bims-kimdis 2025-01-26 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2025–01–26
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart.
D,L-3-hydroxybutyrate in the treatment of glucose transporter 1 deficiency syndrome (Glut1DS).
Ketogenesis nutritionally supports brain during bacterial infection in Drosophila.
Supplementation with essential amino acids in the early stage of carbohydrate reintroduction after a very-low energy ketogenic therapy (VLEKT) improves body cell mass, muscle strength and inflammation.
mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
Hypotonic Swelling Method for the Isolation of Pure Mitochondria From Primary Human Skeletal Myoblasts for Proteomic Studies.
Is Breath Best? A Systematic Review on the Accuracy and Utility of Nanotechnology Based Breath Analysis of Ketones in Type 1 Diabetes.
Greasing the wheels of inflammasome formation: regulation of NLRP3 function by S-linked fatty acids.
Impact of Weight Loss on Testosterone Levels: A Review of BMI and Testosterone.
The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.
Mechanistic Insights Into the Exercise-Induced Changes in Muscle Lipids and Insulin Sensitivity-Expanding on the "Athlete's Paradox": Revisiting a 2011 Diabetes Classic by Amati et al.
Does exercise truly affect brain-wide glucose metabolism?
Mitochondrial protein import stress.
TLR/NLRP3 inflammasome signaling pathways as a main target in frailty, cachexia and sarcopenia.
Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.
Shatavari supplementation during eight weeks of resistance training increases training load, enhances skeletal muscle contractility and alters the skeletal muscle proteome in older women.
The mitochondrial choline transporter, SLC25A48, regulates urine and blood choline levels in humans.
Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.
Effects of aerobic training with blood flow restriction on aerobic capacity, muscle strength, and hypertrophy in young adults: a systematic review and meta-analysis.
Critical power: An important tool for exercise prescription and the assessment of physiological function.
The Effect of High-Intensity Interval Training (HIIT) on Brain-Derived Neurotrophic Factor Levels (BNDF): A Systematic Review.
The efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients aged over 80 years with heart failure.
Androgens differentially modulate glucocorticoid effects on adipose tissue and lean mass.
Toward the Limits of Human Ageing Physiology: Characteristics of the 50-, 60- and 70-yr + Male Indoor Rowing World Champions.
Inter-organ metabolic interaction networks in non-alcoholic fatty liver disease.

Cardiovasc Res. 2025 Jan 18. pii: cvaf004. [Epub ahead of print]

Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart.

Shubham Soni, Rachel J Skow, Stephen Foulkes, Mark J Haykowsky, Jason R B Dyck.

  Recent evidence suggests that ketone bodies have therapeutic potential in many cardiovascular diseases including heart failure (HF). Accordingly, this has led to multiple clinical trials that use ketone esters to treat HF patients, which we term ketone therapy. Ketone esters, specifically ketone monoesters, are synthetic compounds which, when consumed, are de-esterified into two β-hydroxybutyrate (βOHB) molecules and increase the circulating βOHB concentration. While many studies have primarily focused on the cardiac benefits of ketone therapy in HF, ketones can have numerous favorable effects in other organs such as the vasculature and skeletal muscle. Importantly, vascular and skeletal muscle dysfunction are also heavily implicated in the reduced exercise tolerance, the hallmark feature in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, suggesting that some of the benefits observed in HF in response to ketone therapy may involve these non-cardiac pathways. Thus, we review the evidence suggesting how ketone therapy may be beneficial in improving cardiovascular and skeletal muscle function in HF and identify various potential mechanisms that may be important in the beneficial non-cardiac effects of ketones in HF.

Keywords:  Ketone bodies; exercise intolerance; heart failure; skeletal muscle; vasculature; β-hydroxybutyrate

DOI:  https://doi.org/10.1093/cvr/cvaf004
JIMD Rep. 2025 Jan;66(1): e12461

D,L-3-hydroxybutyrate in the treatment of glucose transporter 1 deficiency syndrome (Glut1DS).

Aya Amer, Kathryn Murrell, Liza Edmonds, Isaac Bernhardt, Rhonda Akroyd, Bryony Ryder, Callum Wilson, Emma Glamuzina.

   Background: Deficiency of the Glut1 transporter due to mono-allelic variants in SLC2A1 causes hypoglycorrhachia, resulting in a neurological spectrum from neonatal epilepsy to adult-onset paroxysmal movement disorders (PMD). The brain utilises ketone bodies as an alternative energy source to glucose. Thus, early initiation of the ketogenic diet (KD) is standard care for Glut1 deficiency syndrome (Glut1DS). Commencement and adherence in older Glut1DS patients is difficult to achieve, leaving few treatment options. Oral D,L-3-hydroxybutyrate (D,L-3-HB) crosses the blood-brain barrier, making it a potential treatment for Glut1DS.
Methods: A retrospective case review of patients with Glut1DS under the Adult and Paediatric National Metabolic Service (APNMS) of New Zealand, treated with D,L-3-HB between 2012 and 2023 was performed. Clinical notes, standardised, neuropsychological assessments and subjective data on and off D,L-3-HB were obtained. The best on and off D,L-3-HB measures of working memory (WMI) and processing speed (PSI) were compared to assess the efficacy.
Results: D,L-3-HB was offered to 12 patients with Glut1DS (age 10-52 years). Compliance-dependent improvements in subjective, cognitive and adaptive function were reported by those who were reassessed on-treatment (9/12). Four reported improved PMD. Objective improvements were found in WM (9/9) and PS (6/9). Subjective improvements were reported in patients' health, wellbeing and independence.
Conclusions: KD remains standard of care for Glut1DS, but effective alternatives are lacking for those who do not tolerate this. D,L-3-HB was associated with improved WM, PS and perceived life quality in this small group of patients with Glut1DS, thus providing a potential treatment for this distinct group.

Keywords:  D,L‐3‐HB; D,L‐3‐hydroxybutyrate; Glut1; cognitive impairment; glut1ds; ketogenic; ketones

DOI:  https://doi.org/10.1002/jmd2.12461
Brain Behav Immun. 2025 Jan 15. pii: S0889-1591(25)00017-0. [Epub ahead of print]125 280-291

Ketogenesis nutritionally supports brain during bacterial infection in Drosophila.

Gabriela Krejčová, Diana Novotná, Adam Bajgar.

  Mounting an immune response is a nutritionally demanding process that requires the systemic redistribution of energy stores towards the immune system. This is facilitated by cytokine-induced insulin resistance, which simultaneously promotes the mobilization of lipids and carbohydrates while limiting their consumption in immune-unrelated processes, such as development, growth, and reproduction. However, this adaptation also restricts the availability of nutrients to vital organs, which must then be sustained by alternative fuels. Here, we employed an experimental model of severe bacterial infection in Drosophila melanogaster to investigate whether ketogenesis may represent a metabolic adaptation for overcoming periods of nutritional scarcity during the immune response. We found that the immune response to severe bacterial infection is accompained by increased ketogenesis in the fat body and macrophages, leading to elevated levels of β-hydroxybutyrate in circulation. Although this metabolic adaptation is essential for survival during infection, it is not required for the elimination of the pathogen itself. Instead, ketone bodies predominately serve as an energy source for the brain neurons during this period of nutrient scarcity.

Keywords:  Adipocytes; Brain; Infection; Ketone bodies; Macrophages; Metabolism; Neurons; The fat body; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.bbi.2025.01.008
J Transl Med. 2025 Jan 23. 23(1): 111

Supplementation with essential amino acids in the early stage of carbohydrate reintroduction after a very-low energy ketogenic therapy (VLEKT) improves body cell mass, muscle strength and inflammation.

Giuseppe Annunziata, Ludovica Verde, Vincenzo D'Orsi, Massimiliano Caprio, Stefania Gorini, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri, Luigi Barrea.

   BACKGROUND: Although little is yet known about the long-term maintenance of very low-energy ketogenic therapy (VLEKT) effects on body composition, muscle strength and inflammation, it is plausible to assume that changes may occur, particularly during the steps following the ketogenic step, due to the loss of the protective effects of ketones and the concomitant reintroduction of carbohydrates. For this reason, the present study aimed to evaluate the effects of supplementation with 8 g per day of essential amino acids (EAAs) on these parameters.
METHODS: A total of 68 women of reproductive age and with grade I obesity who had completed 45 days of the ketogenic phase with VLEKT (KeNuT protocol) and 40 days of non-ketogenic phase of KeNuT protocol with VLEKT (phase 3, fruit reintroduction) were included in the study. Half of them (n = 34) followed this first step of the re-educational phase of KeNuT protocol with VLEKT with supplementation with EAAs (Aminotrofic®: 4 g twice daily). Anthropometric parameters, body composition via bioelectrical impedance analysis and high-sensitivity C-reactive protein (hs-CRP) levels were assessed at baseline, pre- and post both dietary interventions.
RESULTS: At the end of 45 days of ketogenic phase with VLEKT (before fruit reintroduction and EAA supplementation), the two groups did not differ in any of the parameters assessed. At the end of the fruit reintroduction phase, the supplemented group showed greater magnitudes of reduction in weight, waist circumference, fat mass (FM) and hs-CRP (p < 0.001 for all) and of increase in muscle strength (p < 0.001), phase angle (p < 0.001), body cell mass (BCM) (p = 0.001), and muscle mass (%) (p < 0.001).
CONCLUSION: These results underline the usefulness of supplementation with EAAs during the first transitional phase post VLEKT to improve body composition (specifically reduction in FM and increase in BCM), muscle strength, and inflammatory status.

Keywords:  Bioelectrical impedance analysis; Body cell mass; Body composition; Essential amino acids; Inflammation; Muscle strength; Obesity; Very-low energy ketogenic therapy

DOI:  https://doi.org/10.1186/s12967-024-06037-2
FASEB J. 2025 Jan 31. 39(2): e70277

mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.

Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.

  The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.

Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202402064R
J Cell Mol Med. 2025 Jan;29(2): e70370

Hypotonic Swelling Method for the Isolation of Pure Mitochondria From Primary Human Skeletal Myoblasts for Proteomic Studies.

Evrim Aksu-Menges, Eray Taha Kumtepe, Gurler Akpinar, Burcu Balci-Hayta.

  Mitochondria play a fundamental role in energy metabolism, particularly in high-energy-demand tissues such as skeletal muscle. Understanding the proteomic composition of mitochondria in these cells is crucial for elucidating the mechanisms underlying muscle physiology and pathology. However, effective isolation of mitochondria from primary human skeletal muscle cells has been challenging due to the complex cellular architecture and the propensity for contamination with other organelles. Here, we compared four different methods to isolate mitochondria from primary human skeletal myoblasts regarding total protein yield, mitochondrial enrichment capacity and purity of the isolated fraction. We presented a modified method that combines differential centrifugation with a hypotonic swelling step and a subsequent purification process to minimise cellular contamination. We validated our method by demonstrating its ability to obtain highly pure mitochondrial fractions, as confirmed by Western Blot with mitochondrial, cytosolic and nuclear markers. We demonstrated that proteomic analysis can be performed with isolated mitochondria. Our approach provides a valuable tool for investigating mitochondrial dynamics, biogenesis and function in the context of skeletal muscle biology in health and disease. This methodological advancement opens new avenues for mitochondrial research and its implications in myopathies, sarcopenia, cachexia and metabolic disorders.

Keywords:  differential centrifugation; hypotonic swelling method; mitochondria isolation; primary human skeletal myoblasts

DOI:  https://doi.org/10.1111/jcmm.70370
Biosensors (Basel). 2025 Jan 19. pii: 62. [Epub ahead of print]15(1):

Is Breath Best? A Systematic Review on the Accuracy and Utility of Nanotechnology Based Breath Analysis of Ketones in Type 1 Diabetes.

Kamal Marfatia, Jing Ni, Veronica Preda, Noushin Nasiri.

  Timely ketone detection in patients with type 1 diabetes mellitus (T1DM) is critical for the effective management of diabetic ketoacidosis (DKA). This systematic review evaluates the current literature on breath-based analysis for ketone detection in T1DM, highlighting nanotechnology as a potential for a non-invasive alternative to blood-based ketone measurements. A comprehensive search across 5 databases identified 11 studies meeting inclusion criteria, showcasing various breath analysis techniques, such as semiconducting gas sensors, colorimetry, and nanoparticle-based chemo-resistive sensors. These studies report high sensitivity and correlation between breath acetone (BrAce) levels and blood ketones, with some demonstrating accuracies up to 94.7% and correlations reaching R2 values as high as 0.98. However, significant heterogeneity in methodologies and cut-off values limits device comparability and precludes meta-analysis. Despite these challenges, the findings indicate that BrAce monitoring could offer significant clinical benefits by enabling the earlier detection of ketone buildup, reducing DKA-related hospitalisations and healthcare costs. Standardising BrAce measurement techniques and sensitivity thresholds is essential to broaden clinical adoption. This review underscores the promise of nanotechnology-based breath analysis as a transformative tool for DKA management, with potential utility across varied ketotic conditions.

Keywords:  DKA; acetone; breath analysis; ketones; nanotechnology; type 1 diabetes

DOI:  https://doi.org/10.3390/bios15010062
Biochem Soc Trans. 2025 Jan 21. pii: BST20241738. [Epub ahead of print]

Greasing the wheels of inflammasome formation: regulation of NLRP3 function by S-linked fatty acids.

Daniel M Williams, Andrew A Peden.

  NLRP3 is an inflammasome seeding pattern recognition receptor that initiates a pro-inflammatory signalling cascade in response to changes in intracellular homeostasis that are indicative of bacterial infection or tissue damage. Several types of post-translational modification (PTM) have been identified that are added to NLRP3 to regulate its activity. Recent progress has revealed that NLRP3 is subject to a further type of PTM, S-acylation (or palmitoylation), which involves the reversible addition of long-chain fatty acids to target cysteine residues by opposing sets of enzymes. This review provides an overview of recent studies that have identified S-acylation as an important modifier of NLRP3 function. The essential role of S-acylation in the recruitment of NLRP3 to intracellular membranes and the consequences of S-acylation-dependent membrane recruitment on NLRP3 localisation and activation are discussed in detail.

Keywords:  NLRP3; inflammasomes; inflammation; membrane trafficking; palmitoylation; post-translational modifications; s-acylation

DOI:  https://doi.org/10.1042/BST20241738
Cureus. 2024 Dec;16(12): e76139

Impact of Weight Loss on Testosterone Levels: A Review of BMI and Testosterone.

Okelue E Okobi, Paola Khoury, Raul J De la Vega, Raphael S Figueroa, Dhaarak Desai, Bernadin Dina A Mangiliman, Olga L Vera Colon, Rodolfo J Urruela-Barrios, Abdul K Abdussalam, Miguel Diaz-Miret, Sergio Hernandez Borges.

  The purpose of this review is to explore the relationship between weight loss (WL), specifically reductions in body mass index (BMI), and increases in testosterone levels. Obesity and excess body fat are linked to reduced testosterone levels, which can lead to metabolic dysfunctions, reduced libido, and diminished muscle mass. To attain this purpose, this review will summarize current evidence on how weight reduction interventions, including dietary changes, exercise, and bariatric surgery, affect testosterone production in overweight and obese individuals. WL, particularly through fat reduction, has a positive influence on testosterone levels. Both moderate and significant reductions in BMI are associated with notable increases in serum testosterone levels. Dietary interventions, particularly low-carbohydrate and Mediterranean diets, have been linked to increased testosterone production in men with obesity. Exercise, particularly resistance training, has also been shown to improve hormonal profiles by lowering fat mass and boosting testosterone levels. Additionally, bariatric surgery has been identified as one of the most effective methods for increasing testosterone in morbidly obese individuals, with improvements sustained over time. The findings have indicated that there is strong evidence that WL, particularly through reductions in BMI, leads to increased testosterone levels. This relationship is mediated by improvements in insulin sensitivity, reduced inflammation, and lower levels of aromatase activity (the enzyme that converts testosterone to estrogen in fat tissue). Effective interventions, including diet, exercise, and bariatric surgery, have the potential to restore hormonal balance, improving overall health outcomes for men with obesity or higher BMI. Further research is needed to optimize interventions and explore long-term benefits.

Keywords:  bariatric surgery; body mass index (bmi); hormonal health; obesity; testosterone levels; weight loss

DOI:  https://doi.org/10.7759/cureus.76139
J Physiol Sci. 2024 ;pii: S1880-6546(24)00096-9. [Epub ahead of print]74(1): 8

The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.

Lin Li, Xiangdeng Lai, Yihan Ni, Siyu Chen, Yaqian Qu, Zhiqiang Hu, Jingquan Sun.

  The athlete's paradox phenomenon involves the accumulation of intramuscular triglycerides (IMTG) in both insulin-resistant and insulin-sensitive endurance athletes. Nevertheless, a complete understanding of this phenomenon is yet to be achieved. Recent research indicates that lactate, a common byproduct of physical activity, may increase the accumulation of IMTG in skeletal muscle. This is achieved through the activation of G protein-coupled receptor 81 (GPR81) leads to the suppression of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway. The mechanism accountable for the increase in mitochondrial content in skeletal muscle triggered by lactate remains incomprehensible. Based on current research, our objective is to explore the role of the GPR81-inhibited cAMP-PKA pathway in the aggregation of IMTG and the increase in mitochondrial content as a result of prolonged exercise. The GPR81-cAMP-PKA-signaling pathway regulates the buildup of IMTG caused by extended periods of endurance training (ET). This is likely due to a decrease in proteins related to fat breakdown and an increase in proteins responsible for fat production. It is possible that the GPR81-cAMP-PKA pathway does not contribute to the long-term increase in mitochondrial biogenesis and content, which is induced by chronic ET. Additional investigation is required to explore the possible hindrance of the mitochondrial biogenesis and content process during physical activity by the GPR81-cAMP-PKA signal.

Keywords:  Endurance training; Intramuscular triglyceride; Lactate; Mitochondrial content; Skeletal muscle; cAMP

DOI:  https://doi.org/10.1186/s12576-024-00902-x
Diabetes. 2025 Feb 01. 74(2): 134-137

Mechanistic Insights Into the Exercise-Induced Changes in Muscle Lipids and Insulin Sensitivity-Expanding on the "Athlete's Paradox": Revisiting a 2011 Diabetes Classic by Amati et al.

Jeffrey F Horowitz, Bret H Goodpaster.

Endurance exercise is widely recognized for its role in mitigating insulin resistance, yet the precise mechanisms remain unclear. In this Classics in Diabetes article, we revisit the article by Amati et al., "Skeletal Muscle Triglycerides, Diacylglycerols, and Ceramides in Insulin Resistance: Another Paradox in Endurance-Trained Athletes?" Published in the October 2011 issue of Diabetes, this article was among the first to highlight the nuanced roles of exercise-induced changes in bioactive lipids such as ceramide and diacylglycerol (DAG) in insulin signaling. The authors' groundbreaking work challenged some existing paradigms, revealing a more complex relationship between DAGs and insulin resistance than previously thought. Their findings helped lay the foundation for further exploration to unravel the intricate biochemical pathways through which exercise influences insulin sensitivity and metabolic health.

DOI: https://doi.org/10.2337/dbi24-0030
J Physiol. 2025 Jan 20.

Does exercise truly affect brain-wide glucose metabolism?

Laust Vind Knudsen, Tanja Maria Michel, Abigail Jane Sheldrick-Michel, Manouchehr Seyedi Vafaee.



Keywords:  FDG; PET; cerebral glucose metabolism; cerebral metabolism; exercise physiology; molecular imaging; physical activity

DOI:  https://doi.org/10.1113/JP288329
Nat Cell Biol. 2025 Jan 22.

Mitochondrial protein import stress.

Nikolaus Pfanner, Fabian den Brave, Thomas Becker.

Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.

DOI: https://doi.org/10.1038/s41556-024-01590-w
Tissue Cell. 2025 Jan 09. pii: S0040-8166(25)00003-5. [Epub ahead of print]93 102723

TLR/NLRP3 inflammasome signaling pathways as a main target in frailty, cachexia and sarcopenia.

Sanaz Keshavarz Shahbaz, Aida Mokhlesi, Roghaye Keshavarz Sadegh, Kimia Rahimi, Tannaz Jamialahmadi, Alexandra E Butler, Prashant Kesharwani, Amirhossein Sahebkar.

  Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.

Keywords:  Cachexia; Frailty; Inflammasome signaling pathways; LR/NLRP3; Sarcopenia

DOI:  https://doi.org/10.1016/j.tice.2025.102723
Trends Cell Biol. 2025 Jan 21. pii: S0962-8924(25)00001-7. [Epub ahead of print]

Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.

Pablo Lanuza-Gracia, Jonas Juan-Mateu, Juan Valcárcel.

The target of rapamycin complex mTORC1 has key roles in cell growth and metabolism and its inhibition delays ageing. Recent work by Ogawa et al. in Caenorhabditis elegans argues that modulation of pre-mRNA splicing factors and alternative splicing are key mediators of mTORC1 signalling and can enhance longevity.

DOI: https://doi.org/10.1016/j.tcb.2025.01.001
Front Nutr. 2024 ;11 1498674

Shatavari supplementation during eight weeks of resistance training increases training load, enhances skeletal muscle contractility and alters the skeletal muscle proteome in older women.

Elsa Greed, Jack Pritchard, Lauren Struszczak, Esra Bozbaş, Georgia Ek, Jordan Acheson, Ben Winney, Aaliyah Qadir, Karl Ka-Lam Wong, Joanna Bowtell, Mary O'Leary.

   Introduction: Shatavari is a herbal dietary supplement that may increase skeletal muscle strength in younger and older adults. Shatavari contains compounds with both estradiol-like and antioxidant properties, which could enhance muscle function. Postmenopausal women may derive the greatest benefit, as estrogen deficiency adversely impacts skeletal muscle function. However, mechanistic insights are limited and the effects of shatavari on muscle function require further characterization.
Methods: In this randomized, double-blind trial, 17 young (23 ± 5 yr) and 22 older (63 ± 5 yr) women completed an 8-week leg resistance training programme. They consumed either a placebo or shatavari (1000 mg/d, equivalent to 26,500 mg/d fresh weight) supplement throughout. Pre and post training, measures of leg strength, neuromuscular function and vastus lateralis (VL) biopsies were obtained. Tandem-mass-tagged VL proteomic analyses were performed. Data were analyzed using a differential expression (Reactome) approach.
Results: Shatavari supplementation increased 8-week training load in older women (leg press repetitions completed, p = 0.049, η p 2 = 0.198; maximum weight lifted each week, p = 0.03, η p 2 = 0.386; ANCOVA). There was no effect of shatavari on muscle strength post-training. VL half relaxation time was shortened post-training in older women supplemented with shatavari (post-training change: shatavari -11.74 ± 11.93%, placebo 0.42 ± 14.73%, p = 0.021; ANCOVA). Shatavari supplementation diminished the expression of extracellular matrix proteins in both cohorts. Expression of proteins related to striated muscle contraction, transcription and translation were decreased by shatavari supplementation in older women.
Discussion: These novel observations support the notion that shatavari supplementation confers resistance to neuromuscular fatigue in older women. This could ameliorate sarcopenic declines in skeletal muscle function.

Keywords:  aging; exercise; muscle; proteomics; resistance training; skeletal

DOI:  https://doi.org/10.3389/fnut.2024.1498674
Kidney Int. 2025 Feb;pii: S0085-2538(24)00811-1. [Epub ahead of print]107(2): 225-227

The mitochondrial choline transporter, SLC25A48, regulates urine and blood choline levels in humans.

Soumya Maity, Kumar Sharma.

Choline is an essential nutrient for the biosynthesis of phospholipids and neurotransmitters and controls several physiological functions in mammals. It is metabolized in the organelles within cells, including mitochondria. However, its subcellular distribution and mode of mitochondrial transport remain poorly understood. Patil et al. identified SLC25A48 as a mitochondrial choline transporter, and its loss-of-function mutations were associated with elevated urine and plasma choline levels in humans.

DOI: https://doi.org/10.1016/j.kint.2024.11.014
Curr Biol. 2025 Jan 20. pii: S0960-9822(24)01646-4. [Epub ahead of print]35(2): R76-R79

Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.

Jorge Oliver-De La Cruz, Pere Roca-Cusachs.

Mechanical forces influence mitochondrial dynamics through previously unexplored mechanisms. A new study demonstrates that actomyosin tension inhibits mitochondrial fission by phosphorylating a key component of the fission complex and that this event regulates the nuclear accumulation of critical transcription factors.

DOI: https://doi.org/10.1016/j.cub.2024.12.006
Front Physiol. 2024 ;15 1506386

Effects of aerobic training with blood flow restriction on aerobic capacity, muscle strength, and hypertrophy in young adults: a systematic review and meta-analysis.

Zhendong Gao, Yan Li, Jinjin Zhang, Liqiang Li, Tao Wang, Xiaolin Wang, Hao Wang.

  Aerobic training with blood flow restriction (AT-BFR) has shown promise in enhancing both aerobic capacity and exercise performance. The aim of this review was to systematically analyze the evidence regarding the effectiveness of this novel training method on aerobic capacity, muscle strength, and hypertrophy in young adults. Studies were identified through a search of databases including PubMed, Scopus, Web of Science, SPORTDiscus, CINAHL, Cochrane Library, and EMBASE. A total of 16 studies, involving 270 subjects, were included in the meta-analysis. The results revealed that AT-BFR induced greater improvements in VO2max (SMD = 0.27, 95%CI: [0.02, 0.52], p < 0.05), and muscle strength (SMD = 0.39, 95%CI: [0.09, 0.69], p < 0.05), compared to aerobic training with no blood flow restriction (AT-noBFR). However, no significant effect was observed on muscle mass (SMD = 0.23, 95%CI: [-0.09, 0.56], p = 0.162). Furthermore, no moderating effects on the outcomes were found for individual characteristics or training factors. In conclusion, AT-BFR is more effective than AT-noBFR in improving aerobic capacity and muscle strength, making it a promising alternative to high-intensity training.
Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024559872.

Keywords:  aerobic capacity; aerobic training; blood flow restriction; muscle hypertrophy; muscle strength

DOI:  https://doi.org/10.3389/fphys.2024.1506386
Exp Physiol. 2025 Jan 22.

Critical power: An important tool for exercise prescription and the assessment of physiological function.

Daniel Muniz Pumares, Samuel Meyler.



Keywords:  exercise prescription; exercise training; fitness testing; maximum oxygen uptake

DOI:  https://doi.org/10.1113/EP092258
Brain Sci. 2024 Dec 30. pii: 34. [Epub ahead of print]15(1):

The Effect of High-Intensity Interval Training (HIIT) on Brain-Derived Neurotrophic Factor Levels (BNDF): A Systematic Review.

Milosz Mielniczek, Tore Kristian Aune.

   BACKGROUND/OBJECTIVES: High-intensity interval training (HIIT) alternates short periods of intense exercise with recovery, effectively enhancing cardiorespiratory fitness, endurance, and strength in various populations. Concurrently, brain-derived neurotrophic factor (BDNF) supports neuronal resilience and activity-dependent plasticity, which are vital for learning and memory. This study aims to systematically review changes in BDNF levels in response to HIIT, with three primary objectives: evaluating the benefits of HIIT for BDNF modulation, assessing methodological quality and the risk of bias in reviewed studies, and identifying patterns in BDNF response based on HIIT protocols and population characteristics.
METHODS: Comprehensive database searches were conducted in PubMed and SPORTDiscus to identify relevant studies published up to April 2024. Given the diversity in study designs and outcomes, a narrative synthesis was performed rather than a meta-analysis. Bias was evaluated using visualization tools such as RobVis, and the review was conducted by a single researcher, which may limit its comprehensiveness.
RESULTS: Twelve studies met the inclusion criteria, with most indicating significant increases in BDNF levels post-HIIT, suggesting HIIT's potential to enhance neuroplasticity and cognitive functions. However, variations in BDNF responses were observed across different HIIT protocols and study populations. Some studies reported decreases or no change in BDNF levels, reflecting the complex regulation of BDNF influenced by factors such as exercise intensity, duration, and individual variability.
CONCLUSIONS: HIIT shows promise as an intervention for increasing BDNF levels, with potential benefits for brain health and cognitive function. These findings underscore the need for further research to confirm the optimal conditions under which HIIT can effectively enhance neurological outcomes. Future studies should explore standardized HIIT protocols and the long-term impact of HIIT on BDNF and neuroplasticity.

Keywords:  adaptation; cognition; endurance; intensity; neuroplasticity

DOI:  https://doi.org/10.3390/brainsci15010034
ESC Heart Fail. 2025 Jan 20.

The efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients aged over 80 years with heart failure.

Kenji Nakano, Kenji Kanenawa, Akihiro Isotani, Takashi Morinaga, Kaori Yamamoto, Norihisa Miyawaki, Euihong Ko, Miho Nakamura, Yuichi Tanaka, Kenichi Ishizu, Toru Morofuji, Masaomi Hayashi, Masato Fukunaga, Makoto Hyodo, Shinichi Shirai, Kenji Ando.

   AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) have demonstrated effectiveness in reducing cardiovascular death and heart failure hospitalization (HFH). However, the efficacy and safety of SGLT2 inhibitors in elderly patients with poor general status, such as very low bodyweight or low nutritional status, who are not included in randomized controlled trials, has not yet been examined. In a real-world setting, the introduction of SGLT2 inhibitors to such elderly patients is a very difficult decision to make. We therefore examined the efficacy and safety of these drugs in elderly heart failure patients in a real-world setting.
METHODS AND RESULTS: In Kokura Memorial Hospital, a retrospective study was conducted on 1559 patients over 80 years old hospitalized for HF between 2018 and 2023. Among them, 1326 were included in the non-SGLT2i group and 233 in the SGLT2i group. A multivariate Cox regression model was used to compare the risk of primary composite outcome (all-cause death and HFH) and secondary safety composite outcome (ischaemic stroke, urinary tract infection and dehydration) at 1 year post-discharge between the two groups. The cumulative 1 year incidence of the composite outcome was significantly higher in the non-SGLT2i group (47.3% vs. 31.6%, P < 0.01). SGLT2 inhibitors independently reduced the risk of all-cause death [adjusted hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.39-0.87, P < 0.01] and HFH (adjusted HR: 0.69, 95% CI: 0.52-0.91, P < 0.01), whereas the risk of safety composite events was not increased (adjusted HR: 0.80, 95% CI: 0.49-1.29, P = 0.36). Subgroup analysis showed no significant interactions between age, diabetes, body mass index, left ventricular ejection fraction, clinical frailty scale, geriatric nutritional risk index and SGLT2 inhibitors consistently reduced composite outcomes across all strata. Similarly, SGLT2 inhibitors did not increase safety composite outcomes at any strata.
CONCLUSIONS: SGLT2 inhibitors reduce the risk of all-cause death and HFH without increasing adverse events, even in patients over 80 years old. It may be that SGLT2 inhibitors are effective and safe in patients who are basically hesitant to be introduced to SGLT2 inhibitors, such as those with high frailty, low nutritional status or very low bodyweight.

Keywords:  all‐cause death; elderly; extremely low bodyweight; frailty; heart failure; sodium‐glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1002/ehf2.15218
J Endocrinol. 2025 Jan 01. pii: JOE-24-0061. [Epub ahead of print]

Androgens differentially modulate glucocorticoid effects on adipose tissue and lean mass.

Vera Sommers, Karel David, Christine Helsen, Karen Moermans, Ingrid Stockmans, Gabriele Ferrari, Ruslan Dmitriev, Steve Stegen, Onno C Meijer, Jan Kroon, Frank Claessens, Vanessa Dubois.

Glucocorticoids and androgens affect each other in several ways. In metabolic organs such as adipose tissue and the liver, androgens enhance glucocorticoid-induced insulin resistance and promote fat accumulation in male mice. However, the direct contribution of the androgen receptor (AR) to these effects is unknown. Furthermore, it is unclear whether the potentiating effect of androgens on glucocorticoid signaling in fat extends to other tissues such as skeletal muscle and bone. In this study, we used two complementary models for androgen deprivation (orchidectomy and chemical castration) to investigate the effects of dihydrotestosterone (DHT) on corticosterone (CORT). We found that after two weeks of intervention DHT alone did not affect fat mass but increased lean mass, while CORT increased fat mass and decreased lean mass. Co-supplementation with DHT counteracted the CORT effect on lean mass but enhanced its effect on adiposity. Glucocorticoid induction of Gilz, Fkbp5 and Mt2a in gonadal white adipose tissue depended on the presence of androgens, while in interscapular brown adipose tissue these genes responded to glucocorticoids also without androgens. To directly assess the impact of the AR on the glucocorticoid response, male global AR knock-out mice were exposed to CORT and compared to WT littermates. CORT exposure resulted in an increase in fat mass and a decrease in lean mass in both genotypes. In conclusion, functional AR signaling is dispensable for the metabolic response to glucocorticoids. However, androgen signaling in WT mice modulates glucocorticoid response in a tissue-dependent manner, by counteracting lean mass and potentiating fat mass effects.

DOI: https://doi.org/10.1530/JOE-24-0061
Med Sci Sports Exerc. 2025 Jan 24.

Toward the Limits of Human Ageing Physiology: Characteristics of the 50-, 60- and 70-yr + Male Indoor Rowing World Champions.

Lorcan S Daly.

PURPOSE: To examine the physiological, power-duration, nutritional intake and training characteristics of the recent lightweight (- 75 kg) 50+, 60+ and 70 + yr world champion indoor rowers.
METHODS: Laboratory assessments, undertaken over 2 visits, examined body composition, pulmonary function, blood lactate/ventilatory landmarks, efficiency, fat/carbohydrate oxidation, primary component time-constant to steady-state [𝜏pc]) and peak oxygen consumption (V̇O2peak). Training, performance and nutritional intake were also reported.
RESULTS: The athletes' world championship 2000 m times were 06:34.8, 06:44.0 and 07:15.2, respectively. Their training distribution could be considered pyramidal, with ≈65% in the moderate domain, ≈30% in heavy/severe domains and ≈5% in the extreme domain (rowing ≈67 km.week-1). The athletes demonstrated highly-developed attributes such as fat free mass (FFM; [63.4 to 68.1 kg]), forced vital capacity (4.9 to 5.5 L), 𝜏PC; [13.8 to 17.4 s]), peak power output (550 to 797 W), V̇O2peak (56.2 to 44.7 mL.kg.min-1) and critical power (217 to 288 W). Comparisons with young Olympic champion rowers suggest that age-related 2000 m performance mean power declines of -21.6 to -41.4% in world champions ≈25-, 35-, and 45-years older may be predominantly driven by 'central' factors (e.g., V̇O2peak, critical power; -18.1 to -43.8%). In contrast, 'peripheral' factors (e.g., gross efficiency, τPC; +6.1 to -25.1%) seem to display notable preservation despite ageing, aligning closely with values seen in young Olympic champions.
CONCLUSIONS: These results challenge conventional perspectives of age-related physiological capacities and decline trajectories. They also suggest that, commensurate with adequate training and nutritional provision, various physiologic systems can exhibit remarkable adaptability and sustain exceptionally high function during ageing. Finally, large differences among the athletes' power-duration and physiological characteristics imply that achieving world-class rowing performance can be predicated by diverse cardiovascular, metabolic and neuromuscular attributes.

DOI: https://doi.org/10.1249/MSS.0000000000003657
Front Endocrinol (Lausanne). 2024 ;15 1494560

Inter-organ metabolic interaction networks in non-alcoholic fatty liver disease.

Yu-Hong Fan, Siyao Zhang, Ye Wang, Hongni Wang, Hongliang Li, Lan Bai.

  Non-alcoholic fatty liver disease (NAFLD) is a multisystem metabolic disorder, marked by abnormal lipid accumulation and intricate inter-organ interactions, which contribute to systemic metabolic imbalances. NAFLD may progress through several stages, including simple steatosis (NAFL), non-alcoholic steatohepatitis (NASH), cirrhosis, and potentially liver cancer. This disease is closely associated with metabolic disorders driven by overnutrition, with key pathological processes including lipid dysregulation, impaired lipid autophagy, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and local inflammation. While hepatic lipid metabolism in NAFLD is well-documented, further research into inter-organ communication mechanisms is crucial for a deeper understanding of NAFLD progression. This review delves into intrahepatic networks and tissue-specific signaling mediators involved in NAFLD pathogenesis, emphasizing their impact on distal organs.

Keywords:  Inter-organ crosstalk; endoplasmic reticulum (ER) stress; fatty acid synthesis; mitochondrial homeostasis; non-alcoholic fatty liver disease

DOI:  https://doi.org/10.3389/fendo.2024.1494560