bims-kimdis 2025-04-06 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–04–06
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging.
Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.
Effects of One-Month Very-Low-Calorie Ketogenic Diet on 24 h Energy Metabolism and Body Composition in Women with Obesity.
Hyperpolarized 13C-MRS can Quantify Lactate Production and Oxidative PDH Flux in Murine Skeletal Muscle During Exercise.
Effects of aging on calcium channels in skeletal muscle.
Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.
Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.
Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training.
Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice.
Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.
Butyrate improves handgrip strength and physical performance by reducing intestinal leak in post-menopausal women, a randomized controlled trial.
Alternate Day Fasting Enhances Intestinal Epithelial Function During Aging by Regulating Mitochondrial Metabolism.
Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential.
Mitochondrial heat production: the elephant in the lab….
Extinction of the human species: What could cause it and how likely is it to occur?
Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.
Anti-sarcopenic effects of active vitamin D through modulation of anabolic and catabolic signaling pathways in human skeletal muscle: A randomized controlled trial.
Exploring the mitigating potential of anthocyanin Malvidin in a mouse model of bleomycin-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and oxidative stress.
Predicting resting energy expenditure.
Three-Dimensional Analysis of Skeletal Muscle Stem Cell Niche Following Tissue Clearing.
Medium-chain triglyceride attenuates obesity by activating brown adipose tissue via upregulating the AMPK signaling pathway.
Nutritional modulation of the mTORC1 pathway in muscle: differential effect according to muscle and sex.

bioRxiv. 2025 Mar 19. pii: 2025.03.18.643760. [Epub ahead of print]

Ketone Catabolism is Essential for Maintaining Normal Heart Function During Aging.

Mariko Aoyagi Keller, Michinari Nakamura.

The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. The cardiac expression of succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme in ketolysis, decreases with aging in female mice. SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cKO mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.

DOI: https://doi.org/10.1101/2025.03.18.643760
J Physiol. 2025 Apr 03.

Ketogenic diet and ketone salts differentially improve cardiometabolic complications in an HFpEF rat model.

Alexandre Gonçalves, Inês N Alves, Cláudia Mendes, Daniela Miranda, Glória Conceição, João Almeida-Coelho, Diana Martins, Isabel Miranda, Alexandre Rodrigues, Carolina Silva, Sandra Marisa Oliveira, José Sereno, Maria João Ferreira, Ulrich Dischinger, Henrique Girão, Adelino F Leite-Moreira, Vasco Sequeira, Inês Falcão-Pires.

  Heart failure with preserved ejection fraction (HFpEF) remains a major health concern with limited therapeutic options. Growing evidence supports the multiple benefits of ketones in heart disease, but their impact on HFpEF remains unknown. We investigated whether increasing ketones can help to manage HFpEF. Using the ZSF1 rat model of HFpEF, 16-week-old rats were randomly assigned to one of three subgroups: (i) control diet; (ii) ketogenic diet (KD); or (iii) control diet with added exogenous ketone salts (KS) in their drinking water for 10 weeks. We found that both KD and KS ameliorated the HFpEF phenotype by improving structural echocardiographic parameters, lowering glycaemia and lipid profiles, and reducing HFpEF-related fibrosis and hypertrophy without impacting in vivo diastolic function. Nevertheless, ex vivo cardiomyocyte preparations showed improved calcium handling and myofilament relaxation, suggesting benefits at the cellular level. Interestingly, KD still proved effective, despite the potentially adverse increase in fat mass. There was decreased myofilament Ca2+ sensitivity and normalized active and passive tension in both groups, especially KS. These results suggest that providing ketone through the diet or supplements could be a valuable strategy to complement HFpEF treatment. Given the well-known challenges of implementing dietary changes, exogenous KS offer a more practical and effective option to achieve these benefits. KEY POINTS: Ketogenic diet and ketone salts effectively reversed the cardiac structural impairments associated with the ZSF1 Obese heart failure with preserved ejection fraction (HFpEF) phenotype by ameliorating left ventricular mass. Both treatments reduced fibrosis and hypertrophy, leading to improved or, in the case of ketone salts, even reversed cardiomyocyte contractile and relaxation performance. Ketone salts also reversed HFpEF-related cardiomyocyte stiffness and prevented a reduction in the development of maximum force. Both treatments improved myofilament Ca2+ sensitivity. Both treatments also improved the metabolic profile, reducing hyperglycaemia, blood triglycerides and levels of NT-proBNP, a well-known biomarker of worsening heart failure.

Keywords:  heart failure; heart failure with preserved ejection fraction; ketogenic diet; ketone salts; ketones

DOI:  https://doi.org/10.1113/JP288229
J Clin Endocrinol Metab. 2025 Apr 02. pii: dgaf196. [Epub ahead of print]

Effects of One-Month Very-Low-Calorie Ketogenic Diet on 24 h Energy Metabolism and Body Composition in Women with Obesity.

Alessio Basolo, Paolo Piaggi, Valentina Angeli, Paola Fierabracci, Chiara Bologna, Edda Vignali, Daniela Troiani, Roberta Jaccheri, Caterina Pelosini, Melania Paoli, Guido Salvetti, Luca Chiovato, Jonathan Krakoff, Alberto Landi, Ferruccio Santini.

   CONTEXT: Very-low-calorie ketogenic diet (VLCKD) is used for weight loss and management of obesity-related comorbidities.
OBJECTIVE: We aimed at evaluating the effects of VLCKD on body composition and energy metabolism.
METHODS: This prospective outpatient study included 17 women with obesity (mean age 41.6 yrs; BMI 37.5 kg/m2) who followed a 1-month VLCKD (700-800 kcal/day, CHO 11%, fat 46%, protein 43%) at the University Hospital of Pisa. Measurements of 24-hour energy expenditure (24hEE) and substrate oxidation were conducted in a metabolic chamber at day 1 (V1), day 8 (V2), and day 29 (V3). Body composition was assessed by DXA. Twenty-two women with obesity fed a balanced isocaloric diet served as controls.
RESULTS: Compared to controls, carbohydrate oxidation (CarbOx) was lower, whereas fat oxidation (FatOx) and protein oxidation (ProtOx) were higher in the VLCKD group at V1. CarbOx decreased by 65%, while FatOx increased by 11% at V3. The rate of protein oxidation was already higher than in controls at V1 and remained stable throughout the study. After 1 month, body weight decreased by 7%, reflecting an 8.8% reduction in fat mass (FM) and a 5.6% reduction in lean soft tissue (LST). A 10% decrease in 24hEE and 24 h sleeping metabolic rate was observed at V3 compared to V1.
CONCLUSION: VLCKD promotes weight loss in women with obesity. Our findings highlight the shift in energy metabolism towards increased fat oxidation accompanied by a modest increase in protein oxidation, a decrease in LST and a reduction in EE.

Keywords:  Ketogenic diet; energy expenditure; obesity; respiratory exchange ratio

DOI:  https://doi.org/10.1210/clinem/dgaf196
NMR Biomed. 2025 May;38(5): e70020

Hyperpolarized 13C-MRS can Quantify Lactate Production and Oxidative PDH Flux in Murine Skeletal Muscle During Exercise.

M Kate Curtis, Jordan J McGing, Brianna J Stubbs, Vicky Ball, Lowri E Cochlin, David P O'Neill, Christoffer Laustsen, Mark A Cole, Peter A Robbins, Damian J Tyler, Jack J Miller.

  Existing techniques for the non-invasive in vivo study of dynamic changes in skeletal muscle metabolism are subject to several limitations, for example, poor signal-to-noise ratios which result in long scan times and low temporal resolution. Hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopy (HP-MRS) allows the real-time visualization of in vivo metabolic processes and has been used extensively to study cardiac metabolism, but has not resolved oxidative phosphorylation in contracting skeletal muscle. Combining HP-MRS with an in vivo muscle hindlimb electrical stimulation protocol that modelled voluntary exercise to exhaustion allows the simultaneous real-time assessment of both metabolism and function. The aim of this work was to validate the sensitivity of the method by assessing pyruvate dehydrogenase (PDH) flux in resting vs. working muscle: measuring the production of bicarbonate (H13CO3 -), a byproduct of the PDH-catalysed conversion of [1-13C]pyruvate to acetyl-CoA. Mice (n = 6) underwent two hyperpolarized [1-13C]pyruvate injections with 13C MR spectra obtained from the gastrocnemius muscle to measure conversion of pyruvate to lactate and bicarbonate, one before the stimulation protocol with the muscle in a resting state and one during the stimulation protocol. The muscle force generated during stimulation was also measured, and 13C MRS undertaken at a point of ~50% fatigue. We observed an increase in the bicarbonate/pyruvate ratio by a factor of ~1.5×, in the lactate/pyruvate ratio of ~2.7×, together with an increase in total carbon (~1.5×) that we attribute to perfusion. This demonstrates profound differences in metabolism between the resting and exercising states. These data therefore serve as preliminary evidence that hyperpolarized 13C MRS is an effective in vivo probe of PDH flux in exercising skeletal muscle and could be used in future studies to examine changes in muscle metabolism in states of disease and altered nutrition.

Keywords:  13C MRS; hyperpolarized 13C; magnetic resonance; mouse models; muscle metabolism

DOI:  https://doi.org/10.1002/nbm.70020
Front Mol Biosci. 2025 ;12 1558456

Effects of aging on calcium channels in skeletal muscle.

Mingyi Dong, Andrés Daniel Maturana.

  In skeletal muscle, calcium is not only essential to stimulate and sustain their contractions but also for muscle embryogenesis, regeneration, energy production in mitochondria, and fusion. Different ion channels contribute to achieving the various functions of calcium in skeletal muscles. Muscle contraction is initiated by releasing calcium from the sarcoplasmic reticulum through the ryanodine receptor channels gated mechanically by four dihydropyridine receptors of T-tubules. The calcium influx through store-operated calcium channels sustains the contraction and stimulates muscle regeneration. Mitochondrial calcium uniporter allows the calcium entry into mitochondria to stimulate oxidative phosphorylation. Aging alters the expression and activity of these different calcium channels, resulting in a reduction of skeletal muscle force generation and regeneration capacity. Regular physical training and bioactive molecules from nutrients can prevent the effects of aging on calcium channels. This review focuses on the current knowledge of the effects of aging on skeletal muscles' calcium channels.

Keywords:  aging; calcium; ion channels; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fmolb.2025.1558456
Sci Adv. 2025 Apr 04. 11(14): eadt4955

Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.

Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.

Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt4955
Exp Physiol. 2025 Mar 30.

Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.

Zoe P Libramento, Louisa Tichy, Traci L Parry.

  Cancer cachexia (CC) is a multifactorial disease marked by a severe and progressive loss of lean muscle mass and characterized further by inflammation and a negative energy/protein balance, ultimately leading to muscle atrophy and loss of muscle tissue. As a result, patients experiencing cachexia have reduced muscle function and thus less independence and a lower quality of life. CC progresses through stages of increasing severity: pre-cachexia, cachexia and refractory cachexia. Two proposed underlying mechanisms that drive cancer-induced muscle wasting are the autophagy-lysosome and ubiquitin-proteasome systems. An increase in autophagic flux and proteolytic activity leads to atrophy of both cardiac and skeletal muscle, ultimately mediated by tumour or immune-secreted inflammatory cytokines. These pathways occur at a basal level to maintain cellular homeostasis; therefore, it is the overactivation of the pathways that leads to muscle atrophy. Recent evidence demonstrates the ability of aerobic and resistance training to restore these pathways to their basal levels. The mechanism is not yet understood, and more research is needed to determine exactly how exercise influences each pathway. However, exercise has great promise as a therapeutic strategy for CC because of the evidence for it preserving muscle mass and function, and attenuating protein degradative pathways. The extent to which exercise affects the ubiquitin-proteasome and autophagy-lysosome systems is determined by the frequency, intensity and duration of the exercise protocol. As such, an ideal exercise prescription is lacking for individuals with CC.

Keywords:  atrophy; cancer cachexia; exercise

DOI:  https://doi.org/10.1113/EP092544
J Physiol. 2025 Apr 04.

Human skeletal muscle possesses both reversible proteomic signatures and a retained proteomic memory after repeated resistance training.

Juha J Hulmi, Eeli J Halonen, Adam P Sharples, Thomas M O'Connell, Lauri Kuikka, Veli-Matti Lappi, Kari Salokas, Salla Keskitalo, Markku Varjosalo, Juha P Ahtiainen.

  Investigating repeated resistance training (RT) separated by a training break enables exploration of the potential for a proteomic memory of RT-induced skeletal muscle growth, i.e. retained protein adaptations from the previous RT. Our aim was to examine skeletal muscle proteome response to 10-week RT (RT1) followed by 10-week training cessation (i.e. detraining, DT), and finally, 10-week retraining (RT2). Thirty healthy, untrained participants conducted either periodic RT (RT1-DT-RT2, n = 17) or a 10-week no-training control period (n = 13) followed by 20 weeks of RT (n = 11). RT included twice-weekly supervised whole-body RT sessions, and resting vastus lateralis biopsies were obtained every 10 weeks for proteomics analysis using high-end dia-PASEF's mass spectrometry. The first RT period altered 150 proteins (93% increased) involved in, for example, energy metabolism and protein processing compared to minor changes during the control period. The proteome adaptations were similar after the second RT compared to baseline demonstrating reproducibility in proteome adaptations to RT. Many of the proteins induced by RT1 were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Interestingly, several proteins which increased after RT1 remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and proteins involved in muscle contraction, cytoskeleton and calcium binding. Among the latter, calcium-activated protease calpain-2 (CAPN2) has been recently identified as an epigenetic muscle memory gene. We show that resistance training evokes retained protein levels even after 2.5 months of no training, which demonstrates a potential proteomic memory of resistance training-induced muscle growth in human skeletal muscle. KEY POINTS: Repeated resistance training in humans separated by a training break (i.e. detraining) enables the identification of temporal protein signatures over the training, detraining and retraining periods, as well as studying reproducibility of protein changes to resistance training. Muscle proteome adaptations were similar after a second period of resistance training, demonstrating reproducibility in proteome adaptations to earlier resistance training. Many of the proteins induced by resistance training were reversed towards baseline after detraining and increased again after retraining. These reversible proteins were especially involved in aerobic energy metabolism. Several proteins increased after resistance training remain elevated (i.e. retained) after detraining, including carbonyl reductase 1 (CBR1) and calcium-binding proteins such as calpain-2 (CAPN2), a recently identified epigenetic muscle memory gene. Human skeletal muscle experiences retained protein changes following resistance training persisting over 2 months, demonstrating a potential proteomic memory of resistance training-induced muscle growth.

Keywords:  CAPN2; CBR1; calpain‐2; detraining; hypertrophy; muscle memory; proteomics

DOI:  https://doi.org/10.1113/JP288104
Mol Cell Endocrinol. 2025 Mar 27. pii: S0303-7207(25)00084-X. [Epub ahead of print]602 112533

Obesity prevention by different exercise protocols (HIIT or MICT) involves beige adipocyte recruitment and improved mitochondrial dynamics in high-fat-fed mice.

Daiana Araujo Santana-Oliveira, Henrique Souza-Tavares, Aline Fernandes-da-Silva, Thatiany Souza Marinho, Flavia Maria Silva-Veiga, Julio Beltrame Daleprane, Vanessa Souza-Mello.

   AIM: This study evaluated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on UCP1-dependent and UCP1-independent thermogenic and mitochondrial dynamics markers in the inguinal sWAT of high-fat-fed mice.
METHODS: Sixty male C57BL/6 mice (3 months old) were divided into six experimental groups: control diet (C), C + HIIT (C-HIIT), C + MICT (C-MICT), high-fat diet (HF), HF + HIIT (HF-HIIT) and HF + MICT (HF-MICT). The diet and exercise protocols started simultaneously and lasted ten weeks.
RESULTS: HIIT and MICT prevented body mass gain and fat pad expansion, improved insulin sensitivity, and induced browning in C-fed and HF-fed animals. Chronic intake of a HF diet caused adipocyte hypertrophy with a proinflammatory adipokine profile and impaired the expression of thermogenic and mitochondrial dynamics markers. However, both exercise intensities increased anti-inflammatory adipokine concentrations and improved gene markers of mitochondrial dynamics, resulting in sustained UCP1-dependent and UCP1-independent thermogenic markers and maintenance of the beige phenotype in inguinal sWAT. The principal component analysis placed all trained groups opposite the HF group and near the C group, ensuring the effectiveness of HIIT and MICT to prevent metabolic alterations.
CONCLUSIONS: This study provides reliable evidence that, regardless of intensity, exercise is a strategy to prevent obesity by reducing body fat accumulation and inducing browning. The anti-inflammatory adipokine profile and the increased expression of UCP1-dependent and UCP1-independent thermogenic markers sustained active beige adipocytes and mitochondrial enhancement to halt metabolic disturbances due to HF-feeding in exercised mice.

Keywords:  Beige adipocyte; Browning; Exercise; HIIT; High-fat diet; Mitochondrial dynamics; Principal component analysis

DOI:  https://doi.org/10.1016/j.mce.2025.112533
Mitochondrion. 2025 Mar 27. pii: S1567-7249(25)00031-5. [Epub ahead of print]83 102034

Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.

Anders Gudiksen, Eva Zhou, Louise Pedersen, Catherine A Zaia, Cecilie E Wille, Elisabeth V Eliesen, Henriette Pilegaard.

  White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mitochondria are important sources of reactive oxygen species (ROS) and oxidative damage may potentially derail adipocyte function when mitochondrial homeostasis is challenged by overproduction of ROS. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α is a transcriptional co-activator that in skeletal muscle plays a central role in mitochondrial biogenesis and function but whether PGC-1α is equally important for mitochondrial function and adaptations in white adipose tissue remains to be fully resolved. The aim of the present study was to characterize the necessity of adipocyte PGC-1α for adaptive regulation of mitochondrial function in distinct white adipose depots. PGC-1α adipose tissue-specific knockout (ATKO) and floxed littermate control mice (CTRL) were subjected to either 24 h of fasting or 48 h of cold exposure. Bioenergetics, ROS handling, basal and adaptive protein responses, markers of protein damage as well as lipid cycling capacity and regulation were characterized in distinct WAT depots. ATKO mice demonstrated impairments in respiration as well as reduced OXPHOS protein content in fed and fasted conditions. Increased ROS emission in tandem with diminished mitochondrial antioxidant defense capacity resulted in increased protein oxidation in ATKO WAT. Adipose tissue PGC-1α knockout also led to changes in regulation of lipolysis and potentially triglyceride reesterification in WAT. In conclusion, PGC-1α regulates adipose tissue mitochondrial respiration and ROS balance as well as lipid cycling during metabolic challenges in a depot specific manner.

Keywords:  Bioenergetics; Cold exposure; Fasting; Mitochondria; PGC-1α; ROS; White adipose tissue

DOI:  https://doi.org/10.1016/j.mito.2025.102034
Eur J Nutr. 2025 Apr 01. 64(3): 141

Butyrate improves handgrip strength and physical performance by reducing intestinal leak in post-menopausal women, a randomized controlled trial.

Rizwan Qaisar, Hina Zuhra, Asima Karim, Firdos Ahmad.

   PURPOSE: Menopause is associated with muscle detriment and physical compromise. However, relevant mechanisms and effective interventions remain elusive. We investigated the therapeutic effects of exogenous butyrate administration on skeletal muscle and physical capacity with relevance to intestinal leak as a potential mechanism in post-menopausal women.
METHODS: We recruited post-menopausal women as placebo (age = 55.4 ± 3.3 years, n = 76) and butyrate (age = 54 ± 2.8 years, n = 70) groups, along with pre-menopausal women (age = 42.3 ± 3 years, n = 75) as controls. The butyrate group received sodium butyrate (570 mg capsules) daily for 12 weeks. We measured plasma biomarkers of intestinal leak (zonulin) and sepsis (lipopolysaccharide-binding protein, LBP) along with handgrip strength (HGS), gait speed, and physical performance (short physical performance battery, SPPB).
RESULTS: Post-menopausal women had higher zonulin and LBP and lower HGS, gait speed, and SPPB scores than pre-menopausal women (all p < 0.05). Butyrate reduced plasma zonulin and LBP levels and improved HGS and SPPB scores in post-menopausal women (all p < 0.05). We found significant correlations of reduction in plasma zonulin and LBP with improvement in HGS and SPPB in the butyrate group (all p < 0.05). Butyrate also modestly improved respiratory muscle strength and reduced systemic inflammation and oxidative stress in post-menopausal women (all p < 0.05).
CONCLUSION: Collectively, our findings demonstrate the muscle-protective effects of butyrate through intestinal mucosal repair. Future research is warranted to elucidate the underlying mechanisms of butyrate in post-menopausal women.

Keywords:  Butyrate; Handgrip strength; Intestinal permeability; LBP; Menopause; SPPB; Sarcopenia; Zonulin

DOI:  https://doi.org/10.1007/s00394-025-03656-3
Aging Cell. 2025 Apr 01. e70052

Alternate Day Fasting Enhances Intestinal Epithelial Function During Aging by Regulating Mitochondrial Metabolism.

Heng Quan, Yao Lu, Yingying Lin, Peng Xue, Yuning Zhang, Yuqi Wang, Weiru Yu, Xiaoya Lin, Wuqi Yang, Cong Lv, Yafei Zhang, Fazheng Ren, Huiyuan Guo.

  With advancing age, the decline in intestinal stem cell (ISC) function can lead to a series of degenerative changes in the intestinal epithelium, a critical factor that increases the risk of intestinal diseases in the elderly. Consequently, there is an urgent imperative to devise effective dietary intervention strategies that target the alterations in senescent ISCs to alleviate senescence-related intestinal dysfunction. The 28-month-old naturally aging mouse model was utilized to discover that the primary factor contributing to the compromised barrier function and digestive absorption of the small intestine was a decrease in both the number and regenerative capacity of ISCs. The underlying mechanism involves the degeneration of mitochondrial function in ISCs, resulting in insufficient energy supply and decreased metabolic capacity. Additionally, our findings indicate that fasting-refeeding can influence the mitochondrial metabolism of ISCs, and that alternate day fasting (ADF) can facilitate the restoration of both the quantity and regenerative capabilities of ISCs, thereby exhibiting a notable antiaging effect on the small intestine. In conclusion, this study provides new insights into the potential beneficial role of ADF in ameliorating intestinal aging, thereby establishing a foundation for future investigations into dietary interventions aimed at addressing age-related intestinal dysfunction.

Keywords:  aging; alternate day fasting; gut; intestinal stem cell; mitochondrial metabolism

DOI:  https://doi.org/10.1111/acel.70052
J Exp Clin Cancer Res. 2025 Mar 29. 44(1): 109

Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential.

Vivek Singh, Saba Ubaid, Mohammad Kashif, Tanvi Singh, Gaurav Singh, Roma Pahwa, Anand Singh.

  Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.

Keywords:  Cancer immunity; Caspase-1; Inflammasome-targeted therapy; Inflammasomes; Innate and adaptive immunity; NLRP3 inflammasome; Pyroptosis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13046-025-03366-y
Trends Biochem Sci. 2025 Mar 31. pii: S0968-0004(25)00051-9. [Epub ahead of print]

Mitochondrial heat production: the elephant in the lab….

Pierre Rustin, Howard T Jacobs, Mügen Terzioglu, Paule Bénit.

  It has long been established that heat represents a major part of the energy released during the oxidation of mitochondrial substrates. However, with a few exceptions, the release of heat is rarely mentioned other than as being produced at the expense of ATP, without having any specific function. Here, after briefly surveying the literature on mitochondrial heat production, we argue for its cellular and organismal importance, sharing our opinions as to what could account for this unbalanced portrayal of mitochondrial energy transactions.

Keywords:  ATP; H(+)-ATPase; heat diffusion; mitochondria; nanoscale; respiratory chain

DOI:  https://doi.org/10.1016/j.tibs.2025.03.002
Camb Prism Extinct. 2025 ;3 e4

Extinction of the human species: What could cause it and how likely is it to occur?

Sean ÓhÉigeartaigh.

  The possibility of human extinction has received growing academic attention over the last several decades. Research has analysed possible pathways to human extinction, as well as ethical considerations relating to human survival. Potential causes of human extinction can be loosely grouped into exogenous threats such as an asteroid impact and anthropogenic threats such as war or a catastrophic physics accident. In all cases, an outcome as extreme as human extinction would require events or developments that either have been of very low probability historically or are entirely unprecedented. This introduces deep uncertainty and methodological challenges to the study of the topic. This review provides an overview of potential human extinction causes considered plausible in the current academic literature, experts' judgements of likelihood where available and a synthesis of ethical and social debates relating to the study of human extinction.

Keywords:  anthropocene; anthropogenic impacts; climate change; existential risk; societal collapse

DOI:  https://doi.org/10.1017/ext.2025.4
bioRxiv. 2025 Mar 13. pii: 2025.03.10.642477. [Epub ahead of print]

Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.

Christian J Elliehausen, Szczepan S Olszewski, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Dennis M Minton, Adam R Konopka.

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

DOI: https://doi.org/10.1101/2025.03.10.642477
Metabolism. 2025 Mar 28. pii: S0026-0495(25)00109-X. [Epub ahead of print]168 156240

Anti-sarcopenic effects of active vitamin D through modulation of anabolic and catabolic signaling pathways in human skeletal muscle: A randomized controlled trial.

DPVD Research Group

   BACKGROUND: The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear.
METHODS: In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined clinical and experimental aspects to investigate the effects and mechanisms of eldecalcitol, an active form of vitamin D, in preventing sarcopenia. We examined changes in molecules involved in muscle synthesis and degradation pathways in muscle samples from 32 participants before and after 1 year of eldecalcitol or placebo treatment. The protein levels of molecules involved in muscle synthesis and degradation pathways were examined using western blotting. Additionally, the skeletal muscle and body fat volumes were measured using bioelectrical impedance analysis with a body composition analyzer.
RESULTS: We found that eldecalcitol treatment for 1 year resulted in higher phosphorylation levels of mTOR and FOXO1 signaling pathways, which are associated with increased muscle mass and strength than those with placebo treatment. Body composition measurements at 1 year showed that the eldecalcitol group had significantly higher skeletal muscle mass (1.9 % vs. -3.4 %, p = 3.26E-9) and muscle strength (4.1 % vs. -0.7 %, p = 2.57E-17), and lower fat mass (-3.2 % vs. 1.8 %, p = 1.73E-12) than those in the placebo group.
CONCLUSION: This study suggested that the active form of vitamin D regulates the protein synthesis and degradation pathways in human skeletal muscle and may help prevent sarcopenia. This study was registered at UMIN clinical trials registry, UMIN 000005394.

Keywords:  Active form of vitamin D; FOXO1; MuRF 1; Sarcopenia; Skeletal muscle; Vitamin D; mTOR

DOI:  https://doi.org/10.1016/j.metabol.2025.156240
J Inflamm (Lond). 2025 Mar 31. 22(1): 14

Exploring the mitigating potential of anthocyanin Malvidin in a mouse model of bleomycin-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and oxidative stress.

Dingzi Zhou, Lin Cai, Jie Xu, Daigang Fu, Ling Yan, Linshen Xie.

   BACKGROUND: Malvidin (MV), an essential anthocyanin, has antioxidant and anti-inflammatory effects that may help treat pulmonary fibrosis (PF), a progressive and occasionally fatal condition characterized by severe lung scarring, oxidative stress, and inflammation.
OBJECTIVE: This study aims to evaluate the therapeutic potential of MV in PF by assessing its effects on inflammation, oxidative stress, and fibrotic markers through in vitro and in vivo models.
METHODS AND MATERIALS: The compound was evaluated by molecular docking. BEAS-2B and RLE-6TN cells were treated with 200 µg/mL BLM to induce inflammation, followed by MV treatment. Cell viability, ROS levels, and wound healing were analyzed. In vivo, BLM-induced mice were evaluated to assess fibrotic and antioxidant biomarkers.
RESULTS: MV interacted with NLRP3 with a binding energy of -7 kcal/mol. MV increased cell viability in BLM-induced cells, reducing ROS and oxidative stress. Wound healing was enhanced in MV-treated groups. A decrease in HYP proteins confirms MV's antifibrotic effects. In the mice model, MV reduced TXNIP, MDA, and MPO while increasing CAT, GSH, and SOD, confirming its antioxidant capacity.
CONCLUSION: MV alleviated PF in the BLM-induced model via the NLRP3 inflammasome pathway, demonstrating its potential as an antifibrotic and antioxidant agent.

Keywords:  Bleomycin; Fibrosis; Inflammation; Malvidin; NLRP3; Oxidative stress

DOI:  https://doi.org/10.1186/s12950-025-00441-1
Am J Clin Nutr. 2025 Apr;pii: S0002-9165(25)00062-0. [Epub ahead of print]121(4): 747-748

Predicting resting energy expenditure.

Klaas R Westerterp.

DOI: https://doi.org/10.1016/j.ajcnut.2025.01.026
Methods Mol Biol. 2025 Apr 05.

Three-Dimensional Analysis of Skeletal Muscle Stem Cell Niche Following Tissue Clearing.

Yoko Asakura, Smrithi Karthikeyan, Atsushi Asakura.

  Skeletal muscle is an intricately structured tissue made up of a complex framework of various cell types. The dynamic spatial and temporal relationships among these cells during both homeostasis and periods of injury contribute to the regenerative abilities of skeletal muscle. Currently, there is a deficiency in quantitative assessment, biological role, and the molecular mechanisms that could elucidate a possible juxtavascular niche for muscle satellite cells, a stem cell population for skeletal muscle regeneration. To fully comprehend the regeneration process by muscle satellite cells, a three-dimensional (3-D) imaging approach is essential. Confocal microscopy serves as an exceptional method for examining the spatial arrangement of cells within a specific tissue. In this protocol, we provide a detailed procedure for preparing optically transparent extensor digitorum longus (EDL) skeletal muscle specimens that are appropriate for confocal microscopy and computational 3-D assessment. We outline the steps for sample preparation, which include perfusion fixation and the tissue clearing process for rodent muscle specimens, as well as guidelines for image capture and computational evaluation featuring sample segmentation and 3-D visualization. This methodology can be utilized to characterize diverse cell types, such as muscle satellite cells and capillary endothelial cells found in rodent skeletal muscle.

Keywords:  3-D imaging; Angiogenesis; Endothelial cell; Muscle regeneration; Muscle stem cell; Muscular dystrophy; Myogenesis; Satellite cell; Skeletal muscle; Tissue clearing

DOI:  https://doi.org/10.1007/7651_2025_618
J Nutr Biochem. 2025 Apr 01. pii: S0955-2863(25)00077-4. [Epub ahead of print] 109914

Medium-chain triglyceride attenuates obesity by activating brown adipose tissue via upregulating the AMPK signaling pathway.

Min Jia, Hao Yue, Xiuxiu Wang, Aizhen Zong, Tongcheng Xu, Yong-Jiang Xu, Yuanfa Liu.

  Medium-chain triacylglycerol (MCT) is a healthy lipid mainly composed of medium-chain fatty acids (MCFA), which has been proven to have physiological activities in improving metabolic disorders, reducing blood cholesterol, and controlling weight. Brown adipose tissue (BAT) has been regarded as a potential organ to fight obesity due to the function of thermogenesis and energy dissipation. Previous reports found that a diet rich in MCT contributed to the activation of BAT. However, the potential mechanism between MCT and BAT remains unknown. In the current study, MCFA was applied on C3H/10T1/2 cells differentiated brown adipocytes, and MCT was applied on high-fat diet (HFD) induced obese mice. The results showed that MCFA and MCT induced browning of adipocytes and activation of BAT, significantly increased the enrichment of mitochondria, and significantly reduced intracellular lipid accumulation and body weights in vivo and in vitro. Mechanically, MCT significantly increased the level of UCP1, AMPK, and the downstream signaling factors of Pgc1α and Ulk1, further significantly elevated the brown differentiation factor of Pparγ. Moreover, The AMPK inhibitor dorsomorphin partially impaired the beneficial effects caused by MCT. In conclusion, this study proved that AMPK is the potential target of MCT to induce BAT activation and provided theoretical evidence for the application of MCT in the future.

Keywords:  AMPK; Medium-chain fatty acid; brown adipose tissue; lipid metabolism; medium-chain triglycerides

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109914
Am J Physiol Regul Integr Comp Physiol. 2025 Apr 04.

Nutritional modulation of the mTORC1 pathway in muscle: differential effect according to muscle and sex.

C Breuillard, S Le Plénier, C Guihenneuc, C Choisy, C Hourdé, Christophe Moinard.

  Numerous studies have focused on nutrient-driven regulation of muscle metabolism/homeostasis through the mTORC1 pathway, but their results fail to converge, perhaps due to differences in mTORC1 pathway protein studied, muscle type and/or sex. The aim of this work was to study the influence of these factors on mTORC1 pathway activation in response to food intake. Rats (16 male and 16 female) were fasted for 20 hours then were randomized into two groups: a postabsorptive group in which the animals were euthanized in the fasted state, and a postprandial group in which the animals were euthanized 30 min after food intake (10 g). Plasma glucose, insulin and amino acids were assayed. Muscles (extensor digitorum longus, tibialis, soleus, gastrocnemius and plantaris) were removed and Western blotted to analyze activation of the mTORC1 pathway (phosphorylation of Akt, 4EBP1, S6K1). Levels of Akt, 4EBP1 and S6K1 activation were compared between muscles and by sex in different nutritional states, and a Kruskal-Wallis test was performed to find statistically significant differences. Food intake led to an increase in plasma concentrations of glucose, insulin and total amino acids (p<0.0001). Levels of Akt, 4EBP1 and S6K1 activation differed significantly between muscles and by sex and nutritional state. Different phosphorylation sites in the same muscle were not correlated with each other. These results suggest that mTORC1 activation level is sensitive to muscle type, sex and nutritional state. Studies on this signal transduction pathway therefore require an individualized approach, considering all the factors that may affect it.

Keywords:  mTORC1 pathway; muscle; postabsorptive state; postprandial state

DOI:  https://doi.org/10.1152/ajpregu.00156.2024