sadat Khodadadi, Siavash Abdolghaderi, Mozhdeh Mohammadpour, Yasaman Shokri, Pouria Kiani, Sajad Ehtiati, Sara Khakshournia, Seyyed Hossein Khatami.

  Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with significant challenges in diagnosis and treatment. Recent research has highlighted the complex nature of ALS, encompassing behavioral impairments in addition to its neurological manifestations. While several medications have been approved to slow disease progression, ongoing research is focused on identifying new therapeutic targets. The current review focuses on emerging therapeutic strategies and personalized approaches aimed at improving patient outcomes. Recent advancements highlight the importance of targeting additional pathways such as mitochondrial dysfunction and neuroinflammation to develop more effective treatments. Personalized medicine, including genetic testing and biomarkers, is proving valuable in stratifying patients and tailoring treatment options. Complementary therapies, such as nutritional interventions like the ketogenic diet and microbiome modulation, also show promise. This review emphasizes the need for a multidisciplinary approach that integrates early diagnosis, targeted treatments, and supportive care to address the multisystemic nature of ALS and improve the quality of life for patients.

Keywords:  Amyotrophic lateral sclerosis; Gut-brain axis; Ketogenic diet; Microbiome; Neuroprotection; Nutrition

DOI:  https://doi.org/10.1007/s12035-025-04830-8
Aging (Albany NY). 2025 Mar 12. 17

DNA methylation entropy is a biomarker for aging.

Jonathan Chan, Liudmilla Rubbi, Matteo Pellegrini.

  The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual's age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon's entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.

Keywords:  DNA methylation; aging; entropy; epigenetic clocks; epigenetics

DOI:  https://doi.org/10.18632/aging.206220
Curr Nutr Rep. 2025 Mar 19. 14(1): 48

Nutritional Approach to Diabetic Sarcopenia: A Comprehensive Review.

Gül Eda Kılınç, Yeliz Vergi.

   PURPOSE OF THE REVIEW: The aim of this review is to discuss and evaluate diabetic sarcopenia (DS) and its relationship with nutrition by discussing the mechanisms of diabetic sarcopenia in detail and comprehensively reviewing the literature.
RECENT FINDINGS: Type 2 diabetes (T2DM) affects approximately 25% of people aged 50 years and over and indicates a significant the cost of health for the elderly. Nutrition is an important part of these treatment approaches, and in this review, the literature was comprehensively reviewed, focusing on understanding the mechanisms of DS and discussing its relationship with nutrition. A comprehensive search was conducted on Web of Science, Google Scholar, Scopus, Science Direct, and PubMed from inception up to July 2024. The aim of nutritional treatment for DS is to improve muscle mass, muscle strength and physical performance while improving diabetes-related metabolic risk and glucose levels. In this context, it is important to determine energy intake in individuals with DS according to calorie intake exceeding 30 kcal/kg. For these individuals, a protein intake of at least 1-1.2 g/kg/day is recommended, with an emphasis on the number and timing of meals and a nutritional pattern rich in branched chain amino acids (BCAA). In addition, it is important to adopt a diet rich in antioxidants and to choose diet patterns that contain sufficient levels of macro and micronutrients. The Mediterranean diet model can be a good diet option for individuals with DS. Comprehensive studies in this field are needed so that clinicians can make specific dietary recommendations for DS.

Keywords:  Diabetes mellitus; Elderly; Nutrition; Sarcopenia

DOI:  https://doi.org/10.1007/s13668-025-00637-0