bims-kimdis 2023-11-12 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–11–12
twenty-two papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications.
Effects of caloric restriction and ketogenic diet on renal fibrosis after ischemia/reperfusion injury.
Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review.
Changes in lipids and inflammation in adults with super-refractory status epilepticus on a ketogenic diet.
Ketogenic Diet: A Nutritional Therapeutic Tool for Lipedema?
Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.
The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases.
A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.
Metabolic effects of an oral carbohydrate-whey protein supplement after fasting in volunteers: A randomized controlled crossover trial.
LC-MS/MS method for quantitative profiling of ketone bodies, α-keto acids, lactate, pyruvate and their stable isotopically labelled tracers in human plasma: An analytical panel for clinical metabolic kinetics and interactions.
Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial.
Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice.
Mitophagy Activation by Urolithin A to Target Muscle Aging.
Acetate and succinate benefit host muscle energetics as exercise-associated post-biotics.
The effects of ketogenic dietary therapies on sleep: A scoping review.
Mechanisms of hepatic fatty acid oxidation and ketogenesis during fasting.
3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.
Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.
[GPR109A partly mediates inhibitory effects of β-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion].
Gut butyrate-producers confer post-infarction cardiac protection.
A century of mitochondrial research, 1922-2022.
Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.

Heliyon. 2023 Nov;9(11): e21098

β-Hydroxybutyrate as an epigenetic modifier: Underlying mechanisms and implications.

Yanqiu He, Xi Cheng, Tingting Zhou, Dongze Li, Juan Peng, Yong Xu, Wei Huang.

  Previous studies have found that β-Hydroxybutyrate (BHB), the main component of ketone bodies, is of physiological importance as a backup energy source during starvation or induces diabetic ketoacidosis when insulin deficiency occurs. Ketogenic diets (KD) have been used as metabolic therapy for over a hundred years, it is well known that ketone bodies and BHB not only serve as ancillary fuel substituting for glucose but also induce anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone deacetylase (HDAC), or G protein-coupled receptors (GPCRs). Recent advances in epigenetics, especially novel histone post-translational modifications (HPTMs), have continuously updated our understanding of BHB, which also acts as a signal transduction molecule and modification substrate to regulate a series of epigenetic phenomena, such as histone acetylation, histone β-hydroxybutyrylation, histone methylation, DNA methylation, and microRNAs. These epigenetic events alter the activity of genes without changing the DNA structure and further participate in the pathogenesis of related diseases. This review focuses on the metabolic process of BHB and BHB-mediated epigenetics in cardiovascular diseases, diabetes and complications of diabetes, neuropsychiatric diseases, cancers, osteoporosis, liver and kidney injury, embryonic and fetal development, and intestinal homeostasis, and discusses potential molecular mechanisms, drug targets, and application prospects.

Keywords:  DNA methylation; Epigenetics; Histone post-translational modification; Ketogenic diet; microRNAs; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.heliyon.2023.e21098
Heliyon. 2023 Nov;9(11): e21003

Effects of caloric restriction and ketogenic diet on renal fibrosis after ischemia/reperfusion injury.

E I Yakupova, D S Semenovich, P A Abramicheva, L D Zorova, I B Pevzner, N V Andrianova, V A Popkov, V N Manskikh, A D Bocharnikov, Y A Voronina, D B Zorov, E Y Plotnikov.

  The beneficial effects of caloric restriction (CR) and a ketogenic diet (KD) have been previously shown when performed prior to kidney injury. We investigated the effects of CR and KD on fibrosis development after unilateral kidney ischemia/reperfusion (UIR). Post-treatment with CR significantly (p < 0.05) affected blood glucose (2-fold decrease), ketone bodies (3-fold increase), lactate (1.5-fold decrease), and lipids (1.4-fold decrease). In the kidney, CR improved succinate dehydrogenase and malate dehydrogenase activity by 2-fold each, but worsened fibrosis progression. Similar results were shown for the KD, which restored the post-UIR impaired activities of succinate dehydrogenase, malate dehydrogenase, and α-ketoglutarate dehydrogenase (which was decreased 2-fold) but had no effect on fibrosis progression. Thus, our study shows that the use of CR or KD after UIR did not reduce the development of fibrosis, as shown by hydroxyproline content, western-blotting, and RT-PCR, whereas it caused significant metabolic changes in kidney tissue after UIR.

Keywords:  Caloric restriction; Glycolysis; Ischemia/reperfusion injury; Ketogenic diet; Kidney fibrosis; Krebs cycle

DOI:  https://doi.org/10.1016/j.heliyon.2023.e21003
Biomed J. 2023 Nov 06. pii: S2319-4170(23)00114-2. [Epub ahead of print] 100677

Impact of fasting & ketogenic interventions on the NLRP3 inflammasome: A narrative review.

Helena Neudorf, Jonathan P Little.

  Overactivation of the NLRP3 inflammasome is implicated in chronic low-grade inflammation associated with various disease states, including obesity, type 2 diabetes, atherosclerosis, Alzheimer's disease, and Parkinson's disease. Emerging evidence, mostly from cell and animal models of disease, supports a role for ketosis in general, and the main circulating ketone body beta-hydroxybutyrate (BHB) in particular, in reducing NLRP3 inflammasome activation to ameliorate chronic inflammation. As a result, interventions that can induce ketosis (e.g., fasting, intermittent fasting, time-restricted feeding/eating, very low-carbohydrate high-fat ketogenic diets) and/or increase circulating BHB (e.g., exogenous ketone supplementation) have garnered increasing interest for their therapeutic potential. The purpose of the present review is to summarize our current understanding of the literature on how ketogenic interventions impact the NLRP3 inflammasome across human, rodent and cell models. Overall, there is convincing evidence that ketogenic interventions, likely acting through multiple interacting mechanisms in a cell-, disease- and context-specific manner, can reduce NLRP3 inflammasome activation. The evidence supports a direct effect of BHB, although it is important to consider the myriad of other metabolic responses to fasting or ketogenic diet interventions (e.g., elevated lipolysis, low insulin, stable glucose, negative energy balance) that may also impact innate immune responses. Future research is needed to translate promising findings from discovery science to clinical application.

Keywords:  Beta-hydroxybutyrate; Fasting; Inflammation; Ketogenic diets; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.bj.2023.100677
Front Mol Biosci. 2023 ;10 1173039

Changes in lipids and inflammation in adults with super-refractory status epilepticus on a ketogenic diet.

Alex M Dickens, Tory P Johnson, Santosh Lamichhane, Anupama Kumar, Carlos A Pardo, Erie G Gutierrez, Norman Haughey, Mackenzie C Cervenka.

  Introduction: This study aims to test the hypothesis that increased ketone body production resulting from a ketogenic diet (KD) will correlate with reductions in pro-inflammatory cytokines and lipid subspecies and improved clinical outcomes in adults treated with an adjunctive ketogenic diet for super-refractory status epilepticus (SRSE). Methods: Adults (18 years or older) were treated with a 4:1 (fat: carbohydrate and protein) ratio of enteral KD as adjunctive therapy to pharmacologic seizure suppression in SRSE. Blood and urine samples and clinical measurements were collected at baseline (n = 10), after 1 week (n = 8), and after 2 weeks of KD (n = 5). In addition, urine acetoacetate, serum β-hydroxybutyrate, lipidomics, pro-inflammatory cytokines (IL-1β and IL-6), chemokines (CCL3, CCL4, and CXCL13), and clinical measurements were obtained at these three time points. Univariate and multivariate data analyses were performed to determine the correlation between ketone body production and circulating lipids, inflammatory biomarkers, and clinical outcomes. Results: Changes in lipids included an increase in ceramides, mono-hexosylceramide, sphingomyelin, phosphocholine, and phosphoserines, and there was a significant reduction in pro-inflammatory mediators, IL-6 and CXCL13, seen at 1 and 2 weeks of KD. Higher blood β-hydroxybutyrate levels at baseline correlated with better clinical outcomes; however, ketone body production did not correlate with other variables during treatment. Higher chemokine CCL3 levels following treatment correlated with a longer stay in the intensive care unit and a higher modified Rankin Scale score (worse neurologic disability) at discharge and 6-month follow up. Discussion: Adults receiving an adjunctive enteral ketogenic diet for super-refractory status epilepticus exhibit alterations in select pro-inflammatory cytokines and lipid species that may predict their response to treatment.

Keywords:  epilepsy; inflammation; ketogenic diet; lipid; status epilepticus

DOI:  https://doi.org/10.3389/fmolb.2023.1173039
Curr Obes Rep. 2023 Nov 04.

Ketogenic Diet: A Nutritional Therapeutic Tool for Lipedema?

Ludovica Verde, Elisabetta Camajani, Giuseppe Annunziata, Antoanstefan Sojat, Ljiljana V Marina, Annamaria Colao, Massimiliano Caprio, Giovanna Muscogiuri, Luigi Barrea.

   PURPOSE OF REVIEW: This review aims to provide an overview of the current evidence on the efficacy, also considering the anti-inflammatory properties and safety of very low-calorie ketogenic diet (VLCKD) as a potential treatment for lipedema, particularly in the context of obesity.
RECENT FINDINGS: Lipedema is a chronic disease characterized by abnormal and painful fat buildup on the legs and/or arms. It is often misdiagnosed as obesity or lymphedema. However, although lipedema and obesity can coexist, unlike obesity, lipedema usually affects the legs and thighs without affecting the feet or hands, and the abnormal deposition of adipose tissue in lipedema is painful. The current lifestyle interventions are often unsuccessful in the management of lipedema. There is no consensus on the most effective nutritional approach for managing lipedema. Recent studies have suggested that VLCKD may be an effective treatment for lipedema, demonstrating that it is also superior to other nutritional approaches such as Mediterranean diet or intermittent fasting. Lipedema is a chronic and debilitating disease characterized by abnormal and painful accumulation of adipose tissue in the legs. VLCKD has been shown to be an effective treatment for lipedema, especially in the context of obesity, due to its anti-inflammatory properties. However, further research is needed to determine the long-term safety and efficacy of VLCKD as a treatment for lipedema.

Keywords:  Diet; Fat; Inflammation; Lipedema; Nutrition; Obesity; Very low-calorie ketogenic diet

DOI:  https://doi.org/10.1007/s13679-023-00536-x
Sci Rep. 2023 Nov 09. 13(1): 19476

Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.

Carl M Öberg, Jan Sternby, Anders Nilsson, Markus Storr, Ralf Flieg, Kai Harenski, Viktoria Roos, Linda Källquist, Sture Hobro.

Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate-lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague-Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI - 0.6 to 1.2). Plasma glucose levels were reduced by 36% (- 4.5 mmol/L), p < 0.05 (95% CI - 6.7 to - 2.5). Standard base excess was increased from - 3.5 mmol/L (IQR - 4 to - 2) to 0.5 mmol/L (IQR - 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.

DOI: https://doi.org/10.1038/s41598-023-46715-7
Nat Rev Cardiol. 2023 Nov 03.

The role of the NLRP3 inflammasome and pyroptosis in cardiovascular diseases.

Stefano Toldo, Antonio Abbate.

An intense, stereotyped inflammatory response occurs in response to ischaemic and non-ischaemic injury to the myocardium. The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a finely regulated macromolecular protein complex that senses the injury and triggers and amplifies the inflammatory response by activation of caspase 1; cleavage of pro-inflammatory cytokines, such as pro-IL-1β and pro-IL-18, to their mature forms; and induction of inflammatory cell death (pyroptosis). Inhibitors of the NLRP3 inflammasome and blockers of IL-1β and IL-18 activity have been shown to reduce injury to the myocardium and pericardium, favour resolution of the inflammation and preserve cardiac function. In this Review, we discuss the components of the NLRP3 inflammasome and how it is formed and activated in various ischaemic and non-ischaemic cardiac pathologies (acute myocardial infarction, cardiac dysfunction and remodelling, atherothrombosis, myocarditis and pericarditis, cardiotoxicity and cardiac sarcoidosis). We also summarize current preclinical and clinical evidence from studies of agents that target the NLRP3 inflammasome and related cytokines.

DOI: https://doi.org/10.1038/s41569-023-00946-3
Commun Biol. 2023 11 03. 6(1): 1115

A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.

Amelia Palermo, Shen Li, Johanna Ten Hoeve, Akshay Chellappa, Alexandra Morris, Barbara Dillon, Feiyang Ma, Yijie Wang, Edward Cao, Byourak Shabane, Rebeca Acín-Perez, Anton Petcherski, A Jake Lusis, Stanley Hazen, Orian S Shirihai, Matteo Pellegrini, Vaithilingaraja Arumugaswami, Thomas G Graeber, Arjun Deb.

The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.

DOI: https://doi.org/10.1038/s42003-023-05478-7
Nutrition. 2023 Oct 04. pii: S0899-9007(23)00279-4. [Epub ahead of print]117 112251

Metabolic effects of an oral carbohydrate-whey protein supplement after fasting in volunteers: A randomized controlled crossover trial.

Paulo L B Nogueira, Cristiane Coimbra de Paula, Diana Borges Dock-Nascimento, José Eduardo de Aguilar-Nascimento.

   OBJECTIVE: Oral supplements containing carbohydrates (CHOs) can be used to reduce preoperative fasting time. The aim of this study was to investigate the early metabolic and acute phase responses to a clear, oral supplement containing CHO and whey protein (WP) in young, healthy volunteers during a fasting-induced organic response.
METHODS: In this controlled crossover clinical trial, volunteers were randomized into groups after a 12-h fast: the CHO+WP group consumed 200 mL CHO enriched with WP (n = 30); the CHO group members consumed 200 mL water plus maltodextrin (n = 30), and the Fast group was fasted only (n = 30). Blood samples were collected after fasting and 3 h after ingestion of the supplement. The samples were analyzed for glucose, glycated hemoglobin, insulin, C-reactive protein, β-hydroxybutyrate, triacylglycerols, albumin, chlorine, and sodium. After 7 d, the groups were inverted, so all volunteers entered the three groups.
RESULTS: The nutritional intervention did not change the biochemical parameters related to the acute phase response or insulin resistance; however, there was a statistically significant reduction (P < 0.001) in serum β-hydroxybutyrate in the CHO+WP group (0.05 ± 0.08 mmol/L) compared with the other two groups (Fast group: 0.11 ± 0.08 mmol/L; CHO group: 0.09 ± 0.13 mmol/L).
CONCLUSIONS: After overnight fasting, the oral supplement containing CHO and WP decreased ketosis. These findings may help select the most efficient oral supplement to be given 2 to 3 h before elective surgeries.

Keywords:  Fasting; Ketone bodies; Metabolism, Blood glucose; Nutritional supplements; Preoperative fast

DOI:  https://doi.org/10.1016/j.nut.2023.112251
J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Oct 31. pii: S1570-0232(23)00316-1. [Epub ahead of print]1230 123906

LC-MS/MS method for quantitative profiling of ketone bodies, α-keto acids, lactate, pyruvate and their stable isotopically labelled tracers in human plasma: An analytical panel for clinical metabolic kinetics and interactions.

Minoo Afshar, Gerrit van Hall.

  An important area within clinical research is in vivo metabolism of ketone bodies (β-hydroxybutyrate and acetoacetate) and in connection metabolites that may affect their production and/or cellular transport such as the keto-acids from the branched-chain amino acids, lactate and pyruvate. To determine in vivo metabolite turnover, availability of accurate and sensitive methods for analyzing the plasma concentrations of these metabolites and their stable isotopically labeled enrichments is mandatory. Therefore, the present study describes a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous analysis of ketone bodies, α-keto acids, lactate, pyruvate, and their tracer enrichments in humans using 2 different derivatization techniques with 4-bromo-N-methylbenzylamine and O-benzylhydroxylamine as derivatization reagents, and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling compound followed by a single LC-MS/MS run. The method was validated for matrix effects, linearity, accuracy, precision, recovery, stability, and enrichment (ratio) analysis of a stable isotopically labelled analytes (tracers) continuously infused in humans divided by the unlabeled endogenous analyte (tracee) that makes it possible to quantify the analyte in vivo synthesis and degradation rates. The applied parallel derivatization procedure yielded good sensitivity for all analytes of interest and their tracers. Despite the double derivatization method, mixing the ethyl acetate portions at the final stage made it possible to simultaneously analyze all compounds in a single LC-MS/MS run. Moreover, the liquid chromatography method was optimized to robustly quantify the keto acids derived from leucine (α-keto-isocaproic acid) and isoleucine (α-keto-β-methylvaleric acid), the compounds with similar chemical structure and identical molecular weights. The presented method is designed and validated for human plasma. However, care should be taken in blood sampling and processing procedures as well as quick freezing and storage at -80 °C due to the instability of especially acetoacetate.

Keywords:  Acetoacetate; LC-MS/MS; Lactate; Plasma; Pyruvate; Tracer enrichment; α-keto acids; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jchromb.2023.123906
Cell Rep Med. 2023 Nov 06. pii: S2666-3791(23)00477-9. [Epub ahead of print] 101283

Feasibility and impact of ketogenic dietary interventions in polycystic kidney disease: KETO-ADPKD-a randomized controlled trial.

Sadrija Cukoski, Christoph Heinrich Lindemann, Sita Arjune, Polina Todorova, Theresa Brecht, Adrian Kühn, Simon Oehm, Sebastian Strubl, Ingrid Becker, Ulrike Kämmerer, Jacob Alexander Torres, Franziska Meyer, Thomas Schömig, Nils Große Hokamp, Florian Siedek, Ingo Gottschalk, Thomas Benzing, Johannes Schmidt, Philipp Antczak, Thomas Weimbs, Franziska Grundmann, Roman-Ulrich Müller.

  Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.

Keywords:  ADPKD; cholesterol; ketogenic diet; ketosis; kidney; lipids; low carb; nutrition; polycystic kidney disease; water fasting

DOI:  https://doi.org/10.1016/j.xcrm.2023.101283
Lipids Health Dis. 2023 Nov 10. 22(1): 191

Opposite effects of low-carbohydrate high-fat diet on metabolism in humans and mice.

Lingli Cai, Xinyi Xia, Yunjie Gu, Lili Hu, Cheng Li, Xiaojing Ma, Jun Yin.

   BACKGROUND: Low-carbohydrate diet (LCD) is effective for weight loss and glycaemic control in humans. Here, the study aimed to explore the effects of LCD/high-fat diet (HFD) in both humans and mice.
METHODS: Twenty-two overweight or obese participants received LCD for 3 weeks. Based on carbohydrate intake > 10% or ≤ 10% of calories, the participants were divided into moderate LCD (MLCD) and very LCD (VLCD) groups. The participants completed a 10-question food preference survey. Meanwhile, C57BL/6J mice were assigned to five groups: chow diet (CD, 10% fat), HFD with 60%, 70%, and 75% fat from cocoa butter (HFD-C), and HFD with 60% fat from lard (HFD-L) and fed for 24 weeks. Eight mice were acclimatised for the food-choice test.
RESULTS: LCD decreased the total energy intake in humans. The VLCD group showed greater weight loss and better glycaemic control than the MLCD group. A food preference survey showed that 65% of participants tended to choose high-carbohydrate foods. In mice, HFD resulted in energy overconsumption, obesity, and metabolic disorders. When CD and HFD-L were administered simultaneously, mice rarely consumed CD. In the HFD-C groups, the energy intake and body weight increased with increasing dietary fat content. Compared with the HFD-C group, the HFD-L group consumed more energy and had poorer metabolism.
CONCLUSIONS: Lower carbohydrate intake contributed to lower energy intake and improved metabolism in humans. In mice, diets with a higher proportion of fat become more attractive and obesogenic by fixing the fat sources. Since the mice preferred lard to cocoa butter, lard induced excess energy intake and poorer metabolism. Different food preferences may be the underlying mechanism behind the opposite effects of the LCD/HFD in humans and mice.
TRIAL REGISTRATION: The clinical trial was registered with the Chinese Clinical Trial Registry ( www.chictr.org.cn ). The registration number is ChiCTR1800016786. All participants provided written informed consent prior to enrolment.

Keywords:  Appetite; Energy intake; Food preference; High-fat diet; Homeostatic mechanism; Ketogenic diet

DOI:  https://doi.org/10.1186/s12944-023-01956-3
Calcif Tissue Int. 2023 Nov 05.

Mitophagy Activation by Urolithin A to Target Muscle Aging.

Julie Faitg, Davide D'Amico, Chris Rinsch, Anurag Singh.

  The age-related loss of skeletal muscle function starts from midlife and if left unaddressed can lead to an impaired quality of life. A growing body of evidence indicates that mitochondrial dysfunction is causally involved with muscle aging. Muscles are tissues with high metabolic requirements, and contain rich mitochondria supply to support their continual energy needs. Cellular mitochondrial health is maintained by expansing of the mitochondrial pool though mitochondrial biogenesis, by preserving the natural mitochondrial dynamic process, via fusion and fission, and by ensuring the removal of damaged mitochondria through mitophagy. During aging, mitophagy levels decline and negatively impact skeletal muscle performance. Nutritional and pharmacological approaches have been proposed to manage the decline in muscle function due to impaired mitochondria bioenergetics. The natural postbiotic Urolithin A has been shown to promote mitophagy, mitochondrial function and improved muscle function across species in different experimental models and across multiple clinical studies. In this review, we explore the biology of Urolithin A and the clinical evidence of its impact on promoting healthy skeletal muscles during age-associated muscle decline.

Keywords:  Aging; Mitochondria; Mitophagy; Muscle health; Urolithin A

DOI:  https://doi.org/10.1007/s00223-023-01145-5
Physiol Rep. 2023 Nov;11(21): e15848

Acetate and succinate benefit host muscle energetics as exercise-associated post-biotics.

Ahmed Ismaeel, Taylor R Valentino, Benjamin Burke, Jensen Goh, Tolulope P Saliu, Fatmah Albathi, Allison Owen, John J McCarthy, Yuan Wen.

  Recently, the gut microbiome has emerged as a potent modulator of exercise-induced systemic adaptation and appears to be crucial for mediating some of the benefits of exercise. This study builds upon previous evidence establishing a gut microbiome-skeletal muscle axis, identifying exercise-induced changes in microbiome composition. Metagenomics sequencing of fecal samples from non-exercise-trained controls or exercise-trained mice was conducted. Biodiversity indices indicated exercise training did not change alpha diversity. However, there were notable differences in beta-diversity between trained and untrained microbiomes. Exercise significantly increased the level of the bacterial species Muribaculaceae bacterium DSM 103720. Computation simulation of bacterial growth was used to predict metabolites that accumulate under in silico culture of exercise-responsive bacteria. We identified acetate and succinate as potential gut microbial metabolites that are produced by Muribaculaceae bacterium, which were then administered to mice during a period of mechanical overload-induced muscle hypertrophy. Although no differences were observed for the overall muscle growth response to succinate or acetate administration during the first 5 days of mechanical overload-induced hypertrophy, acetate and succinate increased skeletal muscle mitochondrial respiration. When given as post-biotics, succinate or acetate treatment may improve oxidative metabolism during muscle hypertrophy.

Keywords:  exercise; metagenomics; microbiome; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.15848
J Sleep Res. 2023 Nov 06. e14073

The effects of ketogenic dietary therapies on sleep: A scoping review.

Ludovica Pasca, Carlo Alberto Quaranta, Serena Grumi, Martina Paola Zanaboni, Anna Tagliabue, Monica Guglielmetti, Helene Vitali, Elena Capriglia, Costanza Varesio, Federico Toni, Lino Nobili, Michele Terzaghi, Valentina De Giorgis.

  Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed.

Keywords:  autism; epilepsy; ketogenic diet; ketogenic diet efficacy; migraine; sleep disorders; sleep quality

DOI:  https://doi.org/10.1111/jsr.14073
Trends Endocrinol Metab. 2023 Nov 06. pii: S1043-2760(23)00215-1. [Epub ahead of print]

Mechanisms of hepatic fatty acid oxidation and ketogenesis during fasting.

Philip M M Ruppert, Sander Kersten.

  Fasting is part of many weight management and health-boosting regimens. Fasting causes substantial metabolic adaptations in the liver that include the stimulation of fatty acid oxidation and ketogenesis. The induction of fatty acid oxidation and ketogenesis during fasting is mainly driven by interrelated changes in plasma levels of various hormones and an increase in plasma nonesterified fatty acid (NEFA) levels and is mediated transcriptionally by the peroxisome proliferator-activated receptor (PPAR)α, supported by CREB3L3 (cyclic AMP-responsive element-binding protein 3 like 3). Compared with men, women exhibit higher ketone levels during fasting, likely due to higher NEFA availability, suggesting that the metabolic response to fasting shows sexual dimorphism. Here, we synthesize the current molecular knowledge on the impact of fasting on hepatic fatty acid oxidation and ketogenesis.

Keywords:  fasting; fatty acid oxidation; ketogenesis; sexual dimorphism; transcriptional regulation

DOI:  https://doi.org/10.1016/j.tem.2023.10.002
Clin Chim Acta. 2023 Nov 05. pii: S0009-8981(23)00431-X. [Epub ahead of print]551 117629

3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.

Elizabeth A Jennings, Zane H Abi-Rached, Dylan E Jones, Robert O Ryan.

  The acylcarnitines comprise a wide range of acyl groups linked via an ester bond to the hydroxyl group of L-carnitine. Mass spectrometry methods are capable of measuring the relative abundance of hundreds of acylcarnitines in a single drop of blood. As such, acylcarnitines can serve as sensitive biomarkers of disease. For certain acylcarnitines, however, their biochemical origin, and biomedical significance, remain unclear. One such example is 3-methylglutaryl (3MG) carnitine (C5-3M-DC). Whereas 3MG carnitine levels are normally very low, elevated levels are detected in discrete inborn errors of metabolism (IEM) as well as different forms of heart disease. Moreover, acute injury, including γ radiation exposure, paraquat poisoning, and traumatic brain injury manifest elevated levels of 3MG carnitine in blood and/or urine. Recent evidence indicates that two distinct biosynthetic routes to 3MG carnitine exist. The first, caused by an inherited deficiency in the leucine catabolism pathway enzyme, 3-hydroxy-3-methylglutaryl (HMG) CoA lyase, leads to a buildup of trans-3-methylglutaconyl (3MGC) CoA. Reduction of the double bond in trans-3MGC CoA generates 3MG CoA, which is then converted to 3MG carnitine by carnitine acyltransferase. This route, however, cannot explain why 3MG carnitine levels increase in IEMs that do not affect leucine metabolism or various chronic and acute disease states. In these cases, disease-related defects in aerobic energy metabolism result in diversion of acetyl CoA to trans-3MGC CoA. Once formed, trans-3MGC CoA is reduced to 3MG CoA and esterified to form 3MG carnitine. Thus, 3MG carnitine, represents a potential biomarker of disease processes associated with compromised mitochondrial energy metabolism.

Keywords:  3-methylglutaryl; Acylcarnitine; Biomarker; Heart disease; Mitochondria

DOI:  https://doi.org/10.1016/j.cca.2023.117629
Immunity. 2023 Oct 31. pii: S1074-7613(23)00444-2. [Epub ahead of print]

Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis.

Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman.

  Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and noncanonical inflammasome activation of mitochondrial damage, pyroptosis, and inflammatory cytokine release were suppressed by genetic ablation of cardiolipin synthase (Crls1) or the scramblase (Plscr3) that transfers cardiolipin to the OMM. Phospholipid scramblase-3 (PLSCR3) deficiency in a tumor compromised pyroptosis-triggered anti-tumor immunity. Thus, mitochondrial damage plays a critical role in pyroptosis.

Keywords:  CRLS1; GSDMD; IL-1; PLSCR3; cardiolipin; mitochondria; pyroptosis

DOI:  https://doi.org/10.1016/j.immuni.2023.10.004
Nan Fang Yi Ke Da Xue Xue Bao. 2023 Oct 20. 43(10): 1744-1751

[GPR109A partly mediates inhibitory effects of β-hydroxybutyric acid on lung adenocarcinoma cell proliferation, migration and invasion].

Y Huang, Y Zhu, J Shi, R Liu, T Zeng, L Han.

   OBJECTIVE: To explore the mechanism that mediates the inhibitory effects of β-hydroxybutyrate (BHB) on lung adenocarcinoma cells.
METHODS: A549 and LLC cell lines treated with 5 or 10 mmol/L BHB were examined for changes in cell viability, proliferation, migration, and invasion using CCK-8 assay, EdU staining, scratch assay, and Transwell assay. The differential expression of GPR109A in lung adenocarcinoma and normal lung tissue was analyzed using GEPIA database. GPR109A expressions in BHB-treated lung adenocarcinoma cells were determined using RT-PCR and Western blotting. The changes in IC50 of BHB were examined in A549 and LLC cells with GPR109A knockdown. The effect of BHB administered via gavage for 21 days on tumor growth was evaluated in nude mouse and Balb/c mouse models bearing xenografts derived A549 and LLC cells with or without GPR109A knockdown.
RESULTS: Treatment with BHB concentration-dependently repressed the viability, proliferation, migration and invasion of A549 and LLC cells. GPR109A expression was significantly decreased in lung adenocarcinoma tissues and A549 and LLC cell lines (P<0.05). Loss of function experiments showed that the inhibitory effects of BHB on A549 and LLC cells were partly mediated by GPR109A, and in the tumor-bearing mouse models, BHB significantly inhibited tumor growth partly by regulating GPR109A expression (P<0.05).
CONCLUSION: BHB can repress the malignant behaviors of A549 and LLC cells and inhibit tumor growth in mice, and these effects are mediated partly by regulating GPR109A expression.

Keywords:  A549 cells; G protein coupled receptor; GPR109A; lung adenocarcinoma; β-hydroxybutyrate

DOI:  https://doi.org/10.12122/j.issn.1673-4254.2023.10.12
Nat Commun. 2023 Nov 09. 14(1): 7249

Gut butyrate-producers confer post-infarction cardiac protection.

Hung-Chih Chen, Yen-Wen Liu, Kuan-Cheng Chang, Yen-Wen Wu, Yi-Ming Chen, Yu-Kai Chao, Min-Yi You, David J Lundy, Chen-Ju Lin, Marvin L Hsieh, Yu-Che Cheng, Ray P Prajnamitra, Po-Ju Lin, Shu-Chian Ruan, David Hsin-Kuang Chen, Edward S C Shih, Ke-Wei Chen, Shih-Sheng Chang, Cindy M C Chang, Riley Puntney, Amy Wu Moy, Yuan-Yuan Cheng, Hsin-Yuan Chien, Jia-Jung Lee, Deng-Chyang Wu, Ming-Jing Hwang, Jennifer Coonen, Timothy A Hacker, C-L Eric Yen, Federico E Rey, Timothy J Kamp, Patrick C H Hsieh.

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.

DOI: https://doi.org/10.1038/s41467-023-43167-5
Enzymes. 2023 ;pii: S1874-6047(23)00008-2. [Epub ahead of print]54 37-70

A century of mitochondrial research, 1922-2022.

Howard T Jacobs.

  Although recognized earlier as subcellular entities by microscopists, mitochondria have been the subject of functional studies since 1922, when their biochemical similarities with bacteria were first noted. In this overview I trace the history of research on mitochondria from that time up to the present day, focussing on the major milestones of the overlapping eras of mitochondrial biochemistry, genetics, pathology and cell biology, and its explosion into new areas in the past 25 years. Nowadays, mitochondria are considered to be fully integrated into cell physiology, rather than serving specific functions in isolation.

Keywords:  Apoptosis; Calcium homeostasis; Cell signalling; Chemiosmotic hypothesis; DNA replication; Endosymbiosis; Eukaryote origins; Heteroplasmy; Immunity; Krebs cycle; Mitochondrial DNA; Mitochondrial disease; Mitochondrial dynamics; Mitophagy; Oxidative phosphorylation; Reactive oxygen species; Supercomplexes

DOI:  https://doi.org/10.1016/bs.enz.2023.07.002
Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00442-1. [Epub ahead of print] 101265

Inflammation-induced mitochondrial and metabolic disturbances in sensory neurons control the switch from acute to chronic pain.

Hanneke L D M Willemen, Patrícia Silva Santos Ribeiro, Melissa Broeks, Nils Meijer, Sabine Versteeg, Annefien Tiggeler, Teun P de Boer, Jędrzej M Małecki, Pål Ø Falnes, Judith Jans, Niels Eijkelkamp.

  Pain often persists in patients with an inflammatory disease, even when inflammation has subsided. The molecular mechanisms leading to this failure in pain resolution and the transition to chronic pain are poorly understood. Mitochondrial dysfunction in sensory neurons links to chronic pain, but its role in resolution of inflammatory pain is unclear. Transient inflammation causes neuronal plasticity, called hyperalgesic priming, which impairs resolution of pain induced by a subsequent inflammatory stimulus. We identify that hyperalgesic priming in mice increases the expression of a mitochondrial protein (ATPSc-KMT) and causes mitochondrial and metabolic disturbances in sensory neurons. Inhibition of mitochondrial respiration, knockdown of ATPSCKMT expression, or supplementation of the affected metabolite is sufficient to restore resolution of inflammatory pain and prevents chronic pain development. Thus, inflammation-induced mitochondrial-dependent disturbances in sensory neurons predispose to a failure in resolution of inflammatory pain and development of chronic pain.

Keywords:  chronic pain; inflammation; metabolism; mitochondria; redox; sensory neurons

DOI:  https://doi.org/10.1016/j.xcrm.2023.101265