bims-kimdis 2025-02-23 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–02–23
thirty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.
Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.
Impact of Ketogenic Diet on Weight, Metabolic, and Endocrine Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.
β-Hydroxybutyrate mitigates the detrimental effects of high glucose in human retinal pigment epithelial ARPE-19 cells.
Determination of Urine Netrin-1 and Beta-Hydroxy Butyrate Levels in Diabetic Ketoacidosis Cases: a Preliminary Report.
β-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting PHD2.
Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate.
High intensity interval training alters gene expression linked to mitochondrial biogenesis and dynamics in high fat diet fed rats.
Breath Acetone Correlates with Capillary β-hydroxybutyrate in Type 1 Diabetes.
Mitochondrial efficiency in resting skeletal muscle in vivo: a novel non-invasive approach using multinuclear magnetic resonance spectroscopy in humans.
A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
Effectiveness of Protein-enriched oral nutritional supplements on muscle function in middle-aged and elderly women: A randomized controlled trial.
Overfeeding induces adipose tissue release of distinct mitochondria.
The flux of energy in critical illness and the obesity paradox.
Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.
Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.
Cognitive and sensorimotor benefits of moderate- and high-intensity exercise are associated with specific expression of neurotrophic markers in older rats.
Targeting Mitochondrial Integrity as a New Senolytic Strategy.
Acute effect of endurance exercise on human milk insulin concentrations: a randomised cross-over study.
Exercise intensity matters: A review on evaluating the effects of aerobic exercise intensity on muscle-derived neuroprotective myokines.
Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
Bayesian classification of OXPHOS deficient skeletal myofibres.
Defining obesity to improve ageing.
Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.
NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury.
Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.
Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
Adenosine metabolism and receptors in aging of the skin, musculoskeletal, immune and cardiovascular systems.
High-Resolution Untargeted Metabolomics Reveals Alternate-Day Fasting May Attenuate Diabetic Kidney Disease Progression in BTBR ob/ob Mice by Affecting the HCA, IPA and Reducing Inflammation.
Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.

Res Sq. 2025 Jan 29. pii: rs.3.rs-5814971. [Epub ahead of print]

A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.

Sarah Lessard, Pattarawan Pattamaprapanont, Roberto Nava, Mia Formato, Eileen Cooney, Ana Pinto, Ana Alves-Wagner, Anamica Das, Yuntian Guan.

VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we tested whether reducing blood glucose with a low-carbohydrate/high-fat "ketogenic" diet could restore aerobic exercise adaptation in a mouse model of hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) and mice were stratified to standard chow (STZ-CHOW), or a ketogenic diet (STZ-KETO), which rapidly normalized blood glucose. After aerobic exercise training, improvements in VO2peak were blunted in STZ-CHOW, but exercise response was restored in STZ-KETO. Improved VO2peak in STZ-KETO was associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density, along with restoration of circulating angiogenic markers. Moreover, KETO induced exercise-independent effects on muscle mitochondrial remodeling and mitochondrial dynamics, significantly increasing fatty acid oxidation. Our results identify a ketogenic diet as a potential therapy to improve aerobic exercise response in the growing population with hyperglycemia due to diabetes and other metabolic conditions.

DOI: https://doi.org/10.21203/rs.3.rs-5814971/v1
Sci Rep. 2025 Feb 18. 15(1): 5849

Myocardial metabolic flexibility following ketone infusion demonstrated by hyperpolarized [2-13C]pyruvate MRS in pigs.

Sabrina Kahina Bech, Esben Søvsø Szocska Hansen, Bent Roni Nielsen, Henrik Wiggers, Mads Bisgaard Bengtsen, Christoffer Laustsen, Jack J Miller.

This study aims to investigate the effects of β-3-hydroxybutyrate (β-3-OHB) infusion on myocardial metabolic flexibility using hyperpolarized [2-13C]pyruvate magnetic resonance spectroscopy (MRS) in the pig heart. We hypothesized that β-3-OHB infusion will cause rapid, quantifiable alterations in tricarboxylic acid (TCA) cycle flux as measured non-invasively by 13C MRS and reflect myocardial work. Five female Danish landrace pigs underwent β-3-OHB infusion during a hyperinsulinemic euglycemic clamp (HEC). Cardiac metabolism and hemodynamics were monitored using hyperpolarized [2-13C]pyruvate MRS and cardiac MRI. β-3-OHB infusion during HEC resulted in significant increases in cardiac output over baseline (from 1.9 to 3.8 L/min, p = 0.0011) and heart rate (from 51 to 85 bpm, p = 0.0004). Metabolic analysis showed a shift towards increased lactate production and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion. Following the termination of the infusion, a normalization of these metabolic markers was observed. These results demonstrate the profound metabolic adaptability of the myocardium to ketone body utilization. The infusion of Na-β-3-OHB significantly alters both the hemodynamics and metabolism of the porcine heart. The observed increase in cardiac output and metabolic shifts towards lactate production suggest that ketone bodies could potentially enhance cardiac function by providing an efficient-energy substrate that, if provided, is preferentially used. This study provides new insights into the metabolic flexibility of the heart and hints at the potential therapeutic benefits of ketone interventions in heart failure treatment.

DOI: https://doi.org/10.1038/s41598-025-90215-9
Gynecol Obstet Invest. 2025 Feb 20. 1-22

Impact of Ketogenic Diet on Weight, Metabolic, and Endocrine Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Camilla Turetta, Andrea Giannini, Maria Grazia Tarsitano, Daniele Gianfrilli, Antonio Paoli, Evangelos Kontopantelis, Emanuele De Angelis, Marianna Minnetti, Eleonora Poggiogalle, Andrea Colizza, Marco De Vincentiis, Antonio Simone Laganà, Giorgio Bogani, Innocenza Palaia, Ludovico Muzii, Violante Di Donato.

Introduction Polycystic ovary syndrome (PCOS) is a widespread disease among women of childbearing age. This pathology embraces a complex spectrum of clinical manifestations. An altered secretion of gonadotropins and high levels of androgens determine menstrual irregularities and ovulatory dysfunction, infertility, hirsutism, alopecia and acne. Moreover, hyperinsulinemia and insulin-resistance (IR) are common, leading to an increased metabolic risk. Whilst various pharmacological strategies have been studied to manage PCOS, the role of lifestyle should be emphasized. Numerous studies highlight the fundamental role that diet plays in the regulation of these hormonal imbalances. The hypothesis that a low-carbohydrate diet, such as the ketogenic diet (KD), may be beneficial in patients with PCOS has been evaluated in some clinical studies. The aim of the present systematic review and meta-analysis has been to evaluate through anthropometric, metabolic, and hormonal parameters the impact of KD in overweight or obese patients with PCOS. Methods A research question according to the PICOS framework was formulated, and a literature search following the PRISMA criteria for systematic review was performed. Studies that reported the following outcomes were included: weight loss, body mass index (BMI), circulating levels of glucose, insulin, Homeostasis Model Assessment - Insulin Resistance (HOMA-IR), LDL- cholesterol, HDL- cholesterol, triglycerides, luteinizing hormone (LH), follicle stimulating hormone (FSH), LH/FSH, estrogens, progesterone, anti-müllerian hormone (AMH), total-testosterone (total-T), free-testosterone (free-T), sex-hormone-binding-globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), pregnancies and live births. The extracted data were analyzed, and pooled results were expressed as standardized mean difference (SMD) with 95% Confidence Interval (CI). Results Seven studies were included in the systematic review. The results of the meta-analysis showed that after KD the patients had a significant weight loss (standard mean difference or SMD 1.31 Kg [95% CI 0.45, 2.17] p=0.003) and lower BMI (SMD 1.27 kg/m2 [95% CI 0.71, 1.83], p<0.001). Blood glucose (SMD 1.36 mg/dL [95% CI 1.08, 1.64], p<0.001), insulin (SMD 1.15 µU/mL 95% CI [0.60, 1.70], p<0.001) and HOMA-IR (SMD 1.84 [95% CI 0.72, 2.96], p=0.001) were all decreased, and lipid profile was improved with higher HDL (SMD 0.38 mg/dL [95% IC 1.45, 0.68], p=0.48, not significant), lower LDL (SMD 0.73 mg/dL [95% CI 0.03, 1.42], p=0.04) and lower triglycerides (SMD 1.11 mg/dL [95% CI 0.53, 1.68], p<0.001). Moreover, LH concentrations were significantly reduced (SMD 1.12 ng/dL [0.39, 1.84] p=0.003), FSH levels raised (SMD -0.76 ng/dL [-1.25, -0.28], p=0.002), the LH/FSH ratio decreased (SMD 2.04 (95% CI 1.04-3.03, p<0.001); testosterone decreased (free-T SMD 0.57 ng/dL [95% CI 0.28, 0.86], p<0.001; total-T SMD 0.54 ng/dL, 95% CI 0.28, 0.80, p<0.001), and SHBG levels were significantly increased (SMD 0.79, 95% CI [1.24-0.34],p<0.001). Data about estrogens, progesterone, DHEAS and pregnancies were too scarce to allow a comparison in the meta-analysis. Conclusion The ketogenic diet seems to offer a substantial benefit in improving all the anthropometric, metabolic and hormonal parameters evaluated. Studies on larger populations of PCOS patients may offer greater understanding of the benefits of low-glycemic diets in this category of patients.

DOI: https://doi.org/10.1159/000543941
Hum Cell. 2025 Feb 20. 38(2): 59

β-Hydroxybutyrate mitigates the detrimental effects of high glucose in human retinal pigment epithelial ARPE-19 cells.

Francesca Argentino, Marta Mallardo, Ciro Costagliola, Aurora Daniele, Ersilia Nigro.

  High glucose leads to cellular damage and dysfunction in the retina. Dietary interventions, including the use of ketogenic diets, have been explored for their potential to reduce the adverse effects of hyperglycemia. β-Hydroxybutyrate (BHB), a ketone body, has immune and anti-inflammatory properties. This study aims to investigate whether BHB ameliorates the harmful effects induced by high glucose in ARPE-19 cells, a model of retinal pigment epithelium. We investigated the effects induced by high glucose and/or BHB on viability, migration, colony-forming ability, cell cycle progression and cytokine production. Our data indicate that high glucose significantly reduces the viability of ARPE-19 cells with no significant changes in apoptosis or autophagy, while inducing cell cytostasis. On the other hand, BHB exerts a protective effect on ARPE-19 cells under hyperglycemic conditions improving cell viability and alleviating glucose-induced cell cycle arrest. Additionally, BHB treatment affects the expression of IL-8 and IL-17α, as well as of MCP-1, modulating the inflammatory response, cell migration and wound healing. In conclusion, this study highlights the potential protective role of BHB against the detrimental effects induced by high glucose on ARPE-19 cells. These findings support the use of ketone bodies in mitigating high glucose-induced cellular damage. Future research will be critical to translate these findings to the clinical practice for metabolic diseases.

Keywords:  Human retinal pigment epithelial ARPE-19 cells; Hyperglycemia; Inflammation; β-Hydroxybutyrate

DOI:  https://doi.org/10.1007/s13577-025-01187-x
Clin Lab. 2025 Feb 01. 71(2):

Determination of Urine Netrin-1 and Beta-Hydroxy Butyrate Levels in Diabetic Ketoacidosis Cases: a Preliminary Report.

Yucel Yuzbasioglu, Cigdem Yucel, Ertan Comertpay, Meryem S Ertugrul, Mustafa G Unlu, Yavuz Katirci.

BACKGROUND: Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood glucose levels, leading to severe complications over time. Diabetic ketoacidosis (DKA) is a critical acute complication of DM marked by hyperglycemia and acidosis due to ketone body accumulation, often seen in younger patients. The pathophysiology involves insulin deficiency and the effects of counter-regulatory hormones, leading to increased gluconeogenesis and lipolysis. This study investigated the relationship between urine netrin-1 and β-hydroxybutyrate (β-OHB) levels in DKA patients.
METHODS: The study included 40 patients diagnosed with DKA and 40 healthy controls. Urine samples were collected, centrifuged, and stored at -80℃. Netrin-1 and β-OHB levels were measured using BTlab quantitative ELISA kits. Data were analyzed using SPSS, with tests for normality and appropriate statistical comparisons conducted.
RESULTS: No significant demographic differences were found between the patient and control groups. Urine ketone and glucose positivity were significantly higher in DKA patients. Blood glucose, urea, lactate, and metabolic acidosis markers were also elevated in DKA patients. No significant difference was found in urine β-OHB and netrin-1 concentrations between the groups. However, a moderate positive correlation between β-OHB and netrin-1 was observed, along with various significant correlations between these markers and other biochemical parameters.
CONCLUSIONS: This study highlights significant biochemical differences between DKA patients and healthy controls, emphasizing the importance of monitoring biochemical parameters for managing DKA. Although no significant differences in urine β-OHB and netrin-1 concentrations were found, their correlation suggests a potential role in DKA pathophysiology, warranting further research with larger sample sizes.

DOI: https://doi.org/10.7754/Clin.Lab.2024.240805
Circ Res. 2025 Feb 17.

β-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting PHD2.

Cheng Wang, Wenjing Xu, Shushu Jiang, Yichen Wu, Jiangchen Shu, Xinyuan Gao, Kai Huang.

   BACKGROUND: Acute myocardial infarction (MI) remains one of the major causes of death worldwide, and innovative treatment strategies for MI represent a major challenge in cardiovascular medicine. Caloric restriction (CR) is the most potent nonpharmacological intervention known to prevent age-related disorders and extend lifespan. CR reduces glycolysis and elevates ketone body metabolism. However, whether and how CR or ketone body prevents the progression of MI remains poorly defined.
METHODS: Mice treated with CR and β-hydroxybutyrate (β-OHB) underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiographic measurements. Histological analysis, fluorescence-activated cell sorting, and immunofluorescence were used to assess myocardial neovascularization and macrophage filtration. The interaction and modification of β-OHB on PHD2 were analyzed by molecular docking, cellular thermal shift assay, liquid chromatography with tandem mass spectrometry, and coimmunoprecipitation. Macrophage-specific PHD2 K239R and K385R knock-in mice were used to determine the functional significance of β-OHB/PHD2 axis in vivo.
RESULTS: Twelve weeks of CR markedly rescued postinfarction cardiac function by enhancing neovascularization. CR significantly increased circulating and cardiac ketone bodies, including β-OHB and acetoacetate. We identified β-OHB but not acetoacetate selectively targeted macrophages to stimulate VEGF (vascular endothelial growth factor) production in the peri-infarct area to promote neovascularization and cardiac repair. Mechanistically, β-OHB binds to and induces lysine β-hydroxybutyrylation of PHD2 at lysines 239 and 385, thus blocking its function in the hydroxylation of HIF-1α (hypoxia-inducible factor 1α) and resulting in enhanced HIF1α-dependent VEGF transcription and secretion. More importantly, specific PHD2 lys239 and lys385 mutations in macrophages abolished the preventive effects of exogenous β-OHB on MI in mice.
CONCLUSIONS: These data reveal a novel regulation of lysine β-hydroxybutyrylation on PHD2 and demonstrate a promising and therapeutic role for β-OHB/PHD2 in effectively accelerating neovascularization and preserving heart function after cardiac ischemia.

Keywords:  acetoacetates; caloric restriction; coronary vessels; longevity; macrophages

DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325179
Nat Commun. 2025 Feb 20. 16(1): 1792

Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate.

Mina Tsenkova, Madita Brauer, Vitaly Igorevich Pozdeev, Marat Kasakin, Susheel Bhanu Busi, Maryse Schmoetten, Dean Cheung, Marianne Meyers, Fabien Rodriguez, Anthoula Gaigneaux, Eric Koncina, Cedric Gilson, Lisa Schlicker, Diran Herebian, Martine Schmitz, Laura de Nies, Ertan Mayatepek, Serge Haan, Carine de Beaufort, Thorsten Cramer, Johannes Meiser, Carole L Linster, Paul Wilmes, Elisabeth Letellier.

Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrates tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.

DOI: https://doi.org/10.1038/s41467-025-56678-0
Sci Rep. 2025 Feb 14. 15(1): 5442

High intensity interval training alters gene expression linked to mitochondrial biogenesis and dynamics in high fat diet fed rats.

Mohammad Jahangiri, Shahnaz Shahrbanian, Reza Gharakhanlou.

  A High-Fat Diet (HFD) leads to disruption of mitochondrial biogenesis and dynamics. Exercise training, especially High-Intensity Interval Training (HIIT) increases mitochondrial biogenesis and dynamics. The present study aimed to investigate the effect of a period of HIIT with and without HFD consumption on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1-α), Mitofusins-2 (Mfn2), Optic atrophy-1 (Opa1), Dynamin-related protein-1 (Drp1) and mitochondrial Fission protein-1 (Fis1) genes as indicators of mitochondrial biogenesis and dynamics function in the soleus muscle of male Wistar rats. Twenty-four healthy male Wistar rats were randomly divided into four groups: (1) Control, (2) Control + HIIT, (3) HFD, and (4) HFD + HIIT. The HIIT training protocol lasted for 10 weeks with a frequency of 3 sessions per week. The Real-Time Quantitative Reverse Transcription PCR method was used to investigate the gene expression. One-way ANOVA and Fisher's post-hoc analyses were used to examine group differences. HFD consumption caused an increase in weight (P < 0.05), the expression of Drp1 and Fis1 genes (P < 0.001), and a decreased expression of Pgc1-α, Mfn2, and Opa1 genes (P < 0.001). HIIT training increased the expression of PGC1-α (P = 0.009), Mfn2 (P < 0.004), and Opa1 (P < 0.011) genes, while it decreased the expression of Drp1 (P = 0.003) and Fis1 genes (P = 0.027). These findings suggest that HIIT can counteract the negative effects of HFD on mitochondrial function by modulating gene expression related to mitochondrial biogenesis and dynamics.

Keywords:  Exercise Training; Fission; Fusion; Mitochondrial Biogenesis; Mitochondrial dynamic; Obesity

DOI:  https://doi.org/10.1038/s41598-025-86767-5
medRxiv. 2025 Jan 31. pii: 2025.01.30.25321320. [Epub ahead of print]

Breath Acetone Correlates with Capillary β-hydroxybutyrate in Type 1 Diabetes.

Kai E Jones, Max C Petersen, Alexander M Markov, Maamoun Salam, Petra Krutilova, Alexis M McKee, Kathryn L Bohnert, Samantha E Adamson, Janet B McGill.

Background: Breath acetone (BrACE) is an end product of ketone metabolism that is measurable by noninvasive breath ketone analyzers. We assessed the correlation between capillary blood β-hydroxybutyrate (BOHB) and BrACE in people with type 1 diabetes (T1D) during 14 days of outpatient care with and without dapagliflozin treatment and during supervised insulin withdrawal studies with and without dapagliflozin.
Methods: In this randomized crossover study, participants completed 14-day two outpatient periods with or without dapagliflozin 10 mg daily. Each 14-day unsupervised outpatient period was followed by a one-day supervised insulin withdrawal study. Paired BOHB and BrACE measurements were obtained three times daily during outpatient periods, then hourly during supervised insulin withdrawal. The correlation between BrACE and BOHB was assessed by Spearman's ρ.
Results: Twenty people with T1D completed the study. During outpatient periods, BrACE and BOHB were moderately correlated (n=1425 paired readings; ρ = 0.41; 95% CI: 0.36 to 0.45; P < 0.0001). However, BrACE and BOHB were strongly correlated during insulin withdrawal (n=246 paired values, ρ = 0.81; 95% CI: 0.77 to 0.85). In ROC analysis, BrACE > 5 ppm demonstrated optimal sensitivity (93%) and specificity (87%) for detecting capillary BOHB ≥ 1.5 mmol/L. No serious adverse events occurred.
Conclusions: In adults with T1D, measurement of breath acetone provides a noninvasive estimate of blood BOHB concentration. The correlation between BrACE and BOHB was suboptimal during unsupervised outpatient care, but was strong during supervised insulin withdrawal. Trial registration: clinicaltrials.gov ( NCT05541484 ).

DOI: https://doi.org/10.1101/2025.01.30.25321320
J Physiol. 2025 Feb 17.

Mitochondrial efficiency in resting skeletal muscle in vivo: a novel non-invasive approach using multinuclear magnetic resonance spectroscopy in humans.

Muhammet Enes Erol, Sean T Bannon, Alexs A Matias, Triantafyllia Siokas, Rajakumar Nagarajan, Yann Le Fur, Song-Young Park, Gwenael Layec.

  Mitochondrial efficiency is a critical metabolic parameter with far-reaching implications for tissue homeostasis. However, the direct measurement of oxygen consumption (VO2) and ATP production from a large tissue sample in vivo remains challenging. Using phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS), this study aimed to non-invasively quantify the skeletal muscle ATP synthesis rate and VO2 to determine mitochondrial efficiency at rest and during muscle contraction in humans. We assessed mitochondrial efficiency in the plantar flexor muscles of 12 healthy adults (21 ± 1 years) using 31P and 1H MRS within a 3T MR system. MRS data were acquired at rest and during constant workloads to quantify oxidative ATP synthesis (ATPox) rate and myoglobin-derived oxygen consumption (Mb-derived VO2). At rest, ATPox was 0.85 ± 0.24 mm min-1, and Mb-derived VO2 was 0.46 ± 0.11 mm min-1, resulting in a P/O ratio of 1.95 ± 0.68. During graded exercise, end-exercise PCr concentration decreased from 29 ± 5.7 mm to 18 ± 4.8 mm, and end-exercise Mb oxygenation declined linearly to 47 ± 11%. ATPox synthesis rate increased linearly with exercise workload (r = 0.65 ± 0.31), whereas there was no significant change in Mb-derived VO2 (r = -0.19 ± 0.60), leading to non-physiological P/O values during exercise (>3). The results indicate that combined 31P/1H-MRS at rest offers a promising approach for non-invasively quantifying mitochondrial efficiency in large muscle samples, suggesting its potential as a clinical endpoint of mitochondrial function. However, further refinement is needed for use during exercise. KEY POINTS: Mitochondrial efficiency, converting chemical energy from carbon fuels into ATP, is a vital metabolic parameter for tissue homeostasis, but measuring oxygen consumption (VO2) and ATP production in vivo has been challenging. This study used phosphorus (31P) and proton (1H) magnetic resonance spectroscopy (MRS) to non-invasively quantify the skeletal muscle ATP synthesis rate and VO2 at rest and during muscle contraction in humans. At rest, the oxidative ATP synthesis (ATPox) and myoglobin-derived VO2 (Mb-derived VO2) were measured, resulting in a P/O ratio of 1.95 in the plantar flexor muscles. During exercise, the ATPox rate increased with workload, but Mb-derived VO2 did not change significantly, leading to non-physiological P/O ratios. The findings suggest that 31P/1H-MRS at rest is a promising method for assessing mitochondrial efficiency and could be used as a clinical endpoint for mitochondrial function in vivo, although further refinement is needed for exercise conditions.

Keywords:  metabolic control; mitochondrial function; myoglobin; phosphorus magnetic resonance spectroscopy; proton spectroscopy

DOI:  https://doi.org/10.1113/JP287412
bioRxiv. 2025 Feb 08. pii: 2025.02.03.635951. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Anna S Monzel, Jack Devine, Darshana Kapri, Jose Antonio Enriquez, Caroline Trumpff, Martin Picard.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3 . All mitochondria share general features, but not all mitochondria are created equal 4 .Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes . By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5 ) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8 , we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.02.03.635951
J Nutr Health Aging. 2025 Feb 13. pii: S1279-7707(25)00031-4. [Epub ahead of print]29(5): 100508

Effectiveness of Protein-enriched oral nutritional supplements on muscle function in middle-aged and elderly women: A randomized controlled trial.

Minji Kang, Hyunkyung Rho, Minhui Kim, Miji Lee, Yunsook Lim, Jinmann Chon, Hyunjung Lim.

   OBJECTIVES: This study evaluated the effects of protein-enriched oral nutritional supplementation (ONS) consumption for 12 weeks on muscle mass, muscular strength, and function in middle-aged and elderly women.
DESIGN: A single-center, double-blind, randomized controlled trial PARTICIPANTS: This study was conducted with 70 healthy female participants aged 50-80.
INTERVENTION AND MEASUREMENTS: Participants were instructed to incorporate two daily packs of either the test ONS (Nucare Active, Daesang Wellife Corp., Seoul, Republic of Korea; 200 kcal/pack, 23 g carbohydrate, 6 g fat, and 15 g protein including branched chain amino acids or placebo ONS (200 kcal/pack, 33 g carbohydrate, 8 g fat, and 1 g protein) into their routine for 12 weeks while maintaining their regular lifestyle. The primary outcome was lean body mass (LBM), while secondary outcomes included muscular strength, physical performance ability, inflammatory markers, and body fat mass (FM).
RESULTS: Sixty-four participants (33 in the test group, 31 in the placebo group; mean ± SD age, [test] 63.06 ± 5.51 years, [placebo] 63.29 ± 3.28 years, p = 0.839) completed the 12-week protocol. The test group exhibited a higher percentage change in LBM than the placebo group (0.26 % [95%CI: -0.27, 0.78] vs. -0.47 % [95%CI: -0.81, -0.13]; p = 0.020). The placebo group experienced a significant increase in FM (38.15 % [95%CI: 36.62, 39.69] to 38.67 % [95%CI: 37.14, 40.21]; p < 0.01). The difference in the changes in LBM/BMI and FM/BMI between the two groups was also visually distinct. There were no significant differences between the two groups in terms of muscular strength, physical performance ability, or inflammatory markers.
CONCLUSIONS: Protein-enriched ONS helped maintain LBM and prevent FM gain in middle-aged and elderly females. This suggests its potential role in preventing frailty and musculoskeletal disorders associated with female aging.

Keywords:  Branched chain amino acid; Lean body mass; Muscle function; Oral nutritional supplements; Protein-enriched ONS; Sarcopenia

DOI:  https://doi.org/10.1016/j.jnha.2025.100508
Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00089-0. [Epub ahead of print]44(2): 115318

Overfeeding induces adipose tissue release of distinct mitochondria.

Joshua H Goodman, Chloé Berland, Rajesh K Soni, Anthony W Ferrante.

  Overfeeding animals beyond what they eat ad libitum causes rapid adipose tissue expansion, leading to an unusual form of obesity characterized by low immune cell accumulation in fat and sustained anorexia. To investigate how overfeeding affects adipose tissue, we studied the protein secretome of fat from equally obese overfed and ad libitum-fed mice. Fat from overfed animals secretes lower amounts of immune regulatory proteins. Unexpectedly, fat from overfed mice releases larger amounts of mitochondrial proteins. Microscopy identified mitochondria in the conditioned medium of cultured fat that were found not within extracellular vesicles but rather as free extracellular organelles. The protein profile of released mitochondria was distinct from the mitochondrial protein profile of the whole fat, suggesting that the metabolic stress of overfeeding leads to the release of a mitochondrial subset favoring de novo lipogenesis. These findings add to growing evidence that cells alter their energy profiles through the release of mitochondria.

Keywords:  CP: Metabolism; adipose tissue; mitochondria; obesity; overfeeding

DOI:  https://doi.org/10.1016/j.celrep.2025.115318
Physiol Rev. 2025 Feb 21.

The flux of energy in critical illness and the obesity paradox.

Ariel Jaitovich, Jesse B Hall.

  During critical illness, systemic inflammation causes organ-specific metabolic changes. In the immune and inflammatory compartments, predominantly anabolic reprogramming supports cellular replication and inflammatory response execution. Pari passu, catabolism of adipose tissue and skeletal muscle supplies carbon skeletons and enthalpy for inflammatory and immune cell anabolism. The liver plays a key role during these metabolic shifts in enabling adequate supply of glucose and ketone bodies to the circulation. While often perceived as passive surrogates of prehospitalization frailty, body mass constituents are active parties of an over-arching metabolic trade-off that is key for survival following acute insults. Muscle and adipose tissue remodel in response to critical illness and thus profoundly influence the systemic metabolic landscape during and after hospitalization. Whether obesity's effect on patient systemic metabolism and survival is paradoxically beneficial or not remains controversial. Substrate-induced epigenetic changes lead to abnormal transcriptional programs which in turn regulate metabolic pathways critical to patient survival. We present a summary of major mechanisms involved in the flux of energy in critical illness from body mass into immune response execution and suggest future research avenues focused on perturbed immune metabolic and epigenetic programs that could lead to improved understanding of these process, and eventually to better outcomes for the critically ill.

Keywords:  Body mass; Immune reprogramming; critical illness; obesity paradox; skeletal muscle

DOI:  https://doi.org/10.1152/physrev.00029.2024
Biochem Pharmacol. 2025 Feb 12. pii: S0006-2952(25)00061-9. [Epub ahead of print]234 116799

Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy.

Yanan Ji, Quan Jiang, Bingqian Chen, Xin Chen, Aihong Li, Dingding Shen, Yuntian Shen, Hua Liu, Xiaowei Qian, Xinlei Yao, Hualin Sun.

  Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.

Keywords:  ERS; Skeletal muscle atrophy; Therapy; UPR

DOI:  https://doi.org/10.1016/j.bcp.2025.116799
J Biomed Sci. 2025 Feb 18. 32(1): 29

Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.

Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero.

   BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.
METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.
RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.
CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.

Keywords:  Apoptosis; BNIP3; Disuse atrophy; Mitochondria; Mitophagy; Skeletal muscle

DOI:  https://doi.org/10.1186/s12929-025-01118-w
Curr Med Sci. 2025 Feb 20.

Partial Regulation of Ketone Metabolism by Hypoxia in H9C2 Cardiomyocytes.

Li-Zhen Chen, Hong-Qing Chen, Xin-Yuan Zhang, Shuang Ling, Jin-Wen Xu.

   OBJECTIVE: Hypoxia plays a critical role in the pathophysiology of cardiomyopathy, myocardial infarction, and heart failure. Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions. However, the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear. This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.
METHODS: H9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state, and the expression of various genes was detected by quantitative real-time PCR. ELISA and lactate dehydrogenase (LDH) cytotoxicity assay were used to measure CoAs, itaconic acid, and LDH levels, respectively, and the dependence of gene expression on hypoxia-inducible factor-1 alpha (HIF-1α) was evaluated using the inhibitor LW6.
RESULTS: H9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia. Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase (SCOT/OXCT1), 3-hydroxybutyrate dehydrogenase 2 (BDH2), and acyl-CoA: cholesterol acyltransferase 1 (ACAT1) in cardiomyocytes, with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA. The HIF-1α inhibitor LW6 could partially reverse the expression of BDH2 and ACAT1, as well as the levels of succinyl-CoA. Interestingly, however, hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1α inhibitor. In addition, hypoxia promoted the expression of inflammatory factors.
CONCLUSION: These data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the pathophysiology of cardiomyopathy, myocardial infarction and heart failure.

Keywords:  Cardiomyocyte; Gene expression; Hypoxia; Ketone metabolism; Succinyl-CoA

DOI:  https://doi.org/10.1007/s11596-025-00002-w
Sci Rep. 2025 Feb 21. 15(1): 6292

Cognitive and sensorimotor benefits of moderate- and high-intensity exercise are associated with specific expression of neurotrophic markers in older rats.

Cécile Marcourt, Caroline Pin-Barre, Antoine Langeard, Claudio Rivera, Jean-Jacques Temprado, Jérôme Laurin.

  Endurance training is strongly recommended for older adults to maintain cognitive and motor function. The respective effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on improving behavioural function and cerebral plasticity remain unknown. The purpose of this study was to determine the relative effects of 4 weeks of MICT and HIIT training on endurance, sensorimotor, and cognitive performance, as well as on the expression of neurotrophic markers in the hippocampus and cerebral cortex in aged rats. Twenty-two old male Wistar rats were assigned to one of the following groups: MICT (n = 7), HIIT (n = 6), and Control (n = 9). Incremental treadmill exercise tests, the forelimb grip strength test, the adhesive removal test, and the novel object recognition test were performed. Cerebral cortex and hippocampus were then removed for ELISA and Western blot measurements. The results showed similar benefits of MICT and HIIT on sensorimotor and cognitive functions, and a greater benefit of HIIT on endurance performance. HIIT and MICT differentially promoted cortical and hippocampal neurotrophic markers, demonstrating their complementarity. However, MICT was found to be more effective in promoting a broader range of markers, suggesting its potential as an initial training strategy for older adults.

Keywords:  Aging; Chloride homeostasis; Cognition; Exercise; Myokines; Neurotrophic factors

DOI:  https://doi.org/10.1038/s41598-025-90719-4
Aging Dis. 2025 Feb 08.

Targeting Mitochondrial Integrity as a New Senolytic Strategy.

Eliska Vacurova, Edita Vlachova, Jan Stursa, Klara Bohacova, Tereza Havrlantova, Vojtech Skop, Barbora Judita Kasperova, Lukas Werner, Jiri Neuzil, Martin Haluzik, Sona Stemberkova Hubackova.

Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.

DOI: https://doi.org/10.14336/AD.2024.1100
Front Nutr. 2024 ;11 1507156

Acute effect of endurance exercise on human milk insulin concentrations: a randomised cross-over study.

Rebecca Lyng Holm, Mads Holmen, Md Abu Jafar Sujan, Guro F Giskeødegård, Trine Moholdt.

   Introduction: Insulin is present in human milk and its concentration correlates with maternal circulating levels. Studies on the association between human milk insulin concentrations and infant weight or growth show conflicting results, but some studies indicate that higher insulin concentrations in the milk can promote infant weight gain. Circulating levels of insulin decrease acutely after exercise, but no prior study has investigated the acute effect of exercise on human milk insulin concentrations. Our aim was to determine the acute effects of two endurance exercise protocols on human milk insulin concentration in exclusively breastfeeding individuals.
Methods: In a randomised cross-over trial, 20 exclusively breastfeeding participants who were 6-12 weeks postpartum completed three conditions on separate days: (1) moderate-intensity continuous training (MICT), (2) high-intensity interval training (HIIT), and (3) no activity (REST). Milk was collected before exercise/rest (at 07:00 h), immediately after exercise/rest (11:00 h), 1 h after exercise/rest (12:00 h), and 4 h after exercise/rest (15:00 h). We determined insulin concentrations in the milk using enzyme-linked immunosorbent assay and compared insulin concentrations after MICT and HIIT with REST using a linear mixed model with time-points and the interaction between time and condition as fixed factors.
Results: We detected insulin in all 240 samples, with an average concentration of 12.3 (SD 8.8) μIU/mL (range 3.2-57.2 μIU/mL). There was no statistically significant effect of exercise on insulin concentration, but a tendency of reduced concentrations 4 h after HIIT (p = 0.093). There was an overall effect of time at 11:00 h and 15:00 h. In the fasted sample obtained at 07:00 h, the concentration was 9.9 (SD 7.2) μIU/mL, whereas the concentration was 12.7 (SD 9.0) μIU/mL at 11:00 h (p = 0.009), and 15.0 (SD 11.7) μIU/mL at 15:00 h (p < 0.001).
Conclusion: One session of endurance exercise, either at moderate- or high intensity, had no statistically significant effect on human milk insulin concentration. Future research should determine the effect of regular exercise on insulin in human milk and potential impact for infant health outcomes.
Clinical trial registration: ClinicalTrials.gov, identifier NCT05042414.

Keywords:  high-intensity interval training; infant; lactation; metabolism; nutrition; obesity; running

DOI:  https://doi.org/10.3389/fnut.2024.1507156
Alzheimers Dement (N Y). 2025 Jan-Mar;11(1):11(1): e70056

Exercise intensity matters: A review on evaluating the effects of aerobic exercise intensity on muscle-derived neuroprotective myokines.

Navabeh Zare, David J Bishop, Itamar Levinger, Mark A Febbraio, James R Broatch.

  Exercise as a medical intervention is effective to help prevent and manage many chronic and complex diseases, including dementia. There is evidence to suggest that regular aerobic exercise protects against age-related brain atrophy and reduces the risk of cognitive decline. The mechanisms by which exercise infers a neuroprotective effect remain to be established but may be related to a maintenance of brain volume and neuronal survival, improved cerebrovascular density and function, and/or increased synaptic plasticity. In addition, there is growing evidence to suggest the beneficial effects of exercise on brain health and cognitive function are, at least in part, mediated by factors released by skeletal muscle during contraction. The fact that the brain responds to exercise suggests that muscle-derived peripheral factors, or "myokines," may play a key role in muscle-brain crosstalk and exercise neuroprotection. However, the most effective "dose" of aerobic exercise to promote beneficial changes in these myokine pathways is currently unknown. Specifically, most of the evidence to date is from studies that have used moderate-intensity exercise, and research investigating the merit of high-intensity exercise is scarce. Considering the well-established role of high-intensity interval training in protecting against numerous medical conditions, more research is needed to identify the most effective "dose" of exercise to improve the beneficial effects of these myokines.
Highlights: Neuroprotection through exercise: Regular aerobic exercise mitigates age-related brain atrophy and cognitive decline via multiple mechanisms, including brain volume maintenance, improved cerebrovascular function, and synaptic plasticity. Myokines as mediators: Muscle-derived factors (myokines) play a crucial role in muscle-brain crosstalk, significantly contributing to the neuroprotective effects of exercise. Intensity matters: The review underscores the necessity to define and study exercise intensity, revealing high-intensity exercise may be as effective, if not more, in promoting neuroprotective myokine levels compared to moderate-intensity exercise. Future research directions: This review emphasizes the need for well-controlled studies to explore the optimal exercise dose for enhancing myokine pathways and their implications for neurodegenerative disease prevention.

Keywords:  dementia; exercise intensity; high‐intensity exercise training; moderate‐intensity exercise training; myokines; neuroprotection

DOI:  https://doi.org/10.1002/trc2.70056
bioRxiv. 2025 Feb 05. pii: 2025.01.14.633043. [Epub ahead of print]

Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.

Ryan J Allen, Ana Kronemberger, Qian Shi, Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca 2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

DOI: https://doi.org/10.1101/2025.01.14.633043
PLoS Comput Biol. 2025 Feb;21(2): e1012770

Bayesian classification of OXPHOS deficient skeletal myofibres.

Jordan Childs, Tiago Bernardino Gomes, Amy E Vincent, Andrew Golightly, Conor Lawless.

Mitochondria are organelles in most human cells which release the energy required for cells to function. Oxidative phosphorylation (OXPHOS) is a key biochemical process within mitochondria required for energy production and requires a range of proteins and protein complexes. Mitochondria contain multiple copies of their own genome (mtDNA), which codes for some of the proteins and ribonucleic acids required for mitochondrial function and assembly. Pathology arises from genetic defects in mtDNA and can reduce cellular abundance of OXPHOS proteins, affecting mitochondrial function. Due to the continuous turn-over of mtDNA, pathology is random and neighbouring cells can possess different OXPHOS protein abundance. Estimating the proportion of cells where OXPHOS protein abundance is too low to maintain normal function is critical to understanding disease severity and predicting disease progression. Currently, one method to classify single cells as being OXPHOS deficient is prevalent in the literature. The method compares a patient's OXPHOS protein abundance to that of a small number of healthy control subjects. If the patient's cell displays an abundance which differs from the abundance of the controls then it is deemed deficient. However, due to the natural variation between subjects and the low number of control subjects typically available, this method is inflexible and often results in a large proportion of patient cells being misclassified. These misclassifications have significant consequences for the clinical interpretation of these data. We propose a single-cell classification method using a Bayesian hierarchical mixture model, which allows for inter-subject OXPHOS protein abundance variation. The model accurately classifies an example dataset of OXPHOS protein abundances in skeletal muscle fibres (myofibres). When comparing the proposed and existing model classifications to manual classifications performed by experts, the proposed model results in estimates of the proportion of deficient myofibres that are consistent with expert manual classifications.

DOI: https://doi.org/10.1371/journal.pcbi.1012770
Lancet Healthy Longev. 2025 Feb 13. pii: S2666-7568(25)00015-7. [Epub ahead of print] 100696

Defining obesity to improve ageing.

The Lancet Healthy Longevity.

DOI: https://doi.org/10.1016/j.lanhl.2025.100696
bioRxiv. 2025 Jan 29. pii: 2025.01.29.635600. [Epub ahead of print]

Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure.

Nadina R Latchman, Tyler L Stevens, Kenneth C Bedi, Benjamin L Prosser, Kenneth B Margulies, John W Elrod.

Background: Cardiomyocyte structural remodeling is reported as a causal contributor to heart failure (HF) development and progression. Growing evidence highlights the role of organelle apposition in cardiomyocyte function and homeostasis. Disruptions in organelle crosstalk, such as that between the sarcoplasmic reticulum (SR) and mitochondria, are thought to impact numerous cellular processes such as calcium handling and cellular bioenergetics; two processes that are disrupted and implicated in cardiac pathophysiology. While the physical distance between organelles is thought to be essential for homeostatic cardiomyocyte function, whether the interactions and coupling of organelles are altered in human heart failure remains unclear.
Methods: Here, we utilized transmission electron microscopy and careful quantification of ultrastructure to characterize the changes in organelle apposition in cardiomyocytes isolated from the hearts of patients diagnosed with various types of HF. Subsequently we employed molecular approaches to examine the expression of proposed organelle tethers.
Results: We demonstrate that cardiomyocytes isolated from dilated cardiomyopathy, hypertrophic cardiomyopathy and ischemic cardiomyopathy hearts display smaller, more rounded mitochondria, as compared to nonfailing controls. Failing cardiomyocytes also exhibited disrupted SR-mitochondria juxtaposition and changes in the expression of proposed molecular tethers. Further analysis revealed alterations in lipid droplet dynamics including decreased lipid droplet content and less lipid droplets in association with mitochondria in failing cardiomyocytes.
Conclusion: Here we observed changes in organelle dynamics in cardiomyocytes isolated from heart failure patients diagnosed with differing etiologies. Our results suggest that organelle structure and apposition may be a ubiquitous contributor to human HF progression.
RESEARCH PERSPECTIVE: What is New? We provide a detailed analysis of organelle apposition in human heart failure, which has been understudied, and report that that failing human cardiomyocytes display an increase in distance between mitochondria and both the sarcoplasmic reticulum and lipid droplets.Structural changes in organelles are correlated with the expression of proposed organelle tethers.Resource of ultrastructural changes in organelle apposition in human heart failure resulting from various etiologies. What Questions Should be Addressed next? The results from this study provide rationale for causal experimentation to elucidate the contribution of organelle apposition to the progression of heart failure. Future studies examining mechanisms of mitochondrial tethering to the SR or lipid droplet will evaluate specific targets for therapeutic application.

DOI: https://doi.org/10.1101/2025.01.29.635600
Drug Des Devel Ther. 2025 ;19 1025-1041

NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury.

Yuzi Jin, Joshua S Fleishman, Yudong Ma, Xiaoqing Jing, Qin Guo, Weiguang Shang, Hongquan Wang.

  Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.

Keywords:  NLRP3; bioactive compounds; pyroptosis; sepsis; sepsis-induced myocardial injury

DOI:  https://doi.org/10.2147/DDDT.S506537
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00024-5. [Epub ahead of print]

Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.

Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Amanda L Smythers, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Joao A Paulo, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman.

  Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Keywords:  MPST; ergothioneine; exercise; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.01.024
J Sport Health Sci. 2025 Feb 15. pii: S2095-2546(25)00007-9. [Epub ahead of print] 101029

A primer on global molecular responses to exercise in skeletal muscle: Omics in focus.

Kevin A Murach, James R Bagley.

  Advances in skeletal muscle omics has expanded our understanding of exercise-induced adaptations at the molecular level. Over the past 2 decades, transcriptome studies in muscle have detailed acute and chronic responses to resistance, endurance, and concurrent exercise, focusing on variables such as training status, nutrition, age, sex, and metabolic health profile. Multi-omics approaches, such as the integration of transcriptomic and epigenetic data, along with emerging ribosomal RNA sequencing advancements, have further provided insights into how skeletal muscle adapts to exercise across the lifespan. Downstream of the transcriptome, proteomic and phosphoproteomic studies have identified novel regulators of exercise adaptations, while single-cell/nucleus and spatial sequencing technologies promise to evolve our understanding of cellular specialization and communication in and around skeletal muscle cells. This narrative review highlights (a) the historical foundations of exercise omics in skeletal muscle, (b) current research at 3 layers of the omics cascade (DNA, RNA, and protein), and (c) applications of single-cell omics and spatial sequencing technologies to study skeletal muscle adaptation to exercise. Further elaboration of muscle's global molecular footprint using multi-omics methods will help researchers and practitioners develop more effective and targeted approaches to improve skeletal muscle health as well as athletic performance.

Keywords:  Epigenomics; Phosphoproteomics; Proteomics; Single cell; Transcriptomics

DOI:  https://doi.org/10.1016/j.jshs.2025.101029
Cell Death Dis. 2025 Feb 14. 16(1): 99

Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.

Irene Pertici, Donato D'Angelo, Denis Vecellio Reane, Massimo Reconditi, Ilaria Morotti, Elena Putignano, Debora Napoli, Giorgia Rastelli, Gaia Gherardi, Agnese De Mario, Rosario Rizzuto, Simona Boncompagni, Laura Baroncelli, Marco Linari, Marco Caremani, Anna Raffaello.

Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT-/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT-/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.

DOI: https://doi.org/10.1038/s41419-025-07381-x
Ageing Res Rev. 2025 Feb 17. pii: S1568-1637(25)00041-8. [Epub ahead of print]106 102695

Adenosine metabolism and receptors in aging of the skin, musculoskeletal, immune and cardiovascular systems.

Piul Rabbani, Bhama Ramkhelawon, Bruce N Cronstein.

  Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A2A and A2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.

Keywords:  Adenosine; Adenosine receptor; Aging; Ectoenzymes; Purine metabolism

DOI:  https://doi.org/10.1016/j.arr.2025.102695
Inflammation. 2025 Feb 21.

High-Resolution Untargeted Metabolomics Reveals Alternate-Day Fasting May Attenuate Diabetic Kidney Disease Progression in BTBR ob/ob Mice by Affecting the HCA, IPA and Reducing Inflammation.

Huiqing Yu, Liping Yan, Jiaqing Ma, Xinduo Zhang, Hongman Wu, Yahui Yan, Hong Shen, Zhiguo Li.

  Diabetic kidney disease (DKD) is one of the most severe complications of diabetes mellitus, with limited effective therapeutic interventions. Alternate-day fasting (ADF) shows potential in treating DKD, though its mechanisms are not fully understood. In this study, BTBR ob/ob mice underwent 12 weeks of ADF, and high-resolution untargeted metabolomics were performed to uncover the underlying mechanisms. After 12 weeks of ADF, the BTBR ob/ob mice exhibited weight loss, lower blood glucose and LDL-C levels, reduced 24-h urinary protein excretion, and decreased renal collagen deposition. A total of 44 metabolites were differentially expressed, with 25 up-regulated and 19 down-regulated. Notably, hyocholic acid (HCA) and indole-3-propionic acid (IPA), both products of intestinal bacteria, can modulating inflammation were differentially expressed. Furthermore, the kidneys of BTBR ob/ob mice showed significantly lower NF-κB pathway activity and reduced inflammation after 12 weeks of ADF. This study indicates that ADF may alleviate DKD progression by modulating HCA, IPA, and decreasing inflammation.

Keywords:  Alternate day fasting; Diabetic kidney disease; Inflammation; Kidney untargeted metabolomics

DOI:  https://doi.org/10.1007/s10753-025-02263-y
bioRxiv. 2025 Jan 27. pii: 2025.01.24.634796. [Epub ahead of print]

Epigenetic small molecule screening identifies a new HDACi compound for ameliorating Duchenne muscular dystrophy.

Ke'ale W Louie, Eva H Hasegawa, Gist H Farr, Amanda Ignacz, Alison Paguio, Alyssa Maenza, Alison G Paquette, Clarissa Henry, Lisa Maves.

Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease. There are currently few effective therapies to treat the disease, although many approaches are being pursued. Certain histone deacetylase inhibitors (HDACi) have been shown to ameliorate DMD phenotypes in mouse and zebrafish animal models, and the HDACi givinostat has recently gained FDA approval for DMD. Our goal was to identify additional HDACi, or other classes of epigenetic small molecules, that are beneficial for DMD. Using an established animal model for DMD, the zebrafish dmd mutant strain sapje , we screened a library of over 800 epigenetic small molecules of various classes. We used a quantitative muscle birefringence assay to assess and compare the effects of these small molecule treatments on dmd mutant zebrafish skeletal muscle. Our screening identified a new HDACi, SR-4370, that ameliorated dmd mutant zebrafish skeletal muscle degeneration, in addition to HDACi previously shown to improve dmd zebrafish. We find that a single early treatment of HDACi can ameliorate dmd zebrafish. Furthermore, we find that HDACi that improve dmd muscle also cause increased histone acetylation in zebrafish larvae, whereas givinostat does not appear to increase histone acetylation or improve zebrafish dmd muscle. Our results add to the growing evidence that HDACi are promising candidates for treating DMD. Our study also provides further support for the effectiveness of small-molecule screening in dmd zebrafish.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.01.24.634796