bims-kimdis 2025-05-04 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–05–04
27 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.
Ketone ester ingestion impairs exercise performance without impacting cognitive function or circulating EPO during acute hypoxic exposure.
Ketogenic Diets for Body Weight Loss: A Comparison with Other Diets.
Evaluation of ketones intensive measurement in women with gestational diabetes (EVOKING) study.
The Influence of the Probiotics, Ketogenic Diets, and Gut Microbiota on Epilepsy and Epileptic Models: A Comprehensive Review.
Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.
Epigenetic Aging Acceleration in Obesity Is Slowed Down by Nutritional Ketosis Following Very Low-Calorie Ketogenic Diet (VLCKD): A New Perspective to Reverse Biological Age.
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
A retrospective analysis of pediatric patients on a ketogenic diet: A comparison of inpatient versus outpatient diet initiations.
Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.
The Evolving Role of Macrophage Metabolic Reprogramming in Obesity.
Updated insights into the molecular networks for NLRP3 inflammasome activation.
Impact of the Addition of Beta-Hydroxybutyrate in the 72-Hour Fast Protocol on Hospitalization Duration: A Quality Improvement Report.
Mitochondria - the CEO of the cell.
Involvement of cholesterol and ketone bodies in early stages of bovine cystic ovarian disease development.
Acute Effect of High-Intensity Interval Training on Postprandial Glycemia in Overweight and Obese Individuals: A Scoping Review.
Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.
How Much Should We Fast? A New Study by the Fontana Group Suggests That Intermittent Fasting May Be Too Mild for Humans.
Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.
Geroscience in heart failure: the search for therapeutic targets in the shared pathobiology of human aging and heart failure.
Mitochondrial Sensitivity to Submaximal [ADP] Following Bed Rest: A Novel Two-Phase Approach Associated With Fibre Types.
Association between Circulating Amino Acids and Childhood Obesity: A Systematic Review and Meta-Analysis.
Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.
Fiber Type-Specific Adaptations to Exercise Training in Human Skeletal Muscle: Lessons From Proteome Analyses and Future Directions.
The role of resistance exercise-induced local metabolic stress in mediating systemic health and functional adaptations: could condensed training volume unlock greater benefits beyond time efficiency?
Resistance training increases myofibrillar protein synthesis in middle-to-older aged adults consuming a typical diet with no influence of protein source: a randomized controlled trial.
Editorial: Preventing sarcopenia and promoting musculoskeletal health in middle-aged adults: the role of exercise and nutrition.

Biomolecules. 2025 Apr 14. pii: 580. [Epub ahead of print]15(4):

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease.

Varshini V Suresh, Sathish Sivaprakasam, Yangzom D Bhutia, Puttur D Prasad, Muthusamy Thangaraju, Vadivel Ganapathy.

  Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by "keto" diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease.

Keywords:  GPR109A; HMGCS2; cancer; epigenetic modification; inflammation; ketoacidosis; ketone body transporters; loss-of-function mutations; neurodegeneration; β-hydroxybutyrate

DOI:  https://doi.org/10.3390/biom15040580
J Appl Physiol (1985). 2025 May 02.

Ketone ester ingestion impairs exercise performance without impacting cognitive function or circulating EPO during acute hypoxic exposure.

Myrthe Stalmans, Domen Tominec, Wout Lauriks, Ruben Robberechts, Monique Ramaekers, Tadej Debevec, Chiel Poffé.

  Background: Altitude-induced hypoxemia impairs exercise performance and cognition. Interestingly, ketone ester (KE) ingestion may attenuate hypoxemia, which likely explains the observation that KE impairs high-intensity exercise performance in normoxia but not in hypoxia. Moreover, KE was reported to attenuate cognitive decline at extreme altitudes (~6,100m). Given that hypoxemia is unaffected by KE in milder conditions, the impact of KE on cognition and performance in the absence of elevated oxygenation remains unknown. As KE may increase post-exercise circulating [erythropoietin] ([EPO]) at sea level, we also assessed if KE might augment the blood [EPO] response after hypoxic exercise. Methods: In a double-blind, cross-over design, thirteen healthy, male participants completed two 5.5-h sessions at 4,000m simulated altitude while receiving either KE or placebo (CON). Throughout a graded exercise test (EXMAX) after 1.5h, and a submaximal exercise bout (EXSUBMAX) after 3h, blood and tissue oxygenation, ventilatory parameters, and acid-base balance were evaluated. Other measurements included cognitive function, and blood [EPO]. Results: KE reduced power output achieved during EXMAX by 3.6%, while blood and cerebral oxygenation were similar. KE ingestion lowered blood pH, [HCO3-], pCO2 and [glucose], but did not impact cognitive function. In both KE and CON, circulating [EPO] increased by ~56% after 5h. Conclusions: These results indicate that KE ingestion impairs high-intensity exercise performance, at least if not compensated by elevated oxygenation. A progressively increasing oxygenation upon KE was unable to protect against hypoxia-induced cognitive declines, and potentially counteracted a KE-induced augmentation of circulating [EPO].

Keywords:  Cognition; Exercise performance; Hypoxia; Ketones; erythropoietin (EPO)

DOI:  https://doi.org/10.1152/japplphysiol.00097.2025
Nutrients. 2025 Mar 10. pii: 965. [Epub ahead of print]17(6):

Ketogenic Diets for Body Weight Loss: A Comparison with Other Diets.

Damian Dyńka, Łukasz Rodzeń, Mateusz Rodzeń, Anna Pacholak-Klimas, Georgia Ede, Shebani Sethi, Dorota Łojko, Karolina Bartoń, Ken Berry, Adam Deptuła, Żaneta Grzywacz, Peter Martin, Jen Unwin, David Unwin.

  With the prevalence of obesity and overweight increasing at an alarming rate, more and more researchers are focused on identifying effective weight loss strategies. The ketogenic diet (KD), used as a treatment in epilepsy management for over 100 years, is additionally gaining popularity as a weight loss method. Although its efficacy in weight loss is well documented, the areas where it may be beneficial to other dietary approaches need to be carefully examined. The objective of this paper is to identify the potential benefits of the KD over alternative dietary weight loss strategies based on a comprehensive literature review. It has been shown that the KD may be more bioenergetically efficient than other dietary strategies, inter alia owing to its effect on curtailing hunger, improving satiety and decreasing appetite (influence on hunger and satiety hormones and the sensation of hunger), inducing faster initial weight loss (associated with lower glycogen levels and reduced water retention), and controlling glycaemia and insulinemia (directly attributable to the low-carbohydrate nature of KD and indirectly to the other areas described). These effects are accompanied by improved insulin sensitivity, reduced inflammation (through ketone bodies and avoidance of pro-inflammatory sugars), reduced need for pharmacological obesity control (the diet's mechanisms are similar to those of medication but without the side effects), and positive impacts on psychological factors and food addiction. Based on the authors' review of the latest research, it is reasonable to conclude that, due to these many additional health benefits, the KD may be advantageous to other diet-based weight loss strategies. This important hypothesis deserves further exploration, which could be achieved by including outcome measures other than weight loss in future clinical trials, especially when comparing different diets of equal caloric value.

Keywords:  appetite; body weight; glycaemic; hunger; inflammation; insulin resistance; ketogenic diet; low carb; metabolic psychiatry; obesity; weight loss

DOI:  https://doi.org/10.3390/nu17060965
Hormones (Athens). 2025 Apr 29.

Evaluation of ketones intensive measurement in women with gestational diabetes (EVOKING) study.

Basilio Pintaudi, Loretta Giunta, Giacoma Di Vieste, Michela Vergani, Matteo Conti, Arianna Pani, Francesco Corrado, Rosario D'Anna, Antonino Di Benedetto.

   PURPOSE: Women with gestational diabetes mellitus (GDM) are frequently asked to check their ketone levels by measuring ketonuria before breakfast. However, ketosis could be present even before lunch and dinner. Furthermore, blood ketone measurement could be a more accurate test. Our aim was to evaluate the effect of a blood ketone intensive measurement in the detection of ketosis in women with GDM with a negative urinary ketone test.
METHODS: This was a single center, observational, prospective study involving consecutive women with GDM. Only women with negative fasting urinary ketone tests were included. During the same gestational weeks (weeks 30-32), all women were asked to perform a blood ketone test before their main meals. Ketosis was defined as the presence for at least 25% of the time of fasting blood ketone levels > 0.1 mmol/L and > 0.2 mmol/L before lunch and dinner.
RESULTS: Overall, a total of 101 women (mean age 34.7 ± 4.8 years, prepregnancy BMI 28.2 ± 5.2 kg/m2) were studied. Blood ketones were present in 37.6% of the cases before breakfast, 13.9% before lunch, and 11.9% before dinner. Women with at least one daily presence of blood ketones composed 40.6% of the sample. Presence of fasting blood ketones was correlated with ketone presence before lunch (r = 0.63, p < 0.0001) and before dinner (r = 0.55, p < 0.0001) and with mean glucose levels (r = 0.23, p = 0.02) 1 h after breakfast.
CONCLUSION: Blood ketone testing in women with GDM can detect a larger number of ketosis episodes than a urinary ketone test. Intensive blood ketone measurement should be recommended to women with GDM.

Keywords:  Blood glucose; Blood ketones; Gestational diabetes; Urinary ketones

DOI:  https://doi.org/10.1007/s42000-025-00663-1
Mol Neurobiol. 2025 May 02.

The Influence of the Probiotics, Ketogenic Diets, and Gut Microbiota on Epilepsy and Epileptic Models: A Comprehensive Review.

Parmida Shirzadi, Parisa Farokh, Sima Osouli Meinagh, Ghazal Izadi-Jorshari, Bardia Hajikarimloo, Ghazaleh Mohammadi, Siavash Parvardeh, Marjan Nassiri-Asl.

  About one-third of epilepsies are resistant to antiepileptic drugs; thus, uncovering new pathways in the pathophysiology of epilepsy can reduce the global disease burden. Probiotics are live, non-pathogenic microorganisms that benefit the host by regulating the gut microbiome. This review aims to study the effect of probiotics and ketogenic diets on gut microbiota and their potential as a therapy for epilepsy. We conducted a systematic search of the databases PubMed, Scopus, Embase, and the Web of Science for pertinent studies that have been published. Our search methodology was meticulously structured to be exhaustive, integrating targeted keywords and Boolean operators to guarantee the acquisition of all potentially pertinent articles. Probiotics interact with the gut microbiome, balance its composition, and influence the gut-brain axis. Moreover, they reduce neuroinflammation and oxidative stress. The ketogenic diet (KD) affects gut bacteria, influencing neurotransmitter levels and short-chain fatty acids (SCFAs), which play a role in the gut-brain axis. Studies have shown the positive effects of various probiotics in animal models of epilepsy. They demonstrate improvements in seizure activity, anxiety, and neuroinflammation. In human studies, probiotics reduced seizure frequency and enhanced quality of life in patients with drug-resistant epilepsy. We believe using probiotics or dietary interventions like KD could be a promising therapeutic strategy for managing epilepsy. This could reduce seizure frequency and make life better for patients with epilepsy.

Keywords:  Epilepsy; Fecal microbiota transplantation; Gut microbiota; Ketogenic diets; Probiotics; Seizure, Short-chain fatty acids

DOI:  https://doi.org/10.1007/s12035-025-04993-4
Front Physiol. 2025 ;16 1554222

Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.

Yuqing Li, Wanjun Zhao, Qi Yang.

  Exercise and physical activity confer health advantages, in part, by enhancing skeletal muscle mitochondrial respiratory function. The objective of this study is to analyze the impacts of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the dynamics and functionality of the mitochondrial network within skeletal muscle. 20 young male participants were assigned to either HIIT or MICT group. Initial assessments of exercise-related indicators were conducted, followed by skeletal muscle biopsies from the vastus lateralis before, 1 day after, and 6 weeks post-experiment. We utilized multi-dimensional myofiber imaging to analyze mitochondrial morphology and arrangement, and assessed citrate synthase activity, complex I activity, and dynamics-related mRNA. Both training modalities increased VO2max, Wmax, citrate synthase and complex I activities, mitochondrial content, and volume density, though the changes differed between the two groups. 6 weeks training induced remodeling of the mitochondrial network within skeletal muscle. Before training, the network appeared sparse and punctate. After MICT, it adopted a grid-like structure with partially robust longitudinal connections. In contrast, HIIT resulted in a less obvious grid structure but showed a stronger longitudinally oriented network. Training also increased mRNA expression of mitochondrial fusion proteins and decreased fission protein expression, with these effects being more pronounced in HIIT. Similarly, peroxisome proliferator-activated receptor γ coactivator 1-alpha mRNA expression showed a comparable trend, though the changes differed between 1 day and 6 weeks of training. In conclusion, HIIT and MICT induce distinct mitochondrial adaptation in skeletal muscle, reflected in different network remodeling and molecular pathways. These findings may be due to HIIT's more pronounced effect on mitochondrial dynamics or respiratory function, but the study has only conducted preliminary observational experiments and further evidence is required for confirmation.

Keywords:  high-intensity interval training; mitochondrial dynamics; mitochondrial network remodeling; moderate-intensity interval training; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2025.1554222
Nutrients. 2025 Mar 18. pii: 1060. [Epub ahead of print]17(6):

Epigenetic Aging Acceleration in Obesity Is Slowed Down by Nutritional Ketosis Following Very Low-Calorie Ketogenic Diet (VLCKD): A New Perspective to Reverse Biological Age.

Andrea G Izquierdo, Paula M Lorenzo, Nicolás Costa-Fraga, David Primo-Martin, Gemma Rodriguez-Carnero, Carolina F Nicoletti, J Alfredo Martínez, Felipe F Casanueva, Daniel de Luis, Angel Diaz-Lagares, Ana B Crujeiras.

  Background/Objectives: Epigenetic clocks have emerged as a tool to quantify biological age, providing a more accurate estimate of an individual's health status than chronological age, helping to identify risk factors for accelerated aging and evaluating the reversibility of therapeutic strategies. This study aimed to evaluate the potential association between epigenetic acceleration of biological age and obesity, as well as to determine whether nutritional interventions for body weight loss could slow down this acceleration. Methods: Biological age was estimated using three epigenetic clocks (Horvath (Hv), Hannum (Hn), and Levine (Lv)) based on the leukocyte methylome analysis of individuals with normal weight (n = 20), obesity (n = 24), and patients with obesity following a VLCKD (n = 10). We analyzed differences in biological age estimates, the relationship between age acceleration and obesity, and the impact of VLCKD. Correlations were assessed between age acceleration, BMI, and various metabolic parameters. Results: Analysis of the epigenetic clocks revealed an acceleration of biological age in individuals with obesity (Hv = +3.4(2.5), Hn = +5.7(3.2), Lv = +3.9(2.7)) compared to a slight deceleration in individuals with normal weight. This epigenetic acceleration correlated with BMI (p < 0.0001). Interestingly, patients with obesity following a VLCKD showed a deceleration in estimated biological age, both in nutritional ketosis (Hv = -3.3(4.0), Hn = -6.3(5.3), Lv = -8.8(4.5)) and at endpoint (Hv = -1.1(4.3), Hn = -7.4(5.6), Lv = -8.2(5.3)). Relevantly, this slowdown in age is associated with BMI (p < 0.0001), ketonemia (p ≤ 0.001), and metabolic parameters (p < 0.05). Conclusions: Our findings highlight the applicability of epigenetic clocks to monitor obesity-related biological aging in precision medicine and show the potential efficacy of the VLCKD in slowing obesity-related epigenetic aging.

Keywords:  DNA methylation; Hannum; Horvath; Levine; blood leukocytes; body weight loss; epigenetic clock; ketone bodies; personalized therapy; precision medicine

DOI:  https://doi.org/10.3390/nu17061060
Aging Cell. 2025 Apr 25. e70054

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.

Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.

  Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria

DOI:  https://doi.org/10.1111/acel.70054
Epilepsy Res. 2025 Apr 29. pii: S0920-1211(25)00057-9. [Epub ahead of print]214 107556

A retrospective analysis of pediatric patients on a ketogenic diet: A comparison of inpatient versus outpatient diet initiations.

Chelsey Stillman, Kelly Knupp, Jennifer Oliver, Alison Conley, Kaitlyn Kennedy, Lori Silveira, Charuta Joshi.

   INTRODUCTION: Ketogenic diet therapies are effective therapies for drug-resistant epilepsy. Conventional initiation of the ketogenic diet occurs via inpatient (IP) admission to a hospital. The COVID19 pandemic forced changes to practices allowing for comparison between inpatient (IP) and outpatient (OP) initiations. Our aim was to evaluate differences between IP and OP initiations including laboratory results, seizure reduction and communications with patients.
METHODS: This is a retrospective chart review of patients initiated on a ketogenic diet (modified Atkins [MAD] or classic ketogenic [CKD]) between 2007 and 2022. We compared variables such as demographic data, communications, lab values, seizure counts, IP or OP initiation, presence of a gastrostomy tube (g-tube), and diet type.
RESULTS: Of the 157 total subjects, 139 subjects initiated CKD and 18 subjects initiated MAD. 39 initiated OP and 118 initiated IP. The odds of a 50 % reduction in seizures at 65 days post initiation increased four times for IP initiation after adjusting for the impact of serum beta hydroxybutyrate (BHB). This difference was no longer present at 196 days post initiation. Number of communications between diet initiation and the first visit post initiation were similar for IP and OP. G-tube presence or absence did not impact outcomes.
CONCLUSION: IP initiation resulted in better seizure control at the first visit post initiation. CKD was the only variable associated with increased communications. Since seizure improvement rates were similar at 196 days, a gradual approach with lower CKD ratios may be considered. G-tube presence had no impact on outcomes and should be weighted less when considering admission.

Keywords:  Diet therapies; Initiation type; Ketogenic diet; Ketosis; Modified Atkins; Pediatric epilepsy; seizures

DOI:  https://doi.org/10.1016/j.eplepsyres.2025.107556
Exerc Sport Sci Rev. 2025 May 01.

Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.

Maya Semel, Cole Lukasiewicz, Russell T Hepple.

   ABSTRACT: Our Perspective for Progress highlights sex differences in skeletal muscle mitochondrial function that evolve with aging, with an influence of denervation emerging in advanced age. Gaps include knowledge about mitochondrial alterations in microdomains of muscle fibers, plasticity of the mitochondrial reticulum to acute muscle contractions, and advanced age of both sexes.

Keywords:  Mitochondria; aging; denervation; heterogeneity; skeletal muscle

DOI:  https://doi.org/10.1249/JES.0000000000000364
Can J Cardiol. 2025 Apr 29. pii: S0828-282X(25)00320-4. [Epub ahead of print]

The Evolving Role of Macrophage Metabolic Reprogramming in Obesity.

Dorcus Makassy, Kyra Williams, Qutuba G Karwi.

  Recent research has extensively explored the critical role of energy metabolism in shaping the inflammatory response and polarization of macrophages in obesity. This rapidly growing field emphasizes the need to understand the connection between metabolic processes that support macrophage polarization in obesity. While most published research in this area has focused on glucose and fatty acids, how the flux through other metabolic pathways (such as ketone and amino acid oxidation) in macrophages is altered in obesity is not well defined. This review summarizes the main alterations in uptake, storage, and oxidation of oxidative substrates (glucose, fatty acids, ketone bodies and amino acids) in macrophages and how these alterations are linked to macrophage polarization and contribution to augmented inflammatory markers in obesity. The review also discusses how oxidative substrates could modulate macrophage energy metabolism and inflammatory responses via feeding into other non-oxidative pathways (such as the pentose phosphate pathway, triacylglycerol synthesis/accumulation), via acting as signalling molecules, or via mediating post-translational modifications (such as O-GlcNAcylation or β-hydroxybutyrylation). The review also identifies several critical unanswered questions regarding the characteristics (functional and metabolic) of macrophages from different origins (adipose tissue, skeletal muscle, bone marrow) in obesity and how these characteristics contribute to early vs late phases of obesity. We also identified a number of new therapeutic targets that could be evaluated in future investigations. Targeting macrophage metabolism in obesity is an exciting and active area of research with significant potential to help identify new treatments to limit the detrimental effects of inflammation in obesity.

Keywords:  Obesity; energy metabolism; insulin resistance; macrophage; polarization

DOI:  https://doi.org/10.1016/j.cjca.2025.04.017
Cell Mol Immunol. 2025 Apr 30.

Updated insights into the molecular networks for NLRP3 inflammasome activation.

Seungwha Paik, Jin Kyung Kim, Hyo Jung Shin, Eun-Jin Park, In Soo Kim, Eun-Kyeong Jo.

  Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.

Keywords:  Inflammatory disease; Licensing; NLRP3 inflammasome; Post-translational modification (PTM); Pyroptosis; Spatiotemporal

DOI:  https://doi.org/10.1038/s41423-025-01284-9
Endocr Pract. 2025 Apr 25. pii: S1530-891X(25)00134-X. [Epub ahead of print]

Impact of the Addition of Beta-Hydroxybutyrate in the 72-Hour Fast Protocol on Hospitalization Duration: A Quality Improvement Report.

Michelle D Lundholm, Dianna Jo Copley, Vinni Makin, Pratibha Pr Rao.

   OBJECTIVES: The 72-hour fast is the gold standard test for detecting insulinoma but imposes significant burdens on patients and expends hospital resources. Balancing diagnostic accuracy with patient comfort and cost remains challenging. We aimed to leverage the metabolic indicator beta-hydroxybutyrate (BHB), indicative of insulin suppression, to curtail inpatient fasting time without missing insulinoma cases.
METHODS: Our institution implemented an inpatient 72-hour fast protocol in 2018, and updated the protocol in 2020 to include a BHB >2.7 mmol/L stopping criterion. In this quality improvement and patient safety project, we retrospectively reviewed all patients who completed a 72-hour fast at our institution by the original (January 2018-June 2020) and updated (June 2020-December 2022) protocols.
RESULTS: Sixty-four patients (78% female, mean age 48±17 years) underwent fasting: 34 patients by the original protocol and 30 patients by the revised protocol. The original protocol had an average fast duration of 57.6 hours (median 72 hours, IQR [49,72]). After the update, 50% (N=15) ended for BHB >2.7 mmol/L, with an average fast duration of 49.7 hours (median 53 hours, IQR [39.1, 71.8], p=0.03). This reduced cumulative inpatient fasting by 376.5 hours and reduced medical costs. All insulinoma cases (N=7) developed hypoglycemia within 43 hours with BHB ≤1.2 mmol/L; no cases were missed.
CONCLUSIONS: Adding a BHB >2.7 mmol/L stopping criterion reduced inpatient hospitalization time, medical costs, and patient burden without compromising insulinoma detection. This evidence-based intervention improves patient adherence and more effectively utilizes hospital resources.

Keywords:  beta-hydroxybutyrate; fasting; hypoglycemia; insulinoma; quality improvement

DOI:  https://doi.org/10.1016/j.eprac.2025.04.015
J Cell Sci. 2025 May 01. pii: jcs263403. [Epub ahead of print]138(9):

Mitochondria - the CEO of the cell.

Laurie P Lee-Glover, Martin Picard, Timothy E Shutt.

  As we have learned more about mitochondria over the past decades, including about their essential cellular roles and how altered mitochondrial biology results in disease, it has become apparent that they are not just powerplants pumping out ATP at the whim of the cell. Rather, mitochondria are dynamic information and energy processors that play crucial roles in directing dozens of cellular processes and behaviors. They provide instructions to enact programs that regulate various cellular operations, such as complex metabolic networks, signaling and innate immunity, and even control cell fate, dictating when cells should divide, differentiate or die. To help current and future generations of cell biologists incorporate the dynamic, multifaceted nature of mitochondria and assimilate modern discoveries into their scientific framework, mitochondria need a 21st century 'rebranding'. In this Opinion article, we argue that mitochondria should be considered as the 'Chief Executive Organelle' - the CEO - of the cell.

Keywords:  Mitochondria; Organelle; mtDNA

DOI:  https://doi.org/10.1242/jcs.263403
Domest Anim Endocrinol. 2025 Apr 21. pii: S0739-7240(25)00034-7. [Epub ahead of print]92 106945

Involvement of cholesterol and ketone bodies in early stages of bovine cystic ovarian disease development.

F M Rodríguez, M L Cattaneo Moreyra, N C Gareis, G J Hein, E Angeli, A F Stassi, H H Ortega, N R Salvetti, F Rey.

  Cystic ovarian disease (COD), characterized by the presence of persistent follicles, is a major cause of subfertility in dairy cows. This study aimed to evaluate the expression of receptors and enzymes involved in ketone body metabolism, cholesterol regulation, and steroidogenesis within ovarian follicular cells at different stages of persistence. The study was conducted in a model of follicular persistence induced by prolonged progesterone administration in dairy cows, and in cows diagnosed with spontaneous COD. The protein levels of key components, including HMG-CoA reductase, mitochondrial HMG-CoA (mHMG-CoA) synthase, SCOT, LDL-R, SRB-1, CYP17A1, CYP19A1, StAR, and 3βHSD, was assessed in follicles through immunohistochemistry. Additionally, total cholesterol, HDL cholesterol, LDL cholesterol concentrations in follicular fluid and plasma were measured using a biochemical autoanalyzer, while β-hydroxybutyrate (BHB) levels were evaluated with reactive strips. Results showed that protein levels of SRB-1 and LDL-R in granulosa cells was higher in cows in late stages of follicular persistence and COD cows than in the control group (P < 0.05). In contrast, mHMG-CoA synthase, HMG-CoA reductase and SCOT revealed an opposite pattern (P < 0.05). In granulosa cells, CYP19A1 levels were lower in follicles with 5 days of persistence than in control follicles and 3βHSD levels were higher in late stages of persistence than in controls. These alterations evidenced an imbalance in relevant components of lipid metabolism and steroidogenesis. Changes observed in late persistence or cyst would be a consequence of follicular persistence contributing to subfertility in cattle.

Keywords:  Cholesterol; Cyst; Follicular persistence; Lipid metabolism

DOI:  https://doi.org/10.1016/j.domaniend.2025.106945
Nutrients. 2025 Apr 17. pii: 1364. [Epub ahead of print]17(8):

Acute Effect of High-Intensity Interval Training on Postprandial Glycemia in Overweight and Obese Individuals: A Scoping Review.

Hugo Alejandro Carrillo-Arango, David Alejandro Gonzalez, Leidy Tatiana Ordoñez-Mora, Miguel Alejandro Atencio-Osorio, Héctor Reynaldo Triana-Reina, Mikel Izquierdo.

   BACKGROUND/OBJECTIVES: High-intensity interval training (HIIT) has emerged as an effective strategy for mitigating postprandial glycemia in overweight or obese individuals. This scoping review aims to examine randomized controlled trials (RCTs) conducted between 2008 and 2024 that evaluated the impact of HIIT on acute postprandial glycemic response.
METHODS: A comprehensive search strategy was employed using terms such as "high-intensity interval training (HIIT)" and "postprandial glycemia", combined with Boolean operators, with no restrictions on study type. Electronic databases searched included PubMed, SPORTDiscus, Scopus, and Web of Science from their inception through 2024. Of the 67 studies that met the inclusion criteria, five RCTs were selected for final analysis. All selected studies involved individuals with a body mass index (BMI) ≥ 25.
RESULTS: Each of the five included RCTs featured at least one HIIT intervention group, with variations in frequency, duration, intensity, and testing protocols. Despite differences in glucose tolerance test timelines, the glucose-loading protocol (75 g) and exercise interventions demonstrated minimal heterogeneity across studies. The findings suggest that short-term HIIT interventions may positively influence acute postprandial glycemic responses in overweight and obese populations.
CONCLUSIONS: Short-term HIIT appears to be a promising intervention for improving postprandial glycemic control in individuals with elevated BMI. Future research is warranted to further elucidate both the acute and long-term effects of HIIT, particularly the role of skeletal muscle in regulating systemic glucose levels in this population.

Keywords:  blood glucose; diabetes; exercise; glycaemia; postprandial; review

DOI:  https://doi.org/10.3390/nu17081364
Commun Med (Lond). 2025 Apr 27. 5(1): 141

Mitochondrial complex I deficiency occurs in skeletal muscle of a subgroup of individuals with Parkinson's disease.

Simon Ulvenes Kverneng, Kjersti Eline Stige, Haakon Berven, Sepideh Mostafavi, Katarina Lundervold, Michele Brischigliaro, Brage Brakedal, Geir Olve Skeie, Irene Hana Flønes, Lilah Toker, Erika Fernandez-Vizarra, Ragnhild Eide Skogseth, Kristoffer Haugarvoll, Yamila N Torres Cleuren, Christian Dölle, Gonzalo S Nido, Charalampos Tzoulis.

BACKGROUND: Widespread neuronal mitochondrial complex I (CI) deficiency was recently reported to be a characteristic in a subgroup of individuals with idiopathic Parkinson's disease (PD). Here, we sought to determine whether a CI-deficient subgroup could be discerned using clinically accessible muscle biopsies. We further hypothesized that the inconsistency of previous findings of mitochondrial respiratory impairment in PD muscle may be due to interindividual variation, with respiratory deficiency only occurring in a subgroup of cases.
METHODS: Using a cross-sectional design, vastus lateralis needle biopsies were collected from 83 individuals with PD and 29 neurologically healthy controls and analyzed by immunohistochemistry for CI and complex IV (CIV), cytochrome c oxidase/succinate dehydrogenase (COX/SDH) histochemistry, and spectrophotometric activity assays of complexes I-IV. Mitochondrial DNA (mtDNA) copy number, deletions, and point variation were analyzed in single muscle fibers and bulk biopsy samples.
RESULTS: We show that PD muscle exhibits reduced CI activity at the group level, with 9% of cases falling below two standard deviations of the control group. In contrast, the activities of CII-CIV are not significantly different between the PD and control groups. No quantitative change of CI or CIV is detected, and the observed functional CI deficiency is not associated with mtDNA abnormalities.
CONCLUSIONS: Our findings support the existence of a PD subpopulation characterized by CI pathology in skeletal muscle and suggest that stratification by extra-neural mitochondrial dysfunction may be informative for selecting individuals for clinical trials.

DOI: https://doi.org/10.1038/s43856-025-00817-7
Aging Biol. 2023 ;pii: e20230004. [Epub ahead of print]1

How Much Should We Fast? A New Study by the Fontana Group Suggests That Intermittent Fasting May Be Too Mild for Humans.

Vera Gorbunova.

DOI: https://doi.org/10.59368/agingbio.20230004
Contact (Thousand Oaks). 2025 Jan-Dec;8:8 25152564251332141

Mitochondria-Plasma Membrane Contact Sites: Emerging Regulators of Mitochondrial Form and Function.

Jason C Casler, Matilde V Neto, Thomas Burgoyne, Laura L Lackner.

  Sites of close apposition between organelles, known as membrane contact sites (MCSs), are critical regulators of organelle function. Mitochondria form elaborate reticular networks that perform essential metabolic and signaling functions. Many mitochondrial functions are regulated by MCSs formed between mitochondria and other organelles. In this review, we aim to bring attention to an understudied, but physiologically important, MCS between mitochondria and the plasma membrane (PM). We first describe the molecular mechanism of mitochondria-PM tethering in budding yeast and discuss its role in regulating multiple biological processes, including mitochondrial dynamics and lipid metabolism. Next, we discuss the evidence for mitochondria-PM tethering in higher eukaryotes, with a specific emphasis on mitochondria-PM contacts in retinal cells, and speculate on their functions. Finally, we discuss unanswered questions to guide future research into the function of mitochondria-PM contact sites.

Keywords:  cell biology; electron microscopy; interorganelle (inter-organelle); membrane contact sites (MCSs)‌; mitochondrion (mitochondria); plasma membrane

DOI:  https://doi.org/10.1177/25152564251332141
J Cardiovasc Aging. 2025 ;5(1):

Geroscience in heart failure: the search for therapeutic targets in the shared pathobiology of human aging and heart failure.

Claire Castro, Constance Delwarde, Yanxi Shi, Jason Roh.

  Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat age-associated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.

Keywords:  Translational research; aging biology; genomics; geroscience; heart failure; proteomics

DOI:  https://doi.org/10.20517/jca.2024.15
J Cachexia Sarcopenia Muscle. 2025 Jun;16(3): e13775

Mitochondrial Sensitivity to Submaximal [ADP] Following Bed Rest: A Novel Two-Phase Approach Associated With Fibre Types.

Lucrezia Zuccarelli, Maria De Martino, Antonio Filippi, Alice E Knapton, Benjamin D Thackray, Giovanni Baldassarre, Boštjan Šimunič, Rado Pišot, Giuseppe Sirago, Elena Monti, Marco Narici, Miriam Isola, Andrew J Murray, Giovanna Lippe, Bruno Grassi.

   BACKGROUND: We recently demonstrated that following a 10-day exposure to inactivity/simulated microgravity impairments of oxidative metabolism were located 'upstream' of mitochondrial function, as evaluated by maximal ADP-stimulated mitochondrial respiration (JO2max) determined ex vivo. The aim of this study was to evaluate mitochondrial sensitivity to submaximal [ADP] by an alternative approach aimed at identifying responses associated with fibre type composition.
METHODS: Isolated permeabilized vastus lateralis fibres were analysed by high-resolution respirometry in 9 young males before and after a 10-day horizontal bed rest. Eleven submaximal titrations of ADP (from 12.5 to 10 000 μM) were utilized to assess complex I + II-linked ADP sensitivity. We applied to JO2 versus [ADP] data a traditional Michaelis-Menten kinetics equation, with the calculation of the apparent Km and maximal respiration (Vmax), and two 'sequential' hyperbolic equations, yielding two Km and Vmax values. The two-hyperbolic equations were solved and the [ADP] value corresponding to 50% of JO2max was calculated. Isoform expression of myosin heavy chains (MyHC) 1, 2A and 2X was also determined. Control experiments were also carried out on rat skeletal muscle samples with different percentages of MyHC isoforms.
RESULTS: The two hyperbolic equations provided an alternative fitting of data and identified two distinct phases of the JO2 versus [ADP] response: a first phase characterized by low Vmax (Vmax1, 28 ± 10 pmol s-1 mg-1) and apparent Km (Km1, 62 ± 54 μM) and a second phase characterized by higher Vmax (Vmax2, 61 ± 16 pmol s-1 mg-1) and Km (Km2, 1784 ± 833 μM). Data were confirmed in control experiments carried out in rat muscle samples with different percentages of MyHC isoforms. Correlation and receiver operating characteristics analyses suggest that the two phases of the response were related to the % of MyHC isoforms.
CONCLUSIONS: A novel mathematical approach (two sequential hyperbolic functions) for the fitting of JO2 versus [ADP] data obtained by high-resolution respirometry on permeabilized skeletal muscle fibres, obtained in humans and rats, provided an alternative fitting of the experimental data compared to the traditional Michaelis-Menten kinetics equation. This alternative model allowed the identification of two distinct phases in the responses, which were related to fibre type composition. A first phase, characterized by low apparent Km and Vmax values, was correlated with the percentage of less oxidative (Type 2A + 2X) MyHC isoforms. A second phase, characterized by high apparent Km and Vmax, was related to more oxidative (Type 1) MyHC isoforms.

Keywords:  ADP; bed rest; mitochondrial sensitivity; myosin heavy chains; skeletal muscle mitochondria

DOI:  https://doi.org/10.1002/jcsm.13775
J Clin Res Pediatr Endocrinol. 2025 Apr 30.

Association between Circulating Amino Acids and Childhood Obesity: A Systematic Review and Meta-Analysis.

Yingli Si, Tingting Zhang, Xiangyu Wang.

  This systematic review and meta-analysis aim to synthesize the existing literature to clarify the role of amino acids as potential indicators or contributors to childhood obesity. The study follows the PRISMA 2020 guidelines. A comprehensive search was conducted across multiple electronic databases, including PubMed, Cochrane Library, Embase, Web of Science, Google Scholar, Semantic Scholar, and ResearchRabbit, using relevant keywords such as "childhood obesity," "amino acids," and "branched-chain amino acids (BCAAs)."Heterogeneity among studies was assessed using the chi-square test and the I² statistic. Publication bias was evaluated using funnel plots and Egger's test. Five studies involving a total of 1,229 participants met the inclusion criteria. A significant association was observed between amino acid levels and obesity in children. Specifically, glutamine was inversely associated with obesity (SMD = -0.48, 95% CI: -0.85 to -0.11), while leucine (SMD = 0.79, 95% CI: 0.20 to 1.38) and valine (SMD = 0.67, 95% CI: 0.18 to 1.15) were positively associated. Additionally, odds ratio analysis indicated that higher glutamine levels were associated with 56% lower odds of obesity (OR = 0.44, 95% CI: 0.21-0.94, P < .01), suggesting a potential protective role. Elevated levels of specific amino acids, particularly BCAAs, were consistently linked to increased body mass index (BMI) and other obesity-related indicators in children. Future research should focus on longitudinal and interventional studies to better understand these associations and explore targeted strategies involving amino acid metabolism to help prevent and manage childhood obesity.

Keywords:  amino acids; branched-chain amino acids (BCAA); childhood obesity; metabolomics

DOI:  https://doi.org/10.4274/jcrpe.galenos.2025.2024-11-11
Antioxid Redox Signal. 2025 Apr 26.

Modes of Mitochondrial Reactive Oxygen Species Production in Inflammation.

Miguel González-Hernández, Laura Gallardo-Andalucía, Pablo Hernansanz-Agustín.

  Background: Inflammation is one of the most important pathways in innate immunity and its relationship with redox biology is becoming increasingly clear in the last decades. However, the specific redox modes and pathways by which inflammation is produced are not yet well defined. Significance: In this review, we provide a general explanation of the reactive oxygen species (ROS) production and quenching modes occurring in mammalian mitochondria, as well as a summary of the most recent advances in mitochondrial redox biology and bioenergetics regarding sodium (Na+) homeostasis. In addition, we provide a collection of examples in which several inflammatory pathways have been associated with specific modes of either mitochondrial ROS production or quenching. Innovation: The role of Na+ in mitochondrial biology is being developed. Since its discovery as a second messenger, the research of its role in the immune system has emerged. Now, the role of Na+ in mitochondrial bioenergetics has recently been identified, which owns unprecedented applications. The potential implication of Na+ in inflammatory mechanisms grows as its role does not only cover ROS production and respiration but also the control through the management of mitochondrial membrane potential. Future directions: Na+ is becoming relevant for mitochondrial biology. Thus, processes regarding mitochondrial bioenergetics, redox state, or metabolism may probably need to include the study of Na+ in their road map. Some of these pathways are involved in inflammation and more are possibly to come. This review is expected to serve as a bridge between both fields. Antioxid. Redox Signal. 00, 000-000.

Keywords:  ROS; antioxidant system; bioenergetics; inflammation; mitochondria; sodium

DOI:  https://doi.org/10.1089/ars.2024.0737
Scand J Med Sci Sports. 2025 May;35(5): e70059

Fiber Type-Specific Adaptations to Exercise Training in Human Skeletal Muscle: Lessons From Proteome Analyses and Future Directions.

Morten Hostrup, Atul S Deshmukh.

  Skeletal muscle is a key determinant of sports performance. It is a highly specialized, yet complex and heterogeneous tissue, comprising multiple cell types. Muscle fibers are the main functional cell type responsible for converting energy into mechanical work. They exhibit a remarkable ability to adapt in response to stressors, such as exercise training. But while it is recognized that human skeletal muscle fibers have distinct contractile and metabolic features, classified as slow/oxidative (type 1) or fast/glycolytic (type 2a/x), less attention has been directed to the adaptability of the different fiber types. Methodological advancements in mass spectrometry-based proteomics allow researchers to quantify thousands of proteins with only a small amount of muscle tissue-even in a single muscle fiber. By exploiting this technology, studies are emerging highlighting that muscle fiber subpopulations adapt differently to exercise training. This review provides a contemporary perspective on the fiber type-specific adaptability to exercise training in humans. A key aim of our review is to facilitate further advancements within exercise physiology by harnessing mass spectrometry proteomics.

Keywords:  athletes; exercise; muscle adaptations; physical activity; proteomics; training

DOI:  https://doi.org/10.1111/sms.70059
Front Physiol. 2025 ;16 1549609

The role of resistance exercise-induced local metabolic stress in mediating systemic health and functional adaptations: could condensed training volume unlock greater benefits beyond time efficiency?

Ivan Curovic.

  The majority of "specialised" exercise configurations (e.g., supersets, drop sets, blood flow restriction) are being assessed as "shortcuts" to hypertrophy and strength improvements. However, these advanced training techniques may also offer significant benefits for systemic health and functional outcomes across recreational and clinical populations via locally induced metabolic responses. Stress-regulating mechanisms are known to enhance the body's resilience by facilitating allostasis, the process of coordinating adaptive processes in reaction to stressors such as physical training. Yet, the role of the local metabolic stress provoked by resistance exercise has not gained much research attention despite its wide potential. Positive effects are not only linked to improved muscular endurance, hypertrophy and strength via primary and secondary mechanisms, but also to the release of myokines, hormones, microRNAs, immune factors, inflammatory substances and other endocrine molecules that initiate numerous health-promoting modifications on a systemic level. Resistance exercise strategies that maximise the local accumulation of metabolites are not well defined, although high volume, close proximity to failure and shorter rests seem to be a necessity. Additionally, blood flow restriction training provides a potent alternative for inducing local acidosis, thereby triggering several pathways associated with improved immunity and physical function even in remote muscle tissues. Future research is warranted to further explore advanced resistance training techniques, as these approaches may offer comparable benefits for physical and mental health to those seen with other forms of exercise such as high-intensity interval training and heavy resistance training.

Keywords:  anaerobic; blood flow restriction; hypertrophy; lactate; muscular endurance; strength; superset

DOI:  https://doi.org/10.3389/fphys.2025.1549609
Am J Clin Nutr. 2025 Apr 25. pii: S0002-9165(25)00236-9. [Epub ahead of print]

Resistance training increases myofibrillar protein synthesis in middle-to-older aged adults consuming a typical diet with no influence of protein source: a randomized controlled trial.

Marie Korzepa, Jonathan I Quinlan, Ryan N Marshall, Lucy M Rogers, Archie E Belfield, Yasir S Elhassan, Alex Lawson, Chloe Ayre, Joan M Senden, Joy Pb Goessens, Elisa I Glover, Gareth A Wallis, Luc Jc van Loon, Leigh Breen.

   BACKGROUND: The primary protein source of a diet may impact skeletal muscle maintenance with advancing age. The impact of the animal and plant protein content of a typical protein-containing diet on muscle anabolism in middle-to-older aged adults is unknown.
OBJECTIVES: To determine muscle adaptive remodelling response to a 10-day dietary intervention containing divergent protein sources, with and without resistance exercise training (RET) in middle-to-older aged adults.
METHODS: In a single-blind randomized control trial, twenty-seven 50-70-year-old participants consumed 1.0g·kg BM-1·day-1 of protein from an animal-focused whey protein-supplemented diet (AW-D) or plant-focused pea protein-supplemented diet (PP-D). Throughout the 10-day diet intervention, unilateral knee extensor RET was performed every other day. Deuterated water ingestion and skeletal muscle biopsies enabled measurement of daily integrated myofibrillar protein synthesis (iMyoPS) rates in the trained, and untrained legs. Changes in metabolic rate, body composition, lipid profiles, renal function, whole-body nitrogen balance (WBNB), strength and muscle architecture were also determined.
RESULTS: Daily iMyoPS rates were significantly greater (P<0.001) in the trained compared to the untrained leg for AW-D (1.44 ± 0.26 vs 1.29 ± 0.27 %⋅day-1) and PP-D (1.50 ± 0.17 vs 1.34 ± 0.21 %⋅day-1) with no differences between groups, within leg. Training and diet did not affect intracellular anabolic signalling, muscle architecture, strength, metabolic rate, renal function or WBNB. Serum non-HDL cholesterol was significantly (P=0.014) lower following the intervention for PP-D only (pre: 3.89 ± 0.84, post 3.37 ± 0.78 mmol⋅L) with no other changes in lipid profiles.
CONCLUSIONS: The 10-day provision of 1.0g·kg BM-1·day-1 from predominantly plant-derived or animal-derived protein does not influence daily iMyoPS rates in middle-to-older aged adults and has little impact on metabolic and renal health parameters. RET enhances rates of daily iMyoPS in middle-to-older aged adults consuming a typical protein-containing diet, with no influence of protein source.
CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov NCT05574205 https://clinicaltrials.gov/study/NCT05574205.

Keywords:  animal protein; human physiology; muscle anabolism; plant protein; resistance exercise; sarcopenia

DOI:  https://doi.org/10.1016/j.ajcnut.2025.04.019
Front Sports Act Living. 2025 ;7 1601326

Editorial: Preventing sarcopenia and promoting musculoskeletal health in middle-aged adults: the role of exercise and nutrition.

Theocharis Ispoglou, Catherine Norton, Deaglan McCullough.



Keywords:  anabolic resistance; gender-specific barriers; gut-muscle axis; middle-aged adults; muscle protein synthesis; resistance training; sarcopenia; ultra-processed foods

DOI:  https://doi.org/10.3389/fspor.2025.1601326