bims-kimdis 2024-11-24 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–11–24
23 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic Food Ameliorates Activity-Based Anorexia of Adult Female Mice.
Rapid modulation of interscapular brown adipose tissue mitochondrial activity by ketosis induced by 1,3-butanediol administration to rats.
Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.
SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.
Metabolic flexibility to lipid during exercise is not associated with metabolic health outcomes in individuals without obesity.
Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.
Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.
A Cross-Sectional Study of Capillary Blood Ketone Concentrations in Heart Failure Based on Sodium-Glucose Co-Transporter-2 Inhibitor Use and Heart Failure Type.
[Human skeletal muscle ageing atlas].
Saponins as potential novel NLRP3 inflammasome inhibitors for inflammatory disorders.
Analysis of physiological and biochemical changes and metabolic shifts during 21-Day fasting hypometabolism.
Human skeletal muscle possesses an epigenetic memory of high intensity interval training.
Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.
Butyrate attenuates high-fat diet induced glomerulopathy through GPR43-Sirt3 pathway.
Circulating β-hydroxybutyrate levels are associated with major adverse clinical events in patients with acute myocardial infarction.
Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.
Skeletal muscle hypertrophy and enhanced mitochondrial bioenergetics following electrical stimulation exercises in spinal cord injury: a randomized clinical trial.
AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
Anabolic Sensitivity in Healthy, Lean, Older Men Is Associated With Higher Expression of Amino Acid Sensors and mTORC1 Activators Compared to Young.
Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions.
MOTS-c modulates skeletal muscle function by directly binding and activating CK2.
Moderate-intensity aerobic exercise inhibits cell pyroptosis to improve myocardial ischemia-reperfusion injury.

Int J Eat Disord. 2024 Nov 16.

Ketogenic Food Ameliorates Activity-Based Anorexia of Adult Female Mice.

Yiru Dong, Yuki Lin, Latika Khatri, Moses Chao, Chiye Aoki.

   OBJECTIVE: Genome-wide association studies implicate metabo-psychiatric origins for anorexia nervosa (AN). There are two case reports totaling six adult females who experienced complete remission of AN following a treatment comprised of ketogenic diet (targeting metabolism) with ketamine infusions (targeting psychiatric origins), but no study has determined the efficacy of ketogenic diet, alone. We addressed this gap in knowledge, with exploration of potential molecular mechanisms, using an animal model.
METHOD: Adult C57BL6 female mice underwent 2 or 3 cycles of activity-based anorexia (ABA1, ABA2, ABA3), an animal model of AN relapse, in which AN-like maladaptive behaviors of hyperactivity and voluntary food restriction are elicited when wheel access is combined with food restriction. ABA was categorized as severe, based on weight loss ≥ 20%, food restriction-evoked increase in wheel counts > 10,000/6 h, and crouching/grimace, and compared across two groups: (1) KG, fed ketogenic food continuously (N = 25); and (2) CON, fed standard diet (N = 28).
RESULTS: 86% of CON versus none of the KG were crouching with grimace during ABA1. 93% of CON versus 11% of KG lost weight severely during ABA2 (p < 0.001, 8% difference of group mean weights). Severe hyperactivity was prevalent among CON (86%) and rare for KG (4%) during ABA2 (p < 0.001 on all food-restricted days). ABA up-regulated BDNF (brain-derived neurotrophic factor) in the hippocampus of both groups but ketone body, β-hydroxybutyrate, in urine was increased only among KG.
DISCUSSION: Ketogenic diet may reduce severity of AN relapse through reduction of compulsive exercise, via mechanisms that are in addition to BDNF up-regulation and involve β-hydroxybutyrate.

Keywords:  BDNF; activity‐based anorexia; anorexia nervosa; beta‐hydroxybutyrate; exercise; food restriction; food‐anticipatory activity; ketogenic diet; ketone bodies; wheel running

DOI:  https://doi.org/10.1002/eat.24323
FASEB J. 2024 Nov 30. 38(22): e70195

Rapid modulation of interscapular brown adipose tissue mitochondrial activity by ketosis induced by 1,3-butanediol administration to rats.

Paola Venditti, Gabriella Pinto, Vincenzo Migliaccio, Giuliana Panico, Gianluca Fasciolo, Rita De Matteis, Lillà Lionetti, Pieter de Lange, Stefania Serpico, Gaetana Napolitano, Claudio Agnisola, Angela Amoresano, Assunta Lombardi.

  Some studies indicate that brown adipose tissue (BAT) represents a promising target in the fight against dysmetabolic diseases, with indications suggesting it as a potential target for the effects of ketone bodies. We investigate whether the elevation of plasma levels of the ketone body β-hydroxybutyrate, achieved through the in vivo administration of its precursor 1,3-butanediol (BD) to rats, could impact interscapular BAT (iBAT) mitochondrial biochemistry and functionality. We examined the effects induced by BD within 3 h and after 2 weeks of treatment. A large-scale quantitative proteomics approach, coupling liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, and Western blot associated with functional studies by respirometry allowed us to evaluate the changes in iBAT mitochondrial protein expression and bioenergetics induced by BD. BD administration increased β-hydroxybutyrate plasma levels, which correlated with an enhancement in iBAT mitochondrial respiration rate, likely due to the activation of the respiratory chain and uncoupling protein-1. The proteomic analysis demonstrated that BD influenced the mitochondrial levels of specific subunits belonging to the five respiratory complexes, uncoupling protein-1, and proteins involved in propanoate metabolism. BD administration also induced lysine β-hydroxybutyrylation of mitochondrial proteins, including specific subunits of the respiratory chain complexes and uncoupling protein-1. Most of the BD-induced effects were observed within 3 h of its administration and persisted/increased after 2 weeks of treatment. In conclusion, by using BD to increase β-hydroxybutyrate levels, we provide evidence supporting the role of β-hydroxybutyrate as a signaling molecule capable of rapidly modulating BAT physiology by acting at the mitochondrial level.

Keywords:  brown adipocyte; ketone bodies; metabolism; mitochondria; thermogenesis

DOI:  https://doi.org/10.1096/fj.202401592RR
Free Radic Biol Med. 2024 Nov 16. pii: S0891-5849(24)01018-9. [Epub ahead of print]226 237-250

Inducible and reversible SOD2 knockdown in mouse skeletal muscle drives impaired pyruvate oxidation and reduced metabolic flexibility.

Ethan L Ostrom, Rudy Stuppard, Aurora Mattson-Hughes, David J Marcinek.

   INTRODUCTION: Skeletal muscle mitochondrial dysfunction is a key characteristic of aging muscle and contributes to age related diseases such as sarcopenia, frailty, and type 2 diabetes. Mitochondrial oxidative stress has been implicated as a driving factor in these age-related diseases, however whether it is a cause, or a consequence of mitochondrial dysfunction remains to be determined. The development of flexible genetic models is an important tool to test the mechanistic role of mitochondrial oxidative stress on skeletal muscle metabolic dysfunction. We characterize a new model of inducible and reversible mitochondrial redox stress using a tetracycline controlled skeletal muscle specific short hairpin RNA targeted to superoxide dismutase 2 (iSOD2).
METHODS: iSOD2 KD and control (CON) animals were administered doxycycline for 3- or 12- weeks and followed for up to 24 weeks and mitochondrial respiration and muscle contraction were measured to define the time course of SOD2 KD and muscle functional changes and recovery.
RESULTS: Maximum knockdown of SOD2 protein occurred by 6 weeks and recovered by 24 weeks after DOX treatment. Mitochondrial aconitase activity and maximum mitochondrial respiration declined in KD muscle by 12 weeks and recovered by 24 weeks. There were no significant differences in antioxidant or mitochondrial biogenesis genes between groups. Twelve-week KD showed a small, but significant decrease in muscle fatigue resistance. The primary phenotype was reduced metabolic flexibility characterized by impaired pyruvate driven respiration when other substrates are present. The pyruvate dehydrogenase kinase inhibitor dichloroacetate partially restored pyruvate driven respiration, while the thiol reductant DTT did not.
CONCLUSION: We use a model of inducible and reversible skeletal muscle SOD2 knockdown to demonstrate that elevated matrix superoxide reversibly impairs mitochondrial substrate flexibility characterized by impaired pyruvate oxidation. Despite the bioenergetic effect, the limited change in gene expression suggests that the elevated redox stress in this model is confined to the mitochondrial matrix.

Keywords:  Inducible SOD2 knockdown; Metabolic inflexibility; Mitochondrial oxidative stress; Mitochondrial respiration; Pyruvate oxidation; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.310
Cardiovasc Diabetol. 2024 Nov 15. 23(1): 408

SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling.

Sven O Göpel, Damilola Adingupu, Jue Wang, Elizaveta Semenova, Margareta Behrendt, Rasmus Jansson-Löfmark, Christine Ahlström, Ann-Cathrine Jönsson-Rylander, V Sashi Gopaul, Russell Esterline, Li-Ming Gan, Rui-Ping Xiao.

   BACKGROUND: SGLT2 inhibitors, a T2DM medication to lower blood glucose, markedly improve cardiovascular outcomes but the underlying mechanism(s) are not fully understood. SGLT2i's produce a unique metabolic pattern by lowering blood glucose without increasing insulin while increasing ketone body and glucagon levels and reducing body weight. We tested if glucagon signaling contributes to SGLT2i induced improvement in CV function.
METHODS: Cardiac contractility and coronary flow velocity reserve (CFVR) were monitored in ob/ob mice and rhesus monkeys with metabolic syndrome using echocardiography. Metabolic status was characterized by measuring blood ketone levels, glucose tolerance during glucose challenge and Arg and ADMA levels were measured. Baysian models were developed to analyse the data.
RESULTS: Dapagliflozin improved CFVR and contractility, co-application of a glucagon receptor inhibitor (GcgRi) blunted the effect on CFVR but not contractility. Dapagliflozin increased the Arg/ADMA ratio and ketone levels and co-treatment with GcgRi blunted only the Dapagliflozin induced increase in Arg/ADMA ratio but not ketone levels.
CONCLUSIONS: Since GcgRi co-treatment only reduced the Arg/ADMA increase we hypothesize that dapagliflozin via a glucagon-signaling dependent pathway improves vascular function through the NO-signaling pathway leading to improved vascular function. Increase in ketone levels might be a contributing factor in SGLT2i induced contractility increase and does not require glucagon signaling.

Keywords:  Argenine/ADMA ratio; Cardiac contractility; Coronary flow velocity reserve; Echocardiography; Glucagon; Heart failure; Metabolic syndrome; SGLT2 inhibitor

DOI:  https://doi.org/10.1186/s12933-024-02491-w
Sci Rep. 2024 Nov 19. 14(1): 28642

Metabolic flexibility to lipid during exercise is not associated with metabolic health outcomes in individuals without obesity.

Rodrigo Fernández-Verdejo, Juan Gutiérrez-Pino, Thomas Hayes-Ortiz, Hermann Zbinden-Foncea, Claudio Cabello-Verrugio, Mayalen Valero-Breton, Mauro Tuñón-Suárez, Ronald Vargas-Foitzick, Jose E Galgani.

  A low metabolic flexibility to lipid (MetF-lip) in skeletal muscle may promote ectopic lipid accumulation, thus inducing metabolic disturbances. We aimed to determine the association between MetF-lip in skeletal muscle and metabolic health outcomes in individuals without obesity. We also explored the association between MetF-lip and the inflammatory signaling pathway in skeletal muscle. This was a cross-sectional study in 17 individuals aged (median [IQR]) 55.4 [48.6, 58.5] years, with a BMI of 24.4 [22.6, 26.0] kg/m2. MetF-lip was assessed as the increase in relative lipid oxidation during a single exercise session (~ 50% VO2max, 2 hours), quantified as the drop in whole-body respiratory exchange ratio (ΔRER = RER at 2 hours - maximum RER attained). HOMA-IR, metabolic syndrome z-score, fat percentage, trunk-to-appendicular fat, and VO2max were included as metabolic health outcomes. The abundance of proteins of the inflammatory pathway was analyzed in resting muscle. Acute exercise progressively increased relative lipid oxidation (ΔRER = -0.04 [-0.08, -0.02]). MetF-lip was not associated with any metabolic health outcome but correlated inversely with p-p38Thr180/Tyr182 in muscle. A low MetF-lip in skeletal muscle does not seem a major determinant of metabolic disturbances but associates with a partial activation of the inflammatory signaling in individuals without obesity.

Keywords:  Body composition; Cardiorespiratory Fitness; Insulin resistance; Mitogen-activated protein kinases

DOI:  https://doi.org/10.1038/s41598-024-79092-w
Sci Rep. 2024 11 16. 14(1): 28296

Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.

Kaade Edgar, Mausbach Simone, Erps Nina, Sylvester Marc, Shakeri Farhad, Ron D Jachimowicz, Gieselmann Volkmar, Thelen Melanie.

Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine. Deactivation of mTORC1 in vivo after short-term starvation causes a depletion of mTORC1 and the associated Ragulator complex in hepatic lysosomes, resulting in diminished phosphorylation of mTORC1 target proteins. While mTORC1 lysosomal protein levels and activity in liver were restored after long-term starvation, the lysosomal levels of Ragulator remained constantly reduced. To determine whether this mTORC1 activity pattern may be organ-specific, we further investigated the key metabolic organs muscle and brain. mTORC1 inactivation, but not re-activation, occurred in muscle after a starvation of 12 h or longer. In brain, mTORC1 activity remained unchanged during starvation. As mTORC1 deactivation is known to induce autophagy, we further investigated the more than 150 non-lysosomal proteins enriched in the lysosomal fraction upon starvation. Proteasomal, cytosolic and peroxisomal proteins dominated after short-term starvation, while after long-term starvation, mainly proteasomal and mitochondrial proteins accumulated, indicating ordered autophagic protein degradation.

DOI: https://doi.org/10.1038/s41598-024-78873-7
JCI Insight. 2024 Nov 22. pii: e184279. [Epub ahead of print]9(22):

Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.

Andrew S Perry, Paolo Piaggi, Shi Huang, Matthew Nayor, Jane Freedman, Kari E North, Jennifer E Below, Clary B Clish, Venkatesh L Murthy, Jonathan Krakoff, Ravi V Shah.

  Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.

Keywords:  Amino acid metabolism; Carbohydrate metabolism; Intermediary metabolism; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.184279
bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

DOI: https://doi.org/10.1101/2024.10.31.621317
Heart Lung Circ. 2024 Nov 18. pii: S1443-9506(24)01770-0. [Epub ahead of print]

A Cross-Sectional Study of Capillary Blood Ketone Concentrations in Heart Failure Based on Sodium-Glucose Co-Transporter-2 Inhibitor Use and Heart Failure Type.

Jia Yong Tan, Luke Andrew Ephraums, Joshua Mark Inglis, Huyen Thi Thanh Nguyen, Mahesh Michael Umapathysivam, Natalie Jane Simpson, Josephine Helen Harris, Christine Mary Burdeniuk, Carmine Gerardo De Pasquale, Tilenka Rosemary Jenni Thynne.

   BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are standard-of-care treatment in heart failure (HF). The risk of ketosis in patients with HF is unclear, especially during hospitalisation.
AIM: We aimed to evaluate the normal ketone concentration range in HF patients.
METHOD: We performed a cross-sectional study of inpatients with acutely decompensated HF and outpatients with stable HF. Ketone concentrations were measured and analysed based on SGLT2i use. Baseline demographic data (age, gender, body mass index [BMI]), time since last meal, HF type, type 2 diabetes status, insulin use, and blood parameters (creatinine, glycosylated haemoglobin A1c [HbA1c] and N-terminal pro-B-type natriuretic peptide) were collected from patients or medical records. The primary outcome was capillary blood ketone concentration in patients with acute decompensated HF and stable chronic HF stratified by SGLT2i use. Multivariate regression was also performed using ketones as the outcome variable, with age, gender, BMI, glucose levels, HbA1c, time since last meal and presence of insulin therapy as predictor variables.
RESULTS: A total of 20 individuals with decompensated HF (n=5 SGLT2i treated) and 47 with stable chronic HF (n=22 SGLT2i treated) were recruited. Median ketone concentrations were similar in all groups irrespective of SGLT2i use and the presence of acute decompensation (0.1 mmol/L, biggest interquartile range 0.2 mmol/L, p=0.49). Apart from time from last meal, multivariate regression analysis showed no association of ketone concentration with SGLT2i use, age, gender, BMI, type 2 diabetes status, insulin use and blood glucose level.
CONCLUSIONS: Ketone concentrations were low in individuals with HF regardless of SGLT2i use or the presence of acute decompensation.

Keywords:  Heart failure; Ketones; Sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.1016/j.hlc.2024.07.013
Med Sci (Paris). 2024 Nov;40 Hors série n° 1 76

[Human skeletal muscle ageing atlas].

Dounia Bouragba.

DOI: https://doi.org/10.1051/medsci/2024160
Arch Pharm Res. 2024 Nov 16.

Saponins as potential novel NLRP3 inflammasome inhibitors for inflammatory disorders.

Jiamei Tang, Yaxiao Liu, Ying Wu, Shixing Li, Dongdong Zhang, Haifang Wang, Wei Wang, Xiaomei Song, Yuze Li.

  Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is a downstream protein from the pattern recognition receptor family that forms the NLRP3 inflammasome. The NLRP3 inflammasome releases caspase-1, IL-1β, and IL-18, contributing to inflammatory responses associated with diabetes mellitus, arthritis, and ischemia-reperfusion injury. Recent studies suggest that specific saponin monomers and extracts from traditional Chinese medicines can inhibit inflammatory responses and related pathways, including the production of inflammatory factors. MCC950 is one of the most influential and specific NLRP3 inhibitors. Comparative molecular docking studies have identified 22 of the 37 saponin components as more robust binders to NLRP3 than MCC950. Dioscin, polyphyllin H, and saikosaponin-a have the highest binding affinities and potential NLRP3 inhibitors, offering a theoretical basis for developing novel anti-inflammatory therapies.

Keywords:  Dioscin; NLRP3 inflammation; Polyphyllin H; Saikosaponin-a; Steroidal saponin; Triterpenoid saponin

DOI:  https://doi.org/10.1007/s12272-024-01517-x
Sci Rep. 2024 11 18. 14(1): 28550

Analysis of physiological and biochemical changes and metabolic shifts during 21-Day fasting hypometabolism.

Zhongquan Dai, Hongyu Zhang, Xiukun Sui, Feng Wu, Cheng Zhang, Zhiqi Fan, Hailong Wang, Yaxiu Guo, Chao Yang, Siyu Jiang, Linjie Wang, Bingmu Xin, Yinghui Li.

  This study aimed to evaluate the impact of prolonged fasting on the physiological and biochemical alterations and metabolic shifts in healthy adults and to provide experimental data and theoretical support for the hypometabolic state induced by prolonged fasting. Thirteen volunteers were selected through public recruitment to undergo a 21-day complete fasting experiment. The experimental period lasted 34 days, including a 3-day baseline, 21-day completing fasting, 5-day calorie restriction and 5-day full recovery diet. Physiological indicators such as body weight, blood pressure, blood glucose, blood ketones, and blood uric acid were evaluated along with resting metabolic rate, routine blood tests, liver function, and heart function indexes employing traditional approaches. During the 21-day complete fasting period, there was a significant decrease in body weight (average - 14.96 ± 1.55%), a reduction in blood glucose (average - 21.63 ± 0.058%), an increase in blood ketones (from baseline 0.1 ± 0.04 mmol/L to 6.61 ± 1.25 mmol/L) and blood uric acid (from baseline 385.38 ± 57.78 µmol/L to 866.31 ± 172.01 µmol/L), a continuous decline in resting energy expenditure (average - 20.3 ± 11.13%), and the respiratory quotient tending towards fat metabolism. Most of the items in the complete blood count and liver indicators remained stable and within the normal range. Heart function showed functional adaptive changes without structural damage. Prolonged fasting can reduce the body's resting energy expenditure and adapt to body weight loss through physiological regulatory mechanisms without adverse effects on basic physiological functions or the structure of important organs. Under medical supervision, healthy adults can safely engage in prolonged fasting for up to 21 days with metabolic adaption and no damage to pivotal organ, which could provide potential technical support for human health and survival strategies in extreme conditions such as food shortages during long-duration manned spaceflight.

Keywords:  Energy expenditure; Hypometabolism, physiological safety; Manned spaceflight; Prolonged fasting; Survival protection techniques

DOI:  https://doi.org/10.1038/s41598-024-80049-2
Am J Physiol Cell Physiol. 2024 Nov 21.

Human skeletal muscle possesses an epigenetic memory of high intensity interval training.

Andrea M Pilotto, Daniel C Turner, Raffaele Mazzolari, Emanuela Crea, Lorenza Brocca, Maria Antonietta Pellegrino, Danilo Miotti, Roberto Bottinelli, Adam P Sharples, Simone Porcelli.

   INTRODUCTION: Human skeletal muscle displays an epigenetic memory of resistance exercise induced by hypertrophy. It is unknown, however, whether high-intensity interval training (HIIT) also evokes an epigenetic muscle memory. This study employed repeated training intervention interspersed with a detraining period to assess epigenetic memory of HIIT.
METHODS: Twenty healthy subjects (25±5yrs) completed two HIIT interventions (training and retraining) lasting 2 months, separated by 3 months of detraining. Measurements at baseline, after training, detraining and retraining included maximal oxygen consumption (V̇ O2max). Vastus lateralis biopsies were taken for genome-wide DNA methylation and targeted gene expression analyses.
RESULTS: V̇ O2max improved during training and retraining (p<0.001) without differences between interventions (p>0.58). Thousands of differentially methylated positions (DMPs) predominantly demonstrated a hypomethylated state after training, retained even after 3-months exercise cessation and into retraining. Five genes; ADAM19, INPP5a, MTHFD1L, CAPN2, SLC16A3 possessed differentially methylated regions (DMRs) with retained hypomethylated memory profiles and increased gene expression. The retained hypomethylation during detraining was associated with an enhancement in expression of the same genes even after 3 months of detraining. SLC16A3, INPP5a, CAPN2 are involved in lactate transport and calcium signaling.
CONCLUSIONS: Despite similar physiological adaptations between training and retraining, memory profiles were found at epigenetic and gene expression level, characterized by retained hypomethylation and increased gene expression after training into long-term detraining and retraining. These genes were associated with calcium signaling and lactate transport. Whilst significant memory was not observed in physiological parameters, our novel findings indicate that human skeletal muscle possesses an epigenetic memory of HIIT.

Keywords:  DNA methylation; endurance exercise; gene transcription; muscle memory

DOI:  https://doi.org/10.1152/ajpcell.00423.2024
Immunity. 2024 Nov 15. pii: S1074-7613(24)00492-8. [Epub ahead of print]

Acute suppression of mitochondrial ATP production prevents apoptosis and provides an essential signal for NLRP3 inflammasome activation.

Benedikt S Saller, Svenja Wöhrle, Larissa Fischer, Clara Dufossez, Isabella L Ingerl, Susanne Kessler, Maria Mateo-Tortola, Oliver Gorka, Felix Lange, Yurong Cheng, Emilia Neuwirt, Adinarayana Marada, Christoph Koentges, Chiara Urban, Philipp Aktories, Peter Reuther, Sebastian Giese, Susanne Kirschnek, Carolin Mayer, Johannes Pilic, Hugo Falquez-Medina, Aline Oelgeklaus, Veerasikku Gopal Deepagan, Farzaneh Shojaee, Julia A Zimmermann, Damian Weber, Yi-Heng Tai, Anna Crois, Kevin Ciminski, Remi Peyronnet, Katharina S Brandenburg, Gang Wu, Ralf Baumeister, Thomas Heimbucher, Marta Rizzi, Dietmar Riedel, Martin Helmstädter, Joerg Buescher, Konstantin Neumann, Thomas Misgeld, Martin Kerschensteiner, Peter Walentek, Clemens Kreutz, Ulrich Maurer, Angelika S Rambold, James E Vince, Frank Edlich, Roland Malli, Georg Häcker, Katrin Kierdorf, Chris Meisinger, Anna Köttgen, Stefan Jakobs, Alexander N R Weber, Martin Schwemmle, Christina J Groß, Olaf Groß.

  How mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.

Keywords:  ATP; NLRP3; OXPHOS; apoptosis; bioenergetics; cell death; chemical biology; cytochrome c; inflammasome; mitochondria; pyroptosis

DOI:  https://doi.org/10.1016/j.immuni.2024.10.012
Br J Nutr. 2024 Nov 22. 1-27

Butyrate attenuates high-fat diet induced glomerulopathy through GPR43-Sirt3 pathway.

Ying Shi, Lin Xing, Ruoyi Zheng, Xin Luo, Fangzhi Yue, Xingwei Xiang, Anqi Qiu, Junyan Xie, Ryan Russell, Dongmei Zhang.

  The incidence of obesity related glomerulopathy (ORG) is rising worldwide with very limited treatment methods. Paralleled with the gut-kidney axis theory, beneficial effects of butyrate, one of short-chain fatty acids produced by gut microbiota, on metabolism and certain kidney diseases have gained growing attention. However, the effects of butyrate on ORG and its underlying mechanism are largely unexplored. In this study, a mice model of ORG was established with high-fat diet (HFD) feeding for 16 weeks, and sodium butyrate treatment was initiated at the 8th week. Podocytes injury, oxidative stress, and mitochondria function were evaluated in mice kidney and validated in vitro in palmitic acid (PA) treated-MPC5 cells. Further, the molecular mechanisms of butyrate on podocytes were explored. Compared with controls, sodium butyrate treatment alleviated kidney injuries and renal oxidative stress in HFD-fed mice. In MPC5 cells, butyrate ameliorated PA-induced podocyte damage and helped maintain the structure and function of the mitochondria. Moreover, the effects of butyrate on podocytes were mediated via GPR43-Sirt3 signal pathway, as evidenced by the diminished effects of butyrate with the intervention of GPR43 or Sirt3 inhibitors. In summary, we conclude that butyrate has therapeutic potential for the treatment of ORG. It attenuates HFD-induced ORG and podocytes injuries through the activation of GPR43-Sirt3 signaling pathway.

Keywords:  butyrate; mitochondria; obesity related glomerulopathy; podocytes

DOI:  https://doi.org/10.1017/S0007114524002964
Nutr Metab Cardiovasc Dis. 2024 Oct 06. pii: S0939-4753(24)00381-8. [Epub ahead of print]35(1): 103762

Circulating β-hydroxybutyrate levels are associated with major adverse clinical events in patients with acute myocardial infarction.

Yining Dai, Lixin Xie, Yeshen Zhang, Yu He, Haobin Liu, Siyu Kong, Weikun Chen, Hailing Li, Yuling Zhan, Ning Tan, Chongyang Duan, Pengcheng He, Yuanhui Liu, Ling Xue.

   BACKGROUND AND AIMS: Acute myocardial infarction is associated with high mortality, and effective biomarkers are required for the risk stratification. In cardiovascular diseases, circulating levels of ketone bodies (KB) such as β-hydroxybutyrate (β-OHB) and acetoacetate are altered. However, the relationship between circulating KB levels and major adverse clinical events (MACE) in patients with ST-elevation myocardial infarction (STEMI) is unknown.
METHODS AND RESULTS: Patients with STEMI undergoing percutaneous coronary intervention (PCI) between January 2010 to June 2020 were enrolled, and divided into T1 (<0.09 mmol/L, n = 219), T2 (0.09-0.28 mmol/L, n = 202), and T3 (>0.28 mmol/L, n = 211) tertiles according to the circulating β-OHB levels within 24 h of admission. The primary endpoint was in-hospital MACE. The incidence of in-hospital MACE in the T3 group (20.9 %) was significantly higher than in the T1 group (10.5 %) and T2 group (14.9 %) (P = 0.012). Multivariate logistic regression analysis showed that elevated circulating β-OHB levels were associated with an increased risk of all-cause mortality and MACE during hospitalization (OR = 1.38, 95 % CI = 1.08-1.77, P = 0.009). During follow-up period, multivariate Cox regression analyses showed that elevated circulating β-OHB levels were associated with higher all-cause mortality and MACE (HR = 1.35, 95 % CI = 1.17-1.56, P < 0.001). The impact of β-OHB on MACE were similar for all the subgroups.
CONCLUSION: Elevated circulating β-OHB levels within 24 h of admission were associated with an increased risk of MACE in patients with STEMI undergoing PCI, and could be a promising prognosis biomarker.

Keywords:  Ketone bodies; Major adverse clinical events; ST-Elevation myocardial infarction; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.numecd.2024.10.002
Neurobiol Dis. 2024 Nov 16. pii: S0969-9961(24)00342-5. [Epub ahead of print] 106740

Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.

Typhaine Comyn, Thomas Preat, Alice Pavlowsky, Pierre-Yves Plaçais.

  Mitochondria are classically viewed as 'on demand' energy suppliers to neurons in support of their activity. In order to adapt to a wide range of demands, mitochondria need to be highly dynamic and capable of adjusting their metabolic activity, shape, and localization. Although these plastic properties give them a central support role in basal neuronal physiology, recent lines of evidence point toward a role for mitochondria in the regulation of high-order cognitive functions such as memory formation. In this review, we discuss the interplay between mitochondrial function and neural plasticity in sustaining memory formation at the molecular and cellular levels. First, we explore the global significance of mitochondria in memory formation. Then, we will detail the memory-relevant cellular and molecular mechanisms of mitochondrial plasticity. Finally, we focus on those mitochondrial functions, including but not limited to ATP production, that give mitochondria their pivotal role in memory formation. Altogether, this review highlights the central role of mitochondrial structural and functional plasticity in supporting and regulating neuronal plasticity and memory.

Keywords:  Energy; Glia; Memory; Mitochondria dynamics; TCA cycle

DOI:  https://doi.org/10.1016/j.nbd.2024.106740
Eur J Appl Physiol. 2024 Nov 22.

Skeletal muscle hypertrophy and enhanced mitochondrial bioenergetics following electrical stimulation exercises in spinal cord injury: a randomized clinical trial.

Ashraf S Gorgey, Refka E Khalil, William Carter, Jeannie Rivers, Qun Chen, Edward J Lesnefsky.

  We examined the combined effects of neuromuscular electrical stimulation-resistance training (NMES-RT) and functional electrical stimulation-lower extremity cycling (FES-LEC) compared to passive movement training (PMT) and FES-LEC on mitochondrial electron transport chain (ETC) complexes and citrate synthase (CS) in adults with SCI. Thirty-two participants with chronic SCI were randomized to 24 weeks of NMES-RT + FES [n = 16 (14 males and 2 females) with an age range of 20-54 years old] or PMT + FES [n = 16 (12 males and 4 females) with an age range of 21-61 years old]. The NMES-RT + FES group underwent 12 weeks of surface NMES-RT using ankle weights followed by an additional 12 weeks of FES-LEC. The PMT + FES performed 12 weeks of passive leg extension movements followed by an additional 12 weeks of FES-LEC. Using repeated measures design, muscle biopsies of the vastus lateralis were performed at baseline (BL), post-intervention 1 (P1) and post-intervention 2 (P2). Spectrophotometer was used to measure ETC complexes (I-III) and CS using aliquots of the homogenized muscle tissue. Magnetic resonance imaging was used to measure skeletal muscle CSAs. A time effect was noted on CS (P = 0.001) with an interaction between both groups (P = 0.01). 46% of the participants per group had zero activities of CI without any changes following both interventions. A time effect was noted in CII (P = 0.023) following both interventions. Finally, NMES-RT + FES increased CIII at P1 compared to BL (P = 0.023) without additional changes in P2 or following PMT + FES intervention. Skeletal muscle hypertrophy may potentially enhance mitochondrial bioenergetics after SCI. NMES-RT is likely to enhance the activities of complex III in sedentary persons with SCI. Clinical trials # NCT02660073.

Keywords:  Citrate synthase; Electron transport chain; Functional electrical stimulation; Mitochondrial complexes; Neuromuscular electrical stimulation; Resistance training; Spinal cord injury

DOI:  https://doi.org/10.1007/s00421-024-05661-6
Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263

AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.

Hui Jiang.

In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.

DOI: https://doi.org/10.1016/j.molcel.2024.10.040
J Cachexia Sarcopenia Muscle. 2024 Nov 19.

Anabolic Sensitivity in Healthy, Lean, Older Men Is Associated With Higher Expression of Amino Acid Sensors and mTORC1 Activators Compared to Young.

Oscar Horwath, Marcus Moberg, Nathan Hodson, Sebastian Edman, Mats Johansson, Eva Andersson, Gerrit van Hall, Olav Rooyackers, Andrew Philp, William Apró.

   BACKGROUND: Sarcopenia is thought to be underlined by age-associated anabolic resistance and dysregulation of intracellular signalling pathways. However, it is unclear whether these phenomena are driven by ageing per se or other confounding factors.
METHODS: Lean and healthy young (n = 10, 22 ± 3 years, BMI; 23.4 ± 0.8 kg/m2) and old men (n = 10, 70 ± 3 years, BMI; 22.7 ± 1.3 kg/m2) performed unilateral resistance exercise followed by intake of essential amino acids (EAA). Muscle biopsies were collected from the rested and the exercised leg before, immediately after and 60 and 180 min after EAA intake. Muscle samples were analysed for amino acid concentrations, muscle protein synthesis (MPS) and associated anabolic signalling.
RESULTS: Following exercise, peak plasma levels of EAA and leucine were similar between groups, but the area under the curve was ~11% and ~28% lower in Young (p < 0.01). Absolute levels of muscle EAA and leucine peaked 60 min after exercise, with ~15 and ~21% higher concentrations in the exercising leg (p < 0.01) but with no difference between groups. MPS increased in both the resting (~0.035%·h-1 to 0.056%·h-1, p < 0.05) and exercising leg (~0.035%·h-1 to 0.083%·h-1, p < 0.05) with no difference between groups. Phosphorylation of S6K1Thr389 increased to a similar extent in the exercising leg in both groups but was 2.8-fold higher in the resting leg of Old at the 60 min timepoint (p < 0.001). Phosphorylation of 4E-BP1Ser65 increased following EAA intake and exercise, but differences between legs were statistically different only at 180 min (p < 0.001). However, phosphorylation of this site was on average 78% greater across all timepoints in Old (p < 0.01). Phosphorylation of eEF2Thr56 was reduced (~66% and 39%) in the exercising leg at both timepoints after EAA intake and exercise, with no group differences (p < 0.05). However, phosphorylation at this site was reduced by ~27% also in the resting leg at 60 min, an effect that was only seen in Old (p < 0.01). Total levels of Rheb (~45%), LAT1 (~31%) and Rag B (~31%) were higher in Old (p < 0.001).
CONCLUSION: Lean and healthy old men do not manifest AR as evidenced by potent increases in MPS and mTORC1 signalling following EAA intake and exercise. Maintained anabolic sensitivity with age appears to be a function of a compensatory increase in basal levels of proteins involved in anabolic signalling. Therefore, our results suggest that age per se does not appear to cause AR in human skeletal muscle.

Keywords:  amino acid sensing; cell signalling; protein synthesis; resistance exercise; sarcopenia

DOI:  https://doi.org/10.1002/jcsm.13613
EXCLI J. 2024 ;23 1208-1225

Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions.

Dylan Wilburn, Emma Fletcher, Evlampia Papoutsi, William T Bohannon, Gleb Haynatzki, Bernd Zechmann, Yuqian Tian, Iraklis I Pipinos, Dimitrios Miserlis, Panagiotis Koutakis.

  Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in myopathy in affected skeletal muscles. Improving our understanding of PAD and developing novel treatment strategies necessitates a comprehensive examination of cellular structural alterations that occur in the muscles with disease progression. Here we aimed to employ electron microscopy to quantify skeletal muscle ultrastructural alterations responsible for the myopathy of PAD. Fifty-two participants (22 controls, 10 PAD Stage II, and 20 PAD Stage IV) were enrolled. Gastrocnemius biopsies were obtained to determine mitochondrial respiration and oxidative stress. Skeletal muscle sarcomere, mitochondria, lipid droplets, and sarcoplasm were assessed using transmission electron microscopy and focused ion beam scanning electron microscopy. Controls and PAD Stage II patients underwent walking performance tests: 6-minute walking test, 4-minute walking velocity, and maximum graded treadmill test. We identified several prominent ultrastructural modifications in PAD gastrocnemius, including reduced sarcomere dimensions, alterations in mitochondria number and localization, myofibrillar disorientation, changes in lipid droplets, and modifications in mitochondria-lipid droplet contact area. These changes correlated with impaired mitochondrial respiration and increased ROS production. We observed progressive deterioration in mitochondrial parameters across PAD stages. Stage II PAD showed impaired mitochondrial function and structure, while stage IV exhibited further deterioration, more pronounced structural alterations, and a decrease in mitochondrial content. The walking performance of Stage II PAD patients was significantly reduced. Our findings suggest that pathological mitochondria play a key role in the skeletal muscle dysfunction of PAD patients and represent an important target for therapeutic interventions aimed at improving clinical and functional outcomes in this patient population. Our data indicate that treatments should be implemented early and may include therapies designed to preserve and enhance mitochondrial biogenesis and respiration, optimize mitochondrial-lipid droplet interactions, or mitigate oxidative stress. Translational Perspective: Peripheral artery disease (PAD) is characterized by skeletal muscle and mitochondrial dysfunction. Ultrastructural changes in skeletal muscle myofibers and mitochondria morphology can provide significant information on the PAD pathophysiology. Here, we investigated skeletal muscle and mitochondria morphological and functional changes at the sarcomere level and across the disease progression and have found that sarcomere lengths and mitochondria count and function are associated with disease progression, indicating loss of skeletal muscle contractile and metabolic function. Ultrastructural changes in the PAD skeletal muscle can provide significant information in the development of new treatments.

Keywords:  intramyocellular lipids; mitochondria; muscle; peripheral artery disease; sarcomere atrophy; sarcoplasm

DOI:  https://doi.org/10.17179/excli2024-7592
iScience. 2024 Nov 15. 27(11): 111212

MOTS-c modulates skeletal muscle function by directly binding and activating CK2.

Hiroshi Kumagai, Su-Jeong Kim, Brendan Miller, Hirofumi Zempo, Kumpei Tanisawa, Toshiharu Natsume, Shin Hyung Lee, Junxiang Wan, Naphada Leelaprachakul, Michi Emma Kumagai, Ricardo Ramirez, Hemal H Mehta, Kevin Cao, Tae Jung Oh, James A Wohlschlegel, Jihui Sha, Yuichiro Nishida, Noriyuki Fuku, Shohei Dobashi, Eri Miyamoto-Mikami, Mizuki Takaragawa, Mizuho Fuku, Toshinori Yoshihara, Hisashi Naito, Ryoko Kawakami, Suguru Torii, Taishi Midorikawa, Koichiro Oka, Megumi Hara, Chiharu Iwasaka, Yosuke Yamada, Yasuki Higaki, Keitaro Tanaka, Kelvin Yen, Pinchas Cohen.

  MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

Keywords:  Physiology; cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.111212
Mol Biol Rep. 2024 Nov 21. 52(1): 5

Moderate-intensity aerobic exercise inhibits cell pyroptosis to improve myocardial ischemia-reperfusion injury.

Yu Wang, Yushan Li, Chaofan Chen, Hailong Zhang, Weili Liu, Chao Wu, Haonan Chen, Ran Li, Jinghan Wang, Yingchao Shi, Shengfang Wang, Chuanyu Gao.

   BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) significantly impacts the patients with acute myocardial infarction (AMI), with the NLRP3-mediated necrosis exacerbates the pathological progression of myocardial infarction. Exercise, recognized as a crucial approach for both disease prevention and treatment, is widely utilized in clinical practice worldwide and has demonstrated broad effectiveness in cardiovascular disease (CVD) prevention.
PURPOSE: To explore the cardio protective effect of exercise preconditioning and the mechanism by which exercise modulation of NLRP3 improves myocardial ischemia and reperfusion injury.
METHODS AND RESULTS: In this study, C57BL/6 N mice were employed to establish an exercise preconditioning model and a MI/RI model. The exercise intervention involved moderate-intensity aerobic exercise on a treadmill (50-70% VO2max) for small animals. Our research findings indicate that moderate-intensity aerobic exercise intervention improved cardiac function, reduced myocardial injury and inflammatory response, decreased myocardial infarction area and degree of cell apoptosis in mice compared to those raised under conventional conditions. Additionally, the expression of NLRP3 in the myocardial tissue of mice with MI/RI was reduced after exercise intervention. Moreover, exercise inhibited the activation of apoptosis related proteins such as Caspase-1 and GSDMD, while reducing the levels of inflammatory factors such as IL-1β and IL-18.
CONCLUSIONS: This study found that moderate-intensity aerobic exercise can reduce the inflammatory response, reduce the degree of cell pyroptosis, reduce myocardial ischemia and reperfusion injury, and achieve endogenous protective effects on the myocardium.

Keywords:  Moderate-intensity aerobic exercise; Myocardial ischemia-reperfusion injury (MI/RI); NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1007/s11033-024-10065-y