bims-kimdis 2024-12-01 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–12–01
35 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

β-hydroxybutyrate suppresses pathological changes of blood-induced arthropathy in rats.
Generalized Ketogenic Diet Induced Liver Impairment and Reduced Probiotics Abundance of Gut Microbiota in Rat.
Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets.
A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice.
Exploring diet-induced ketosis with exogenous ketone supplementation as a potential intervention in post-traumatic stress disorder: a feasibility study.
The Impact of a Ketogenic Diet on Late-Stage Pancreatic Carcinogenesis in Mice: Efficacy and Safety Studies.
Low-Dose Ketone Monoester Administration in Adults with Cystic Fibrosis: A Pilot and Feasibility Study.
The effects of ketogenic diet on metabolic and hormonal parameters in patients with polycystic ovary syndrome: a systematic review and meta-analysis of clinical trials.
Ketogenic Diet Improves Sleep Quality and Daytime Sleepiness in Chronic Migraine: A Pilot Study.
Association of circulating ketone bodies with cognitive performance and dementia in the Multi-Ethnic Study of Atherosclerosis (MESA).
Ketogenic diet in adult patients with mitochondrial myopathy.
Measuring the effects of ketogenic diet on neuropsychiatric disorder: A scoping review.
Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
Living Conditions Alter Ketogenic Diet-induced Metabolic Consequences in Mice through Modulating Gut Microbiota.
Effects of Hyperthermia and Acidosis on Mitochondrial Oxidative Phosphorylation.
Impact of daily fasting duration on body composition and cardiometabolic risk factors during a time-restricted eating protocol: a randomized controlled trial.
Role of NLRP3 Inflammasome in Heart Failure Patients Undergoing Cardiac Surgery as a Potential Determinant of Postoperative Atrial Fibrillation and Remodeling: Is SGLT2 Cotransporter Inhibition an Alternative for Cardioprotection?
Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1.
Exercise Training Counteracts Compromised Mitochondrial Capacity Induced by Energy Restriction in Prediabetics in a Sex-Dependent Manner.
Effect of Intermittent Fasting on Immune Parameters and Intestinal Inflammation.
Acute and Chronic Resistance Training, Acute Endurance Exercise, nor Physiologically Plausible Lactate In Vitro Affect Skeletal Muscle Lactylation.
Muscular strength, endothelial function and cognitive disorders: state of the art.
Understanding the Role of NLRP3 Inflammasome in Acute Pancreatitis.
The Switching of the Type of a ROS Signal from Mitochondria: The Role of Respiratory Substrates and Permeability Transition.
The role of NLRP3 and NLRP12 inflammasomes in glioblastoma.
Impact of Exercise Training at Maximal Fat Oxidation Intensity on Metabolic and Epigenetic Parameters in Patients with Overweight and Obesity: Study Protocol of a Randomized Controlled Trial.
Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner.
Importance of proteins and mitochondrial changes as freshness indicators in fish muscle post-mortem.
Palmitic acid and eicosapentaenoic acid supplementation in 3T3 adipocytes: impact on lipid storage and oxidative stress.
Continuous glucose monitoring in para cyclists: An observational study.
Mitochondria as sensors of intracellular pathogens.
From oxidative stress to metabolic dysfunction: The role of TRPM2.
Diet and exercise in frailty and sarcopenia. Molecular aspects.
Lactate Dehydrogenase A Is a Novel Positive Regulator of Vascular Smooth Muscle Cell Ferroptosis During Aortic Dissection.

Sci Rep. 2024 Nov 29. 14(1): 29696

β-hydroxybutyrate suppresses pathological changes of blood-induced arthropathy in rats.

Ryohei Kawasaki, Asuka Sakata, Kohei Tatsumi, Seiji Mitani, Maiko Takeda, Shogo Kasuda, Naoki Matsumoto, Suguru Harada, Tetsuhiro Soeda, Yukiko Nishida, Yasushi Yoshimura, Midori Shima.

Arthropathy is a common complication in haemophilia and decreases quality of life. It has been known that concentrations of β-hydroxybutyrate (BHB) in blood are increased by a ketogenic diet, and elevated levels of circulating BHB restricts the progression of inflammation-mediated joint pathological changes. We hypothesized that elevation of blood BHB concentrations could be effective for reducing the progression of bleeding-induced arthropathy by moderating the inflammatory responses of macrophages. In this study, we investigated whether BHB alleviates the arthropathy caused by repeated intra-articular blood injection in rats. To increase blood BHB levels, rats were fed with ketogenic diet. Repeated intra-articular blood injection induced significant joint swelling, whereas ketogenic diet intake significantly increased blood BHB concentrations and ameliorated the joint swelling. The periarticular tissue-fibrosis observed in the control diet intake group appeared to be significantly alleviated in the ketogenic diet intake group. In addition, the IL-1β, which is involved in the progression of arthropathy, levels in the supernatants of blood-exposed macrophages derived from THP-1 cell line were significantly suppressed by BHB supplementation. In summary, BHB moderated the pathological joint changes caused by intra-articular blood exposure.

DOI: https://doi.org/10.1038/s41598-024-77074-6
Biology (Basel). 2024 Nov 04. pii: 899. [Epub ahead of print]13(11):

Generalized Ketogenic Diet Induced Liver Impairment and Reduced Probiotics Abundance of Gut Microbiota in Rat.

Ge Song, Dan Song, Yongwei Wang, Li Wang, Weiwei Wang.

  The ketogenic diet is becoming an assisted treatment to control weight, obesity, and even type 2 diabetes. However, there has been no scientific proof supporting that the ketogenic diet is absolutely safe and sustainable. In this study, Sprague-Dawley (SD) rats were fed different ratios of fat to carbohydrates under the same apparent metabolizable energy level to evaluate the effects of a ketogenic diet on healthy subjects. The results showed that the ketogenic diet could relatively sustain body weight and enhance the levels of serum alanine aminotransferase (ALT) and serum alkaline phosphatase (SAP), leading to more moderate lipoidosis and milder local non-specific inflammation in the liver compared with the high-carbohydrate diet. In addition, the abundance of probiotic strains such as Lactobacillus, Lactococcus, and Faecalitalea were reduced with the ketogenic diet in rats, while an abundance of pathogenic strains such as Anaerotruncus, Enterococcus, Rothia, and Enterorhabdus were increased with both the ketogenic diet and the high-carbohydrate diet. This study suggests that the ketogenic diet can lead to impairments of liver function and changed composition of the gut microbiota in rats, which to some extent indicates the danger of consuming a generalized ketogenic diet.

Keywords:  apparent metabolizable energy; generalized ketogenic diet; gut microbiota; lipoidosis

DOI:  https://doi.org/10.3390/biology13110899
bioRxiv. 2024 Nov 18. pii: 2024.11.17.624030. [Epub ahead of print]

Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets.

Siming Liu, Israel Wipf, Aditya Joglekar, Aidan Freshly, Corinne E Bovee, Lucy Kim, Syreine L Richtsmeier, Spencer Peachee, Shayla Kopriva, Anamika Vikram, Dalal El Ladiki, Fatma Ilerisoy, Beyza Ilerisoy, Gianna Sagona, Claudia Jun, Michelle Giedt, Tina L Tootle, James Ankrum, Yumi Imai.

Knockdown (KD) of lipid droplet (LD) protein perilipin 2 (PLIN2) in beta cells impairs glucose-stimulated insulin secretion (GSIS) and mitochondrial function. Here, we addressed a pathway responsible for compromised mitochondrial integrity in PLIN2 KD beta cells. In PLIN2 KD human islets, mitochondria were fragmented in beta cells but not in alpha cells. Glucagon but not insulin level was elevated. While the formation of early LDs followed by fluorescent fatty acids (FA) analog Bodipy C12 (C12) was preserved, C12 accumulated in mitochondria over time in PLIN2 KD INS-1 cells. A lysosomal acid lipase inhibitor Lali2 prevented C12 transfer to mitochondria, mitochondrial fragmentation, and the impairment of GSIS. Direct interactions between LD-lysosome and lysosome-mitochondria were increased in PLIN2 KD INS-1 cells. Thus, FA released from LDs by microlipophagy cause mitochondrial changes and impair GSIS in PLIN2 KD beta cells. Interestingly, glucolipotoxic condition (GLT) caused C12 accumulation and mitochondrial fragmentation similar to PLIN2 KD in beta cells. Moreover, Lali2 reversed mitochondrial fragmentation and improved GSIS in human islets under GLT. In summary, PLIN2 regulates microlipophagy to prevent excess FA flux to mitochondria in beta cells. This pathway also contributes to GSIS impairment when LD pool expands under nutrient load in beta cells.

DOI: https://doi.org/10.1101/2024.11.17.624030
Cell Commun Signal. 2024 Nov 27. 22(1): 568

A ketogenic diet alleviates the apoptosis of granulosa cells by inhibiting the activation of cGAS-STING signaling pathway in PCOS mice.

Bining Zhao, Haowen Wu, Qiyang Yao, Wenpei Bai, Jihong Kang.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the reproductive phenotype in an androgen-induced PCOS mouse model, yet the underlying molecular mechanisms remain largely unclear. The aim of the present study was to investigate the effect of KD on the reproductive phenotype of a letrozole-induced PCOS mouse model.
METHODS: Female C57BL/6N mice were divided into three groups, designated control, letrozole, and letrozole + KD groups. Mice of control and letrozole groups were fed the control diet, whereas letrozole + KD mice were fed a KD with 89.9% (kcal) fat for 3 weeks after the PCOS mouse model was generated. β-hydroxybutyrate (BHB), the most abundant ketone body in the body, was used to treat KGN cells with testosterone (T) to simulate the KD effect on PCOS mouse ovaries in vitro.
RESULTS: Our data showed that KD treatment significantly increased blood ketone levels and reduced body weight. Ovarian functions were improved in some letrozole + KD mice. Results from in vitro experiments indicated mitochondrial damage owing to high T levels, which resulted in the leakage of cytochrome C and mitochondrial DNA into the cytosol and thus induced the activation of the intracellular caspase cascade and the cGAS-STING-NF-κB pathway, leading to granulosa cell inflammation and apoptosis. BHB exhibited certain protective effects on mitochondria of T-treated KGN cells via inhibiting the cGAS-STING pathway. Moreover, the cGAS-STING pathway was activated in ovaries of letrozole mice and was down-regulated in letrozole + KD mice.
CONCLUSION: These findings, for the first time, revealed that hyperandrogenism induced ovarian dysfunction possibly through activation of the cGAS-STING pathway, which could be partially inhibited by ketone bodies produced from KD administration.

Keywords:  Apoptosis; Hyperandrogenemia; Inflammation; Ketogenic diet; Mitochondrial dysfunction; Polycystic ovary syndrome; cGAS-STING pathway

DOI:  https://doi.org/10.1186/s12964-024-01939-6
Front Nutr. 2024 ;11 1406366

Exploring diet-induced ketosis with exogenous ketone supplementation as a potential intervention in post-traumatic stress disorder: a feasibility study.

Maria G P Edwards, Tobias Furuholmen-Jenssen, Erik Ganesh Iyer Søegaard, Suraj Bahadur Thapa, Jens R Andersen.

   Background: Post-Traumatic Stress Disorder (PTSD) is a severe and pervasive mental disorder, and patients experience numerous distressing symptoms and impairments that significantly impact their lives. In addition to being a mental disorder, PTSD is strongly associated with a wide range of metabolic abnormalities that affect the entire body. Existing treatment options of psychotherapy and medications are often ineffective. Exploring other potential treatments is necessitated. The ketogenic diet has shown potential as a metabolic therapy in certain neurological and mental disorders and is a promising intervention in the treatment of PTSD.
Aim: This study aimed to examine if a 4-week ketogenic diet intervention supplemented with exogenous ketones (KD-KS) was feasible in adult patients with PTSD, to what extent it was possible to recruit patients, attain and maintain ketosis (plasma concentration of β-hydroxybutyrate (BHB) ≥ 0.5 mmol/L), the occurrence of serious adverse reactions and adverse reactions to KD-KS, and acceptance of treatment. Our exploratory aims were changes in PTSD symptoms and health-related quality of life (QoL) from baseline to 4 weeks.
Methods: Patients 18 ≤ 65 years old, diagnosed with PTSD, and receiving outpatient treatment for PTSD at Southern Oslo District Psychiatric Centre (DPC), Oslo University Hospital, Oslo, Norway, were included. The intervention consisted of a ketogenic diet supplemented with β-hydroxybutyrate salt to obtain ketosis. PTSD symptoms were measured with the PTSD Checklist for DSM-5 (PCL-5) and QoL was measured with the RAND 36-Item Health Survey 1.0.
Results: During a 21-week inclusion period, three of four eligible patients (75% [95% CI: 30 to 95%]) were included. Two patients (67% [95% CI: 21 to 94%]) completed the 4-week intervention and one patient (33% [95% CI: 6 to 79%]) completed 2 weeks of intervention before discontinuing. Ketosis was achieved on day 1 in one patient, and on day 2 in two patients, and was maintained in 87% of the intervention. There were no serious adverse reactions. Adverse reactions were reported in a total of 70% of intervention days, the most frequent being headache followed by fatigue. The participant-perceived degree of adverse reactions was low to moderate. The treatment was accepted by patients on all intervention days. PCL-5 decreased by 20 points (70 to 50) in patient 1 and by 10 points (50 to 40) in patient 2, from baseline to 4 weeks, which is a reliable and clinically meaningful improvement. QoL improved in six of eight RAND-36 subscales in patient 1 and three of eight in patient 2. Patient 3 did not complete assessments after week 2.
Conclusion: To the best of our knowledge, this feasibility study is the first study examining a ketogenic diet intervention in patients with PTSD. Three of four predefined feasibility criteria were achieved. Ketosis was attained fast and maintained, patients were compliant and there were clinically meaningful improvements in PTSD symptoms and QoL. Despite the small sample size, the knowledge obtained in this study is important for the planning of future studies with ketogenic diet interventions in this patient group. It is a first step for potential dietary and metabolic therapies in PTSD. Further feasibility and pilot studies with larger sample sizes are needed to determine feasibility and safety before planning future randomised controlled trials investigating an effect.
Clinical trial registration: https://ClinicalTrials.gov, identifier NCT05415982.

Keywords:  exogenous ketones; ketogenic diet (KD); ketogenic metabolic therapy (KMT); ketone salts (KS); ketosis; post-traumatic stress disorder (PTSD); β-hydroxybutyrate (BHB)

DOI:  https://doi.org/10.3389/fnut.2024.1406366
Nutrients. 2024 Nov 16. pii: 3919. [Epub ahead of print]16(22):

The Impact of a Ketogenic Diet on Late-Stage Pancreatic Carcinogenesis in Mice: Efficacy and Safety Studies.

Natalia E Cortez, Tarek A Bacha, Aya Samir Ead, Cecilia Rodriguez Lanzi, Cassandra Lacroix, Anais Franceschetti, Brian V Hong, Karen Matsukuma, Gerardo G Mackenzie.

   BACKGROUND: High-fat diets (HFDs) have been associated with an increased risk of pancreatic cancer. In contrast, ketogenic diets (KDs) have been shown to display anti-tumor characteristics. The objective of this work was to evaluate the efficacy of a KD on late-stage pancreatic carcinogenesis in a genetically modified mouse model of pancreatic cancer [LSL-KrasG12D/+; Ptf1-Cre (KC) mice], as well as its liver safety, and to compare it to that of an HFD.
METHODS: Six-month-old female and male KC mice were randomly allocated to either a control diet (CD) (%kcal: 20% fat, 15% protein, 65% carbohydrates), an HFD (%kcal: 40% fat, 15% protein, 45% carbohydrate) or a KD (%kcal: 84% fat, 15% protein, 1% carbohydrate) and fed these diets for 6 months.
RESULTS: HFD-fed, but not KD-fed, mice showed a 15% increase in body weight, plus elevated serum insulin (2.4-fold increase) and leptin (2.9-fold increase) levels, compared to CD-fed mice. At the pancreas level, no differences in pancreatic cancer incidence rates were observed among the diet groups. Regarding the liver safety profile, the HFD-fed mice had higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), when compared to the CD and KD groups. In addition, upon histologic examination, an HFD, but not a KD, showed a ~2-fold increase in both macro- and microsteatosis, as well as 35% and 32% higher levels of TLR4 and NF-κB activation, respectively, compared to CD-fed mice.
CONCLUSIONS: In summary, although a KD intervention alone did not prevent pancreatic carcinogenesis, our data suggests that a KD modulates insulin signaling and hepatic lipid metabolism, highlighting its beneficial effects on healthspan and liver function when compared to an HFD.

Keywords:  high-fat diet; ketogenic diet; pancreatic cancer; pancreatic carcinogenesis

DOI:  https://doi.org/10.3390/nu16223919
Nutrients. 2024 Nov 19. pii: 3957. [Epub ahead of print]16(22):

Low-Dose Ketone Monoester Administration in Adults with Cystic Fibrosis: A Pilot and Feasibility Study.

Eric P Plaisance, Jonathan M Bergeron, Mickey L Bolyard, Heather Y Hathorne, Christina M Graziano, Anastasia Hartzes, Kristopher R Genschmer, Jessica A Alvarez, Amy M Goss, Amit Gaggar, Kevin R Fontaine.

   INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have greatly improved outcomes in persons with CF (pwCF); however, there is still significant heterogeneity in clinical responses, particularly with regard to respiratory infection and inflammation. Exogenous administration of ketones has profound systemic anti-inflammatory effects and produces several nutrient-signaling and metabolic effects that may benefit multiple organ systems affected in pwCF. This pilot study was designed to determine the feasibility of administration of a ketone monoester (KME) to increase circulating D-beta hydroxybutyrate concentrations (D-βHB) and to improve subjective measures of CF-specific quality of life and markers of inflammation in serum and sputum in adults with CF.
METHODS: Fourteen participants receiving modulator therapy were randomized to receive either KME (n = 9) or placebo control (PC, n = 5) for 5-7 days during hospitalization for treatment of acute pulmonary exacerbation or as outpatients under standard care.
RESULTS: The KME was well tolerated, with only mild reports of gastrointestinal distress. D-βHB concentrations increased from 0.2 ± 0.1 mM to 1.6 ± 0.6 mM in the KME group compared to 0.2 ± 0.0 to 0.3 ± 0.1 in the PC group (p = 0.011) within 15 min following consumption and remained elevated, relative to baseline, for over 2 h. Pulmonary function was not altered after single- or short-term KME administration, but participants in the KME group self-reported higher subjective respiratory scores compared to PC in both cases (p = 0.031). Plasma inflammatory markers were not statistically different between groups following the short-term (5-7 d) intervention (p > 0.05). However, an exploratory analysis of plasma pre- and post-IL-6 concentrations was significant (p = 0.028) in the KME group but not PC. Sputum IFNγ (p = 0.057), IL-12p70 (p = 0.057), IL-1β (p = 0.100), IL-15 (p = 0.057), IL-1α (p = 0.114), and MPO (p = 0.133) were lower in the KME group compared to PC but did not achieve statistical significance.
CONCLUSIONS: With the emerging role of exogenous ketones as nutrient signaling molecules and mediators of metabolism, we showed that KME is well tolerated, increases circulating D-βHB concentrations, and produces outcomes that justify the need for large-scale clinical trials to investigate the role of KME on whole-body and tissue lipid accumulation and inflammation in pwCF.

Keywords:  inflammation; ketogenic diet; ketones; low-carbohydrate diet; pulmonary function

DOI:  https://doi.org/10.3390/nu16223957
J Diabetes Metab Disord. 2024 Dec;23(2): 1573-1587

The effects of ketogenic diet on metabolic and hormonal parameters in patients with polycystic ovary syndrome: a systematic review and meta-analysis of clinical trials.

Niloofarsadaat Eshaghhosseiny, Mohammad Ahmadi, Bahareh Izadi, Mohebat Vali, Maryam Akbari, Isaac Azari, Hamed Akbari.

   Purpose: In recent years, using the ketogenic diet (KD) as a potential intervention for polycystic ovary syndrome (PCOS) has gained attention. Therefore, this study aimed to conduct a meta-analysis to determine the effects of KD on sexual hormones, glycemic and lipid parameters in women diagnosed with PCOS.
Methods: A comprehensive literature search was performed using online databases such as Medline/PubMed, Scopus, Web of Science (ISI), Embase, and the Cochrane Library and clinical trials were selected based on the inclusion criteria. Data extraction and quality assessment were conducted independently by two investigators using appropriate tools. The effects of a KD on metabolic biomarkers and hormonal parameters were pooled using a random-effects model and were considered as the weighted mean difference (WMD) with corresponding 95% confidence intervals (CIs). Heterogeneity across studies was assessed using Cochran's Q test and the I-square test.
Results: Ten studies including 408 women were analyzed in this analysis. Findings showed that KD significantly decreased triglycerides levels (WMD = -44.03 mg/dL; 95% CI, -56.29, -31.76), total cholesterol (-18.95 mg/dL; -29.06, -8.83), and low-density lipoprotein cholesterol (LDL) (-18.11 mg/dL; -29.56, -6.67) compared to the control groups. KD also led to a notable reduction in fasting glucose (-10.30 mg/dL; -14.10, -6.50) and HOMA-IR (-1.93; -3.66, -0.19). Also, this diet led to a significant decrease in luteinizing hormone (LH) levels (-3.75 mIU/mL; -3.84, -3.65) and total testosterone levels (-7.71 ng/dL); -12.08, -3.35), while follicle-stimulating hormone (FSH) increased (0.43 mIU/mL; 0.29, 0.57).
Conclusion: The KD demonstrated promising outcomes in improving metabolic and hormonal parameters in women diagnosed with PCOS.

Keywords:  Hormonal parameters; Ketogenic diet; Metabolic biomarkers; Polycystic ovary syndrome; Systematic review

DOI:  https://doi.org/10.1007/s40200-024-01441-3
Neurol Int. 2024 Oct 25. 16(6): 1203-1213

Ketogenic Diet Improves Sleep Quality and Daytime Sleepiness in Chronic Migraine: A Pilot Study.

Yan Tereshko, Simone Dal Bello, Enrico Belgrado, Cherubino Di Lorenzo, Alice Pittino, Francesca Filippi, Francesca Valdemarin, Christian Lettieri, Gian Luigi Gigli, Annacarmen Nilo, Gaia Pellitteri, Giovanni Merlino, Mariarosaria Valente.

   AIMS: The aim of this study is to assess the sleep quality and daytime sleepiness improvement in chronic migraineurs after 6 months of a 2:1 KD (ketogenic diet) and LGID (low-glycemic-index diet).
METHODS: Twenty-six patients underwent 2:1 KD (11 patients) and LGID (15 patients). PSQI (Pittsburgh sleep quality index) and ESS (Epworth sleepiness scale) were administered at the baseline and the 3-month and 6-month follow-up. MIDAS (Migraine Disability Assessment), HIT-6 (Headache Impact Test 6), migraine frequency (migraine days per month), migraine intensity, BMI (Body Mass Index), FM (Fat Mass), and FFM (Fat-Free Mass) were also assessed.
RESULTS: PSQI (F1.544, 38.606 = 7.250; p = 0.004), ESS (F1.988, 49.708 = 9.938; p < 0.001), HIT-6 (F1.432, 35.805 = 12.693; p < 0.001), migraine frequency (F1.522, 38.041 = 23.070; p < 0.001), migraine intensity (F1.949, 48.721 = 18.798; p < 0.001), BMI (F1.274, 31.857 = 38.191; p < 0.001), and FM (F1.245, 31.134 = 45.487; p < 0.001) improved significantly. The MIDAS (F1.005, 25.121 = 3.037; p = 0.093) and the FMM (F1.311, 32.784 = 1.741; p = 0.197) did not improve significantly. The ESS (p = 0.712) and PSQI (p = 0.776) data at 3-month and 6-month follow-ups did not differ significantly, as well as for migraine frequency, migraine intensity, BMI, FM, and HIT-6. A mild correlation emerged between the mean FM and mean ESS reduction during the 6 months (r = 0.497, p = 0.010).
CONCLUSIONS: Six months of LGID and 2:1 KD can improve sleep quality and daytime sleepiness in patients with chronic migraine. The effectiveness on migraine, sleep quality, and daytime sleepiness does not differ significantly between the 3-month and 6-month follow-up periods.

Keywords:  2:1 ketogenic diet; headache; ketogenic diet; low-glycemic index diet; migraine; migraine prevention

DOI:  https://doi.org/10.3390/neurolint16060091
Alzheimers Dement (Amst). 2024 Oct-Dec;16(4):16(4): e70039

Association of circulating ketone bodies with cognitive performance and dementia in the Multi-Ethnic Study of Atherosclerosis (MESA).

Parag Anilkumar Chevli, Christopher L Schaich, Alexis C Wood, Luqman A Tk, Anurag Mehta, Vardhmaan Jain, Margery Connelly, Suzanne Craft, Elad Shemesh, José A Luchsinger, Kathleen M Hayden, Bonnie Colleen Sachs, Timothy M Hughes, Michael D Shapiro.

   Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases.
Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi-Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000-02) and detailed cognitive testing at Exam 5 (2010-2012, N = 4392), Exam 6 (2016-2018, N = 1838), and in MESA-MIND (2019-2021, N = 2060).
Results: Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio [HR]: 1.14 [1.04-1.29]). Higher total KB was associated with worse cognitive performance in the Digit Span test at exam 5 [β: -0.30 (-0.47, -0.14)]. We also found that a higher KB was associated with greater functional impairment and a higher Quick Dementia Rating Scale (QDRS) score.
Discussion: In a diverse, cardiovascular disease-free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains.
Highlights: A study of ketone bodies (KB) and cognitive performance and incident dementia.Nuclear magnetic resonance (NMR) spectroscopy was used to measure plasma KB at baseline.Doubling of baseline total KB was associated with higher incident dementia.Higher KB was also associated with worse performance on a test of working memory.

Keywords:  cognitive testing; dementia; ketone bodies; multi‐ethnic; β‐hydroxybutyrate

DOI:  https://doi.org/10.1002/dad2.70039
Mol Genet Metab. 2024 Nov 10. pii: S1096-7192(24)00494-3. [Epub ahead of print]143(4): 108610

Ketogenic diet in adult patients with mitochondrial myopathy.

Heidi E E Zweers, Sophie H Kroesen, Gijsje Beerlink, Elke Buit, Karlijn Gerrits, Astrid Dorhout, Annemiek M J van Wegberg, Mirian C H Janssen, Saskia B Wortmann, Silvie Timmers, Christiaan G J Saris.

   BACKGROUND: This study aimed to explore the feasibility, safety and efficacy of a Modified Atkins Diet (MAD) in patients with mitochondrial myopathy (MM).
METHODS: Patients with genetically proven mitochondrial disorder and exercise intolerance or muscle weakness followed a twelve week MAD. Feasibility was measured by diet duration and ketone levels. Safety was assessed by monitoring adverse events (AE). Efficacy was assessed by a maximal incremental test and a muscle performance test.
RESULTS: Eight out of twenty patients completed the twelve week intervention. Reasons to discontinue were the occurrence of AE: rhabdomyolysis (n = 3), vomiting (n = 1), fatigue (n = 6), constipation (n = 1), in combination with a lack of improvement and adherence difficulties. On an individual level, various positive effects were reported including improvements in VO2peak (n = 6), anaerobic threshold (n = 9), muscle fatigue resistance (n = 5), muscle strength (n = 7), fatigue (n = 6), glucose tolerance (n = 7), migraine (n = 3), sleep (n = 3), and gastrointestinal complaints (n = 2). Lipid profile improved and thirteen patients lost weight. All patients with mitochondrial DNA (mtDNA) deletions, experienced muscle related AE. The five patients with the m.3243A>G mutation achieved the longest diet duration.
DISCUSSION/CONCLUSION: MAD feasibility, safety and efficacy is variable in MD patients. MAD appears to be unsuitable for MD patients with mtDNA deletions. All patients should be monitored closely for adverse events when initiating the diet. Further research should focus on predictive factors to consider the diet, effectiveness of less stringent carbohydrate restricted diets.

Keywords:  Adverse event; Ketogenic diet; Maximal incremental testing; Mitochondrial DNA deletion; Mitochondrial myopathy; Modified Atkins diet

DOI:  https://doi.org/10.1016/j.ymgme.2024.108610
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Nov 26. pii: S0278-5846(24)00273-2. [Epub ahead of print]136 111205

Measuring the effects of ketogenic diet on neuropsychiatric disorder: A scoping review.

Wali Yousufzai, Monika Singh, Leeda Ahmadi, Shreya Balamurali, Divyaraj Bavishi, Sahar Ashraf, Daniel B Stuart, Regina Baronia, Wail Amor.

   OBJECTIVE: This scoping review aims to examine the available literature on the ketogenic diet's (KD) efficiency as a potential therapeutic intervention for various neuropsychiatric disorders.
INTRODUCTION: The KD is a high-fat, low-carbohydrate diet that has been studied for its potential benefits in managing neuropsychiatric disorders. However, the extent of its effectiveness across a spectrum of these conditions remains unclear.
INCLUSION CRITERIA: The study designs considered eligible encompassed randomized and non-randomized controlled trials, retrospective and prospective observational studies, and comparative effectiveness assessments. The criteria for including each study were specifically related to neuropsychiatric disorders, referring to the DSM-5 coding guidelines.
METHODS: A systemic search was performed by an experienced reference librarian across multiple databases to pinpoint studies relevant to the influence of the ketogenic diet on neuropsychiatric disorders. All relevant articles were included that ranged over the last thirteen years. All relevant records identified were compiled into the Covidence systematic review software.
RESULTS: A total of 30 studies were reviewed, which reported effects of the KD on neuropsychiatric disorders, including improvements in Global Developmental Delay, Childhood Autism, Attention Deficit/Hyperactivity Disorder (ADHD) symptoms, psychotic symptoms, Bipolar and Related Disorders, Depressive Disorder symptoms, anxiety symptoms, eating disorders, Substance-Related and Addictive Disorders, Major and Mild Neurocognitive Disorders, and Seizure Disorders.
CONCLUSION: The KD may serve as a promising therapeutic intervention for various neuropsychiatric disorders. However, the evidence is heterogeneous, and further rigorous research is needed to establish the KD as a standard treatment for these disorders and to understand the underlying mechanisms of its effects.
IMPLICATIONS FOR PRACTICE: This review underscores the need for healthcare professionals to consider the potential benefits and limitations of the KD when managing patients with neuropsychiatric disorders. It also highlights the importance of individualized treatment plans based on the specific needs and responses of each patient.

Keywords:  Anxiety disorder; Autism; Cognitive impairment; Depressive disorder; Eating disorder; Epilepsy; Ketogenic diet; Neuropsychiatric disorder; Parkinson's disease

DOI:  https://doi.org/10.1016/j.pnpbp.2024.111205
Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]

Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.

Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi.

  Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
Phenomics. 2024 Aug;4(4): 313-326

Living Conditions Alter Ketogenic Diet-induced Metabolic Consequences in Mice through Modulating Gut Microbiota.

Jie Yang, Xiao Li, Chen Dai, Yongduan Teng, Linshan Xie, Haili Tian, Shangyu Hong.

  Many laboratories have demonstrated that the ketogenic diet (KD) can lead to weight loss and reduced fasting glucose levels, while also increasing total serum cholesterol levels. However, it's worth noting that the specific outcomes induced by KD can vary across different research settings. Certain studies have indicated that environmental factors, such as housing conditions and the acidity of drinking water, can influence physiological parameters and gut microbes in mice. Thus, our current study aimed to investigate whether differences in housing conditions and pH levels of drinking water contribute to variations in KD-induced phenotypes and gut microbes. Our findings revealed that mice housed in conventional (CV) conditions experienced more significant weight loss, lower fasting blood glucose levels, and a greater elevation of blood cholesterol levels compared to those in the specific pathogen-free (SPF) condition. Additionally, similar differences were observed when comparing mice fed with non-acidified water versus acidified water. Furthermore, we analyzed cecum content samples using 16S rRNA sequencing to assess gut microbial composition and found that the tested environmental variables also had an impact on the gut microbial composition of KD-fed mice, which was correlated with their phenotypic alterations. In summary, both housing conditions and the pH of drinking water were identified as crucial environmental factors that influenced KD-induced changes in metabolic phenotypes and gut microbes. Our study emphasizes the importance of considering these factors in animal studies related to KD and gut microbes, as well as in other types of animal research.
Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-024-00161-1.

Keywords:  Environmental factors; Gut microbes; Ketogenic diet; Metabolic phenotypes

DOI:  https://doi.org/10.1007/s43657-024-00161-1
J Appl Physiol (1985). 2024 Nov 27.

Effects of Hyperthermia and Acidosis on Mitochondrial Oxidative Phosphorylation.

Michael S Davis, Warwick M Bayly, Cristina M Hansen, Montana R Barrett, Cara A Blake.

  The intracellular environment of skeletal muscle can develop pronounced hyperthermia and acidosis during strenuous exercise, and these alterations in the typical intracellular conditions have been shown to alter mitochondrial respiration. However, the impact of these conditions on ATP synthesis is poorly understood. We used Thoroughbred racehorses to test the hypothesis that both hyperthermia and acidosis decrease the rate of ATP synthesis, but that athletic conditioning mitigates this loss of phosphorylation capacity. Isolated mitochondria were harvested from skeletal muscle before and after a 9-week racetrack conditioning program that increased whole-body aerobic capacity by 19%, and oxidative phosphorylation capacity was tested ex vivo under normothermic and hyperthermic conditions, as well as normal pH and acidic pH created by the addition of lactic acid. In unfit horses, hyperthermia caused a 30-55% decrease in the rate of ATP synthesis and loss of phosphorylation efficiency (P/O ratio decreased from 4.2 to 1.7 during maximal oxidative phosphorylation). Aerobic conditioning resulted in increased phosphorylation efficiency under hyperthermic conditions. Lactic acidosis had a small negative effect on ATP synthesis in unfit horses, but aerobic conditioning increased the sensitivity of isolated mitochondria to the deleterious effects of lactic acidosis. These data support a prominent role of hyperthermia in skeletal muscle fatigue during exercise, particularly in unfit subjects. However, acidosis may be a more important cause of failure of ATP synthesis in fit subjects.

Keywords:  ATP synthesis; Skeletal muscle; high-resolution respirometry; horse

DOI:  https://doi.org/10.1152/japplphysiol.00418.2024
J Transl Med. 2024 Nov 29. 22(1): 1086

Impact of daily fasting duration on body composition and cardiometabolic risk factors during a time-restricted eating protocol: a randomized controlled trial.

A Sampieri, A Paoli, G Spinello, E Santinello, T Moro.

   BACKGROUND: Time-restricted eating (TRE) is a dietary regimen that limits food intake for at least 12 h daily. Unlike other fasting protocols, TRE does not dictate what or how much to eat but rather focuses on the timing of meals. This approach has been previously demonstrated to improve body composition in individuals with obesity or metabolic impairments. However, its impact on body composition and cardiometabolic factors in healthy individuals remains unclear. Furthermore, the optimal fasting duration is still debated. Thus, we aimed to compare the effects of 8 weeks of different fasting durations on body composition and biochemical parameters in metabolically healthy, non-trained individuals using a parallel randomized controlled trial.
METHODS: Forty-one volunteers were randomly assigned to one of the four experimental groups: TRE 16:8 (16 h of fasting,8 h of eating), TRE 14:10 (14 h of fasting,10 h of eating), TRE 12:12 (12 h of fasting,12 h of eating) or a normal diet group (ND; no dietary restriction). Participants underwent body composition measurements and blood tests for lipid profiles (i.e., total cholesterol, LDL, HDL, and triglycerides), fasting glucose, leptin, and anabolic hormones (i.e., insulin and testosterone) levels. Data were analyzed using both intention-to-treat (ITT) and per-protocol (PP) analysis to account for compliance. A two-way ANOVA for repeated measures was employed to assess interactions between time and group.
RESULTS: In the ITT analysis, TRE 16:8 reduced body mass (-2.46%, p = 0.003) and absolute fat mass (-8.65%, p = 0.001) with no changes in lean soft tissue and in calorie intake. These results were consistent with the PP analysis which included 8 participants in TRE 16:8, 5 in TRE 14:10, 9 in TRE 12:12, and the entire ND group. Participants in the TRE 16:8 group spontaneously reduced their total caloric intake, although this reduction was not statistically significant. None of the other measurements significantly changed after 8 weeks.
CONCLUSIONS: Our results suggest that a 16-hour fasting window, even without caloric restriction, may be a viable strategy for improving body composition in healthy and non-trained individuals, whereas a shorter fasting period may be insufficient to produce significant changes in a healthy population.
TRIAL REGISTRATION: NCT, NCT04503005. Registered 4 August 2020, https://clinicaltrials.gov/study/NCT04503005 .

Keywords:  Body composition; Body mass loss; Fat mass; Intermittent fasting; Time-restricted eating

DOI:  https://doi.org/10.1186/s12967-024-05849-6
Antioxidants (Basel). 2024 Nov 14. pii: 1388. [Epub ahead of print]13(11):

Role of NLRP3 Inflammasome in Heart Failure Patients Undergoing Cardiac Surgery as a Potential Determinant of Postoperative Atrial Fibrillation and Remodeling: Is SGLT2 Cotransporter Inhibition an Alternative for Cardioprotection?

Rodrigo L Castillo, Jorge Farías, Cristian Sandoval, Alejandro González-Candia, Esteban Figueroa, Mauricio Quezada, Gonzalo Cruz, Paola Llanos, Gonzalo Jorquera, Sawa Kostin, Rodrigo Carrasco.

  In heart failure (HF) patients undergoing cardiac surgery, an increased activity of mechanisms related to cardiac remodeling may determine a higher risk of postoperative atrial fibrillation (POAF). Given that atrial fibrillation (AF) has a negative impact on the course and management of HF, including the need for anticoagulation therapy, identifying the factors associated with AF occurrence after cardiac surgery is crucial for the prognosis of these patients. POAF is thought to occur when various clinical and biochemical triggers act on susceptible cardiac tissue (first hit), with oxidative stress and inflammation during cardiopulmonary bypass (CPB) surgery being potential contributing factors (second hit). However, the molecular mechanisms involved in these processes remain poorly characterized. Recent research has shown that patients who later develop POAF often have pre-existing abnormalities in calcium handling and activation of NLRP3-inflammasome signaling in their atrial cardiomyocytes. These molecular changes may make cardiomyocytes more susceptible to spontaneous Ca2+-releases and subsequent arrhythmias, particularly when exposed to inflammatory mediators. Additionally, some clinical studies have linked POAF with elevated preoperative inflammatory markers, but there is a need for further research in order to better understand the impact of CPB surgery on local and systemic inflammation. This knowledge would make it possible to determine whether patients susceptible to POAF have pre-existing inflammatory conditions or cellular electrophysiological factors that make them more prone to developing AF and cardiac remodeling. In this context, the NLRP3 inflammasome, expressed in cardiomyocytes and cardiac fibroblasts, has been identified as playing a key role in the development of HF and AF, making patients with pre-existing HF with reduced ejection fraction (HFrEF) the focus of several clinical studies with interventions that act at this level. On the other hand, HFpEF has been linked to metabolic and non-ischemic risk factors, but more research is needed to better characterize the myocardial remodeling events associated with HFpEF. Therefore, since ventricular remodeling may differ between HFrEF and HFpEF, it is necessary to perform studies in both groups of patients due to their pathophysiological variations. Clinical evidence has shown that pharmacological therapies that are effective for HFrEF may not provide the same anti-remodeling benefits in HFpEF patients, particularly compared to traditional adrenergic and renin-angiotensin-aldosterone system inhibitors. On the other hand, there is growing interest in medications with pleiotropic or antioxidant/anti-inflammatory effects, such as sodium-glucose cotransporter 2 inhibitors (SGLT-2is). These drugs may offer anti-remodeling effects in both HFrEF and HFpEF by inhibiting pro-inflammatory, pro-oxidant, and NLRP3 signaling pathways and their mediators. The anti-inflammatory, antioxidant, and anti-remodeling effects of SGLT-2 i have progressively expanded from HFrEF and HFpEF to other forms of cardiac remodeling. However, these advances in research have not yet encompassed POAF despite its associations with inflammation, oxidative stress, and remodeling. Currently, the direct or indirect effects of NLRP3-dependent pathway inhibition on the occurrence of POAF have not been clinically assessed. However, given that NLRP3 pathway inhibition may also indirectly affect other pathways, such as inhibition of NF-kappaB or inhibition of matrix synthesis, which are strongly linked to POAF and cardiac remodeling, it is reasonable to hypothesize that this type of intervention could play a role in preventing these events.

Keywords:  NLRP3 inflammasome; SGLT2 inhibitors; heart failure with preserved ejection fraction; oxidative stress; postoperative atrial fibrillation; ventricular remodeling

DOI:  https://doi.org/10.3390/antiox13111388
bioRxiv. 2024 Nov 15. pii: 2024.11.14.621733. [Epub ahead of print]

Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.

Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Shixin Ma, McLane J Watson, Ryan D Sheldon, Michael P Vincent, Benjamin K Johnson, Abigail E Ellis, Molly T Soper-Hopper, Christine N Isaguirre, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Connie M Krawczyk, Russell G Jones.

Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.

DOI: https://doi.org/10.1101/2024.11.14.621733
Pharmaceuticals (Basel). 2024 Nov 07. pii: 1495. [Epub ahead of print]17(11):

From Microcirculation to Aging-Related Diseases: A Focus on Endothelial SIRT1.

Martin Law, Pei-Chun Wang, Zhong-Yan Zhou, Yu Wang.

  Silent information regulator sirtuin 1 (SIRT1) is an NAD+-dependent deacetylase with potent anti-arterial aging activities. Its protective function in aging-related diseases has been extensively studied. In the microcirculation, SIRT1 plays a crucial role in preventing microcirculatory endothelial senescence by suppressing inflammation and oxidative stress while promoting mitochondrial function and optimizing autophagy. It suppresses hypoxia-inducible factor-1α (HIF-1α)-mediated pathological angiogenesis while promoting healthy, physiological capillarization. As a result, SIRT1 protects against microvascular dysfunction, such as diabetic microangiopathy, while enhancing exercise-induced skeletal muscle capillarization and energy metabolism. In the brain, SIRT1 upregulates tight junction proteins and strengthens their interactions, thus maintaining the integrity of the blood-brain barrier. The present review summarizes recent findings on the regulation of microvascular function by SIRT1, the underlying mechanisms, and various approaches to modulate SIRT1 activity in microcirculation. The importance of SIRT1 as a molecular target in aging-related diseases, such as diabetic retinopathy and stroke, is underscored, along with the need for more clinical evidence to support SIRT1 modulation in the microcirculation.

Keywords:  angiogenesis; artery aging; capillarization; endothelium; microcirculation

DOI:  https://doi.org/10.3390/ph17111495
Scand J Med Sci Sports. 2024 Dec;34(12): e14768

Exercise Training Counteracts Compromised Mitochondrial Capacity Induced by Energy Restriction in Prediabetics in a Sex-Dependent Manner.

Magni Mohr, Jerónimo Aragón Vela, May-Britt Skoradal, Martin Thomassen, Søren Andersen Skriver, Mette Hansen, Ioannis G Fatouros, Peter Krustrup, Nikolai B Nordsborg.

  The objective of this randomized controlled trial was to examine if exercise training can counteract energy restriction-induced impairment of mitochondrial capacity in skeletal muscle of 55-70-years people with prediabetes and metabolic syndrome. The potential impact of sex was explored. Fifty sedentary men and women with prediabetes and metabolic syndrome (age: 61 ± 6 (±SD) years, BMI: 29.6 ± 4.7 kg·m-2, body fat content: 37.5% ± 8.2% and VO2max: 22.3 ± 5.7 mL·min-1·kg-1) were randomized to either exercise training and dietary advice (EX-DI) or dietary advice only (DI). Dietary advice aimed to induce weight loss and improve glycemic control. Exercise consisted of 32 ± 2 mixed 30-60 min training sessions with recreational small-sided soccer distributed across 16 weeks. Maximal activity and protein abundance of key regulatory mitochondrial enzymes were determined in m. vastus lateralis pre- and post-intervention. Muscle glycogen content was also determined. Dietary advice only (DI), impaired (p < 0.001) citrate synthase (CS), and 3-hydroxyacyl-CoA dehydrogenase (HAD) maximal activity by 18% ± 43% and 23% ± 19%, respectively. When combined with exercise training, no dietary impairment of CS or HAD maximal activity was detectable. Superoxide dismutase 2 (SOD2) and CS protein expression also declined (p < 0.05) in DI and remained unchanged in EX-DI. In terms of sex differences, a decrease in maximal CS activity in both EX-DI and DI was observed exclusively in men (all p < 0.05). In conclusion, 16 weeks of exercise training counteracts energy restriction-induced impairment in skeletal mitochondrial function in 55- to 70-year-old women and men with prediabetes and metabolic syndrome.

Keywords:  gender; metabolism; muscle glycogen; nutrition; oxidative capacity; soccer

DOI:  https://doi.org/10.1111/sms.14768
Nutrients. 2024 Nov 19. pii: 3956. [Epub ahead of print]16(22):

Effect of Intermittent Fasting on Immune Parameters and Intestinal Inflammation.

Eva Haasis, Anna Bettenburg, Axel Lorentz.

  Intermittent fasting (IF), including alternate day fasting (ADF) and time-restricted feeding (TRF) or, in humans, time-restricted eating (TRE), has been associated with the prevention and improvement of diseases, including inflammatory bowel disease (IBD). This review summarizes 20 animal and human studies on the influence of IF on intestinal inflammation. In the animal studies, TRF and ADF improved histological scores, inflammatory markers, markers of oxidative stress, and microbiota composition. Apart from the studies on Ramadan fasting, there are no studies on IF in IBD patients, so human studies on IF in healthy people were included. The studies on Ramadan fasting showed almost no effects, but this particular type of fasting is not directly comparable to TRE or ADF. However, TRE and ADF appear to have anti-inflammatory effects in healthy individuals, as they significantly reduce CRP levels and inflammatory markers. TRE also improved the composition of microbiota and the circadian oscillation of clock genes. The beneficial effects of TRE and ADF in healthy people appear to depend on the number of uninterrupted days of fasting, while in animal studies improvements in colitis have been observed regardless of the duration of fasting.

Keywords:  alternate day fasting; colitis; immune parameters; inflammation; intermittent fasting; time-restricted feeding

DOI:  https://doi.org/10.3390/nu16223956
Int J Mol Sci. 2024 Nov 14. pii: 12216. [Epub ahead of print]25(22):

Acute and Chronic Resistance Training, Acute Endurance Exercise, nor Physiologically Plausible Lactate In Vitro Affect Skeletal Muscle Lactylation.

Madison L Mattingly, Derick A Anglin, Bradley A Ruple, Maira C Scarpelli, Joao G Bergamasco, Joshua S Godwin, Christopher B Mobley, Andrew D Frugé, Cleiton A Libardi, Michael D Roberts.

  We examined changes in skeletal muscle protein lactylation and acetylation in response to acute resistance exercise, chronic resistance training (RT), and a single endurance cycling bout. Additionally, we performed in vitro experiments to determine if different sodium lactate treatments affect myotube protein lactylation and acetylation. The acute and chronic RT study (12 college-aged participants) consisted of 10 weeks of unilateral leg extensor RT with vastus lateralis (VL) biopsies taken at baseline, 24 h following the first RT bout, and the morning of the last day of the RT bout. For the acute cycling study (9 college-aged participants), VL biopsies were obtained before, 2 h after, and 8 h after 60 min of cycling. For in vitro experiments, C2C12 myotubes were treated with varying levels of sodium lactate, including LOW (1 mM for 24 h), HIGH (10 mM for 24 h), and PULSE (10 mM for 30 min followed by 1 mM for 23.5-h). Neither acute nor chronic RT significantly affected nuclear or cytoplasmic protein lactylation. However, cytoplasmic protein acetylation was significantly reduced following one RT bout (-15%, p = 0.002) and chronic RT (-16%, p = 0.006). Cycling did not acutely alter post-exercise global protein lactylation or acetylation patterns. Lastly, varying 24 h lactate treatments did not alter nuclear or cytoplasmic protein lactylation or acetylation, cytoplasmic protein synthesis levels, or myotube diameters. These findings continue to support the idea that exercise induces more dynamic changes in skeletal muscle protein acetylation, but not lactylation. However, further human research with more sampling timepoints and a lactylomics approach are needed to determine if, at all, different exercise modalities affect skeletal muscle protein lactylation.

Keywords:  hypertrophy; protein acetylation; protein lactylation; skeletal muscle

DOI:  https://doi.org/10.3390/ijms252212216
J Physiol. 2024 Nov 29.

Muscular strength, endothelial function and cognitive disorders: state of the art.

Yuri Sanchez-Martinez, Jose P Lopez-Lopez, Isabela Gomez-Montoya, Daniela Hernandez-Quiñones, Gabriela Ruiz-Uribe, Zully Rincón-Rueda, Ronald G Garcia, Patricio Lopez-Jaramillo.

  In recent years, the ageing population has increasingly grown. This process carries a range of pathophysiological changes involving alterations in the skeletal muscle, vascular endothelium and brain function, becoming an important risk factor for developing cognitive disorders and cardiovascular diseases. With ageing, there is a decrease in muscle mass and muscle strength, and a relationship between muscle strength decrease and cognitive decline has been shown. Lower handgrip strength has been linked to memory impairment, lower global cognitive function, decreased attention and reduced visuospatial abilities in the elderly, but understanding of the underlying mechanisms that explain the link between altered skeletal muscle function and structure, endothelial dysfunction, and the role of endothelial dysfunction in the onset of cognitive disorders has been scarcely explored. This review aims to detail the cellular and molecular mechanisms by which the progressive changes associated with ageing can alter healthy skeletal muscle and endothelial function, creating an environment of oxidative stress, inflammation and mitochondrial dysfunction. These changes can lead to reduced muscle strength, and the secretion of detrimental endothelial factors, resulting in endothelial dysfunction, blood-brain barrier disruption, and damage to neurons and microglia, ultimately accelerating the onset of cognitive disorders in the elderly. In addition, we aimed to describe the mechanisms that potentially explain how preserving muscular function with resistance training could prevent brain function deterioration, including the production of different factors that allow an improved endothelial function, haemodynamic parameters and brain plasticity, ultimately delaying the onset of cognitive impairment and chronic diseases.

Keywords:  ageing; chronic diseases; cognitive impairment; endothelium; muscle strength

DOI:  https://doi.org/10.1113/JP285939
Biology (Basel). 2024 Nov 18. pii: 945. [Epub ahead of print]13(11):

Understanding the Role of NLRP3 Inflammasome in Acute Pancreatitis.

Konstantinos Papantoniou, Ioanna Aggeletopoulou, Christos Michailides, Ploutarchos Pastras, Christos Triantos.

  Acute pancreatitis (AP) remains a serious clinical condition, with current treatment options being largely supportive. The discovery of inflammasomes, particularly the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, has significantly advanced our knowledge regarding many inflammatory diseases' pathogenesis, including AP. The NLRP3 inflammasome is central in mediating the inflammatory process in AP through its diverse activation mechanisms and its involvement in multiple signal transduction pathways. This has made NLRP3 an appealing target for novel therapeutic strategies aimed at modulating inflammation in AP. Despite the growing interest in NLRP3 as a therapeutic target, there remains a notable gap in clinical research, with few clinical trials exploring the efficacy of NLRP3 inhibitors in AP. Results of several preclinical studies and animal models are promising and suggest that the use of NLRP3 inhibitors could result in reduced inflammation and improved patient outcomes in AP. Further research is urgently needed to assess their potential benefits, safety, and applicability in human patients and address the underlying inflammatory processes driving AP.

Keywords:  NLRP3 inflammasome; activation; inhibitors; pancreatitis; prognosis

DOI:  https://doi.org/10.3390/biology13110945
Antioxidants (Basel). 2024 Oct 29. pii: 1317. [Epub ahead of print]13(11):

The Switching of the Type of a ROS Signal from Mitochondria: The Role of Respiratory Substrates and Permeability Transition.

Alexey G Kruglov, Anna B Nikiforova.

  Flashes of superoxide anion (O2-) in mitochondria are generated spontaneously or during the opening of the permeability transition pore (mPTP) and a sudden change in the metabolic state of a cell. Under certain conditions, O2- can leave the mitochondrial matrix and perform signaling functions beyond mitochondria. In this work, we studied the kinetics of the release of O2- and H2O2 from isolated mitochondria upon mPTP opening and the modulation of the metabolic state of mitochondria by the substrates of respiration and oxidative phosphorylation. It was found that mPTP opening leads to suppression of H2O2 emission and activation of the O2- burst. When the induction of mPTP was blocked by its antagonists (cyclosporine A, ruthenium red, EGTA), the level of substrates of respiration and oxidative phosphorylation and the selective inhibitors of complexes I and V determined the type of reactive oxygen species (ROS) emitted by mitochondria. It was concluded that upon complete and partial reduction and complete oxidation of redox centers of the respiratory chain, mitochondria emit H2O2, O2-, and nothing, respectively. The results indicate that the mPTP- and substrate-dependent switching of the type of ROS leaving mitochondria may be the basis for O2-- and H2O2-selective redox signaling in a cell.

Keywords:  OXPHOS substrates; hydrogen peroxide; kinetics; mitochondria; redox signaling; superoxide anion

DOI:  https://doi.org/10.3390/antiox13111317
Genes Immun. 2024 Nov 27.

The role of NLRP3 and NLRP12 inflammasomes in glioblastoma.

Sushmita Rajkhowa, Sushmita Jha.

Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

DOI: https://doi.org/10.1038/s41435-024-00309-z
J Funct Morphol Kinesiol. 2024 Oct 31. pii: 214. [Epub ahead of print]9(4):

Impact of Exercise Training at Maximal Fat Oxidation Intensity on Metabolic and Epigenetic Parameters in Patients with Overweight and Obesity: Study Protocol of a Randomized Controlled Trial.

Marco Antonio Hernández-Lepe, David Alfredo Hernández-Ontiveros, Isaac Armando Chávez-Guevara, Arnulfo Ramos-Jiménez, Rosa Patricia Hernández-Torres, Reymond Josué López-Fregoso, Omar Ramos-Lopez, Francisco José Amaro-Gahete, Raquel Muñiz-Salazar, Francisco Javier Olivas-Aguirre.

  Background: Exercise is an essential pillar for human health, as it contributes to physical, mental, and emotional well-being. Well-recognized international organizations, such as the World Health Organization, advocate for integrating exercise into healthy lifestyles, recognizing its importance in disease prevention and improving quality of life. However, despite the consensus on its value, there is no universal agreement on specific prescriptions for vulnerable groups, highlighting the need for personalized approaches that consider the unique characteristics and needs of everyone. Emerging studies have demonstrated that exercise training performed at the intensity that elicits maximal fat oxidation improves insulin sensitivity, cardiorespiratory fitness, and body composition in patients with obesity, making it a highly effective strategy for long-term weight management and metabolic health in this specific population. Methods: The present study protocol settles the basis for a 16-week randomized clinical trial based on exercise prescription at the maximal fat oxidation rate combined with resistance training in young individuals with overweight and obesity. Expected Results: This study will elucidate how FatMax, with or without resistance exercises, can enhance metabolic flexibility, increase fat oxidation, and improve body composition, evaluating changes in biochemical parameters (cholesterol, glucose, triglycerides, and inflammatory markers), metabolic biomarkers (determination of fat and carbohydrate utilization rates during rest and exercise), and epigenetic indicators (focusing on microRNAs associated with adipogenesis, inflammation, and fat metabolism). ClinicalTrials.gov identification number: NCT06553482 (FatMax Training on Metabolic and Epigenetic Parameters).

Keywords:  FatMax; exercise; obesity; overweight

DOI:  https://doi.org/10.3390/jfmk9040214
Free Radic Biol Med. 2024 Nov 27. pii: S0891-5849(24)01080-3. [Epub ahead of print]

Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner.

Hongyang Xu, Jacob L Brown, Shylesh Bhaskaran, Holly Van Remmen.

  One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

Keywords:  Aging; Mitochondria; Neuromuscular Junction; Sarcopenia; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.046
J Sci Food Agric. 2024 Nov 30.

Importance of proteins and mitochondrial changes as freshness indicators in fish muscle post-mortem.

Nima Hematyar, Tomas Policar, Turid Rustad.

  Evaluating protein and mitochondrial alterations post-mortem can contribute to determining correlations between fish-processing parameters and ultimate fish muscle quality. The myofibrillar protein alteration during rigor mortis directly affects the texture of fish muscle. To identify the mechanisms behind post-mortem softness and quality deterioration, it is crucial to understand the conditions linked to the breakdown of myofibrillar proteins in fish skeletal muscle. Therefore, monitoring protein breakdown at the molecular level and finding target proteins would be considered a marker for fish freshness. Mitochondria play an important role in executing and regulating cell death processes, including apoptosis and necrosis. The mitochondria are the seat of cellular respiration and experience significant alterations in post-mortem tissues. Processes used to reduce protein degradation, such as optimizing chilling and handling practices, would also minimize mitochondrial changes in fillet quality. Moreover, pH fluctuations are considered a critical point that influences both protein and mitochondrial changes. This review considered the implications of protein and mitochondrial alteration during post-mortem storage in fish fillets and the possible pathways of their interaction on fillet quality. Mitochondrial characteristics, such as membrane integrity, pH, and ATP levels, are important for post-mortem muscle cell changes, serving as an early indicator of fish freshness. Understanding the mechanisms behind protein degradation in fish muscle led to maintaining fillet quality and requires further experiments. Label-free proteomics combined with bioinformatics is crucial for comprehending protein degradation mechanisms to provide customers with safe and fresh fish products while minimizing economic losses associated with fillet deterioration. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Keywords:  mitochondrial changes; myofibrillar protein; post‐mortem; protein oxidation

DOI:  https://doi.org/10.1002/jsfa.14044
Redox Rep. 2024 Dec;29(1): 2430882

Palmitic acid and eicosapentaenoic acid supplementation in 3T3 adipocytes: impact on lipid storage and oxidative stress.

Edina Bakondi, Tobias Jung, Susanna Marg, Vanessa Schnell, Daniela Weber, Tim J Schulz, Tilman Grune, Annika Höhn.

   OBJECTIVES: Obesity is a worldwide public health problem, predisposing individuals to serious cardiovascular and metabolic complications such as type 2 diabetes mellitus. White adipose tissue serves as an important regulator of energy balance, and its expansion in obesity can trigger inflammatory reactions and oxidative stress, which can also lead to insulin resistance. Adipocytes, with a key role in regulating metabolic homeostasis, respond to increased calorie intake and altered fatty acid composition with hypertrophy or hyperplasia. Of particular interest are saturated fatty acids such as palmitic acid and omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), which have differential effects on adipocyte function and inflammation.
METHODS: Using 3T3-L1 cells as a model for adipocytes, we evaluated the effects of PA and EPA on lipid accumulation, droplet size, and oxidative stress markers.
RESULTS: We were able to show that EPA supplementation in 3T3 adipocytes does not lead to excessive lipid accumulation, but rather reduces the size of lipid droplets and also induces redox changes due to the unsaturated nature of EPA.
DISCUSSION: These results emphasize the contrasting roles of PA and EPA and the importance of fatty acid composition in the regulation of adipocyte function.

Keywords:  Obesity; adipocytes; eicosapentaenoic acid; fatty acids; lipid droplets; lipid storage; oxidative stress; palmitic acid

DOI:  https://doi.org/10.1080/13510002.2024.2430882
Eur J Sport Sci. 2024 Nov 25.

Continuous glucose monitoring in para cyclists: An observational study.

Vera Weijer, Rob van der Werf, Myrthe van der Haijden, Asker Jeukendrup, Luc J C van Loon, Jan-Willem van Dijk.

  Continuous glucose monitoring (CGM) is an emerging tool for dietary counseling in athletes. This study aimed to explore blood glucose profiles in Para cyclists and evaluate CGM accuracy at rest and during exercise. Thirteen Para cyclists, comprising eight hand bikers and five cyclists, wore a CGM sensor (Abbott) for 2 weeks. Participants recorded the timing of meals and regular training sessions and executed one standardized training session. Fifteen capillary blood glucose reference values (seven at rest and eight during the standardized training) were obtained by finger pricks. Mean glucose concentrations and time spent in hypoglycemia (<3.9 mmol/L), euglycemia (3.9-7.8 mmol/L), and hyperglycemia (>7.8 mmol/L) were calculated over 24 hrs and during daytime, nighttime, exercise, and 2 hrs postprandial periods. Mean absolute relative differences (MARD) were calculated between the CGM and capillary blood glucose. The mean glucose concentration over the 24 hr-period was 5.7 (5.6-5.8) mmol/L. Athletes were in the euglycemia range 91% of the time. Hyperglycemia was almost exclusively observed postprandially and during exercise. Hypoglycemia was restricted to the night and was particularly observed in athletes with a spinal cord injury. CGM accuracy was acceptable at rest (MARD: 12%) but markedly lower during exercise (MARD: 34%; p = 0.01), especially for hand bikers (MARD: 41%) compared with cyclists (MARD: 24%; p = 0.01). Para cyclists generally do not display signs of disturbed glucose regulation. However, the increased risk for nocturnal hypoglycemia in athletes with a spinal cord injury warrants attention. Furthermore, CGM accuracy is compromised during exercise, especially if the sensor is in proximity to highly active muscles.

Keywords:  continuous glucose monitoring; exercise; glucose; hyperglycemia; hypoglycemia; paralympic; spinal cord injury

DOI:  https://doi.org/10.1002/ejsc.12220
Trends Endocrinol Metab. 2024 Nov 22. pii: S1043-2760(24)00291-1. [Epub ahead of print]

Mitochondria as sensors of intracellular pathogens.

Jose M Delgado, Lena Pernas.

  Mitochondria must sense their environment to enable cells and organisms to adapt to diverse environments and survive during stress. However, during microbial infection, an evolutionary pressure since the inception of the eukaryotic cell, these organelles are traditionally viewed as targets for microbes. In this opinion we consider the perspective that mitochondria are domesticated microbes that sense and guard their 'host' cell against pathogens. We explore potential mechanisms by which mitochondria detect intracellular pathogens and induce mitochondria-autonomous responses that activate cellular defenses.

Keywords:  MAVS; PAMPs; domesticated microbes; import receptors; microbial sensors; mitochondria

DOI:  https://doi.org/10.1016/j.tem.2024.10.009
Int J Biol Macromol. 2024 Nov 25. pii: S0141-8130(24)08892-5. [Epub ahead of print] 138081

From oxidative stress to metabolic dysfunction: The role of TRPM2.

Ying-Shuang Li, Hua-Cheng Ren, Hui Li, Man Xing, Jian-Hua Cao.

  Metabolic syndromes including atherosclerosis, diabetes, obesity, and hypertension are increasingly prevalent worldwide. The disorders are the primary attributes of oxidative stress and inflammation. The transient receptor potential M2 (TRPM2) channel is a pivotal mediator linking oxidative stress to metabolic dysfunction. TRPM2, a non-selective cation channel activated by reactive oxygen species (ROS) and adenosine diphosphate ribose (ADPR), regulates calcium influx, inflammation, and cell death across various tissues. This review explores the structural and activation mechanisms of TRPM2, emphasizing its significance in metabolic diseases. Elevated levels of TRPM2 play a vital role in the disease progression by influencing physiological and cellular processes such as endothelial dysfunction, immune cell activation, and mitochondrial impairment. In conditions such as atherosclerosis, ischemic stroke, diabetes, obesity, and hypertension; TRPM2 exacerbates oxidative damage, amplifies inflammatory responses, and disrupts metabolic homeostasis. Recent research highlights the potential of TRPM2 as a therapeutic target, developing specified inhibitors. This review underscores the multifaceted role of TRPM2 in metabolic disorders and its promise as a target for therapeutic interventions.

Keywords:  Metabolic dysfunction; Oxidative stress; The transient receptor potential M2

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138081
Mol Aspects Med. 2024 Nov 25. pii: S0098-2997(24)00081-5. [Epub ahead of print]100 101322

Diet and exercise in frailty and sarcopenia. Molecular aspects.

Fernando Millan-Domingo, Esther Garcia-Dominguez, Juan Gambini, Gloria Olaso-Gonzalez, Jose Viña, Maria Carmen Gomez-Cabrera.

Function declines throughout life although phenotypical manifestations in terms of frailty or disability are only seen in the later periods of our life. The causes underlying lifelong function decline are the aging process "per se", chronic diseases, and lifestyle factors. These three etiological causes result in the deterioration of several organs and systems which act synergistically to finally produce frailty and disability. Regardless of the causes, the skeletal muscle is the main organ affected by developing sarcopenia. In the first section of the manuscript, as an introduction, we review the quantitative and qualitative age-associated skeletal muscle changes leading to frailty and sarcopenia and their impact in the quality of life and independence in the elderly. The reversibility of frailty and sarcopenia are discussed in the second and third sections of the manuscript. The most effective intervention to delay and even reverse frailty is exercise training. We review the role of different training programs (resistance exercise, cardiorespiratory exercise, multicomponent exercise, and real-life interventions) not only as a preventive but also as a therapeutical strategy to promote healthy aging. We also devote a section in the text to the sexual dimorphic effects of exercise training interventions in aging. How to optimize the skeletal muscle anabolic response to exercise training with nutrition is also discussed in our manuscript. The concept of anabolic resistance and the evidence of the role of high-quality protein, essential amino acids, creatine, vitamin D, β-hydroxy-β-methylbutyrate, and Omega-3 fatty acids, is reviewed. In the last section of the manuscript, the main genetic interventions to promote robustness in preclinical models are discussed. We aim to highlight the molecular pathways that are involved in frailty and sarcopenia. The possibility to effectively target these signaling pathways in clinical practice to delay muscle aging is also discussed.

DOI: https://doi.org/10.1016/j.mam.2024.101322
Antioxid Redox Signal. 2024 Nov 26.

Lactate Dehydrogenase A Is a Novel Positive Regulator of Vascular Smooth Muscle Cell Ferroptosis During Aortic Dissection.

Xin Feng, Xin Yi, Bo Huo, Hanshen Luo, Jingjie Chen, Xian Guo, Ze-Min Fang, Fu-Han Gong, Xiang Wei, Ding-Sheng Jiang, Yue Chen.

  Aims: Vascular smooth muscle cell (VSMC) ferroptosis is a pivotal event in the process of aortic dissection (AD), and a number of agents have a protective role against AD by inhibiting VSMC ferroptosis. While glycolysis is an ancient pathway related to almost all biological processes, its precise involvement in VSMC ferroptosis and AD remains unclear. Results: In this study, bioinformatics analysis revealed that glycolysis-related molecules and pathways were involved in VSMC ferroptosis and AD. We focused on the key enzyme of glycolysis, lactate dehydrogenase A (LDHA), and found that LDHA overexpression promoted ferroptosis and lipid peroxidation in cystine deprivation- or imidazole ketone erastin-treated VSMCs and vice versa. Clinical specimens showed a negative correlation between elevated LDHA levels in dissected aortae and ferroptosis-related molecules glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and ferroptosis suppressor protein 1 (FSP1). In VSMC ferroptosis, LDHA overexpression led to the suppression of GPX4, SLC7A11, and FSP1. Furthermore, the interaction between LDHA and nuclear factor (erythroid-derived 2)-like 2 (NRF2) was identified, and the overexpression or agonist of NRF2 reversed the contribution of LDHA on VSMC ferroptosis and lipid peroxidation. Innovation and Conclusion: These results highlight a significant association between LDHA and VSMC ferroptosis in AD development mediated through NRF2. These findings present LDHA as a potential target for AD intervention by inhibiting its expression. Antioxid. Redox Signal. 00, 000-000.

Keywords:  aortic dissection; ferroptosis; glycolysis; lactate dehydrogenase A; nuclear factor (erythroid-derived 2)-like 2; smooth muscle cell

DOI:  https://doi.org/10.1089/ars.2024.0585