bims-kimdis 2024-03-31 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–03–31
twenty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.
Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.
Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart.
Keto Clarity: A Comprehensive Systematic Review Exploring the Efficacy, Safety, and Mechanisms of Ketogenic Diet in Pediatric Epilepsy.
Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.
Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.
Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial.
Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
Cardiac Mitochondrial Metabolism During Pregnancy and the Postpartum Period.
Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.
Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.
MRI quantitative assessment of the effects of low-carbohydrate therapy on Hashimoto's thyroiditis.
Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors.
Fasting reduces satiety and increases hunger but does not affect the performance in resistance training.
Notopterol mitigates IL-1β-triggered pyroptosis by blocking NLRP3 inflammasome via the JAK2/NF-kB/hsa-miR-4282 route in osteoarthritis.
Substrate metabolism in male astronauts onboard the International Space Station: the ENERGY study.
Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.
Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model.
SLC25A3 negatively regulates NLRP3 inflammasome activation by restricting the function of NLRP3.
Endurance exercise preserves physical function in adult and older male C57BL/6 mice: high intensity interval training (HIIT) versus voluntary wheel running (VWR).
Mitochondrial respiration in peripheral arterial disease depends on stage severity.

Diabetes Metab Syndr Obes. 2024 ;17 1391-1401

Effect of Ketogenic Diet on Obesity and Other Metabolic Disorders: Narrative Review.

Temesgen Baylie, Tiget Ayelgn, Markeshaw Tiruneh, Kibur Hunie Tesfa.

  Obesity is defined as an abnormal or excessive accumulation of fat that increases the burden of different chronic diseases in the population. It has reached epidemic proportions and is a major risk factor for a variety of diseases, including hypertension, cardiovascular disease, type 2 diabetes, dyslipidaemia, atherosclerosis, and some malignancies. Weight gain is a result of excessive energy intake compared to energy expenditure (energy loss from metabolism and physical exercise). A ketogenic diet has a more useful effect on obesity than other diets. A ketogenic diet is a low-carbohydrate, high-fat, moderate-protein diet that induces the production of ketone bodies by mimicking the breakdown of a fasting state. The mechanism behind the ketogenic diet is still unknown, although it obviously helps people with obesity lose weight. Several pathways for the ketogenic diet effect on weight loss have been hypothesized by researchers, including reduced appetite due to effects on appetite control hormones and a possible direct appetite suppressant action of ketone bodies; reduced lipogenesis and increased lipolysis; greater metabolic efficiency; and increased metabolic costs.

Keywords:  Ketone Body; ketogenic diet; metabolic disorder; obesity

DOI:  https://doi.org/10.2147/DMSO.S447659
Mol Metab. 2024 Mar 27. pii: S2212-8778(24)00057-7. [Epub ahead of print] 101926

Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.

Lionel Carneiro, Rocco Bernasconi, Adriano Bernini, Cendrine Repond, Luc Pellerin.

   OBJECTIVE: Ketone bodies (such as β-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset.
METHODS: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet.
RESULTS: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms.
CONCLUSION: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.

Keywords:  ketone bodies; metabolism; neuroscience; obesity

DOI:  https://doi.org/10.1016/j.molmet.2024.101926
J Clin Med. 2024 Mar 07. pii: 1541. [Epub ahead of print]13(6):

Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart.

Constantin L Palm, Irina Shalaurova, Margery A Connelly, Stephan J L Bakker, Berend Daan Westenbrink, Robin P F Dullaart.

  Background: Heart failure (HF) features a shift in metabolism towards enhanced utilization of ketone bodies. While elevations in plasma natriuretic peptides represent a biochemical hallmark of HF, natriuretic peptides may promote lipolysis, thereby contributing to fatty acid availability for ketogenesis. Methods: We cross-sectionally tested to what extent fasting plasma total ketone bodies (measured using nuclear magnetic resonance spectroscopy) are associated with N-terminal pro-BNP (NT-proBNP; electrochemiluminescent sandwich immunoassay) in individuals with and without HF. Results: Among 6217 participants from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, 203 were identified with HF. NT-proBNP was four-fold and total ketone bodies were 25% higher in HF participants (each p < 0.001). In both participants with and without HF, total ketone body levels correlated with NT-proBNP (r = 0.116 and 0.185, respectively; p < 0.001). In multivariable linear regression analysis adjusted for relevant covariates, total ketone bodies remained associated with NT-proBNP in the whole cohort (std β = 0.08, p < 0.001), without a difference in participants with and without HF (p interaction: 0.52). Conclusion: This general population-based study reveals an independent association of fasting total body ketone bodies with plasma NT-proBNP. Our findings suggest that a metabolic defense mechanism could be operative, providing the myocardium with ketone bodies to meet its energy demands.

Keywords:  N-terminal pro-B-type natriuretic peptide; cardiology; epidemiology; heart failure; ketone bodies

DOI:  https://doi.org/10.3390/jcm13061541
Cureus. 2024 Feb;16(2): e54863

Keto Clarity: A Comprehensive Systematic Review Exploring the Efficacy, Safety, and Mechanisms of Ketogenic Diet in Pediatric Epilepsy.

Youmna Faheem, Amisha Jaiswal, Kainaat Shergill, Kusalik Boppana, Naiela E Almansouri, Saloni Bakkannavar, Ann Kashmer Yu.

  Epilepsy, a widespread neurological disorder characterized by recurrent seizures, affects millions globally, with a significant impact on the pediatric population. Antiepileptic drugs (AEDs) constitute the primary treatment; however, drug-resistant epilepsy (DRE), especially in children, poses a therapeutic challenge. Alternative interventions, such as surgery, vagus nerve stimulation, and the ketogenic diet (KD), have been explored. This systematic review aims to investigate various types of KDs, their distinctions, their effectiveness, and their safety concerning the reduction of seizure frequency, achieving seizure freedom, and the occurrence of adverse events. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search was conducted using databases such as PubMed Central (PMC), MedLine, and Science Direct to identify relevant articles. Eligibility criteria and quality assessment tools were applied to evaluate the potential risk of bias and select 11 articles for inclusion in this review. The selected articles encompassed four randomized controlled trials (RCTs), two systematic reviews, and five narrative reviews. The data collected for this review was completed on October 2, 2023. Challenges, such as palatability, cultural factors, and adherence difficulties, were identified. Family or caregiver involvement plays a pivotal role in treatment success. Despite numerous RCTs and reviews, information gaps persist, hindering conclusive outcomes. Evaluating the risk-benefit ratio is crucial, considering potential side effects. The highly individualized nature of KD therapy, influenced by diverse seizure types and syndromes, necessitates a trial-and-error approach monitored by a multidisciplinary team. Long-term safety and efficacy demand continuous real-life patient data review. In summary, while KD presents a promising alternative for DRE, its success relies on meticulous planning, individualized implementation, and ongoing research to address existing challenges and information gaps.

Keywords:  classic ketogenic diet; drug-resistant epilepsy (dre); epilepsy; ketogenic diet; low glycemic index treatment (lgit); medium-chain triglyceride ketogenic diet (mctkd); modified atkins diet (mad); pediatric neurology; pediatrics; seizure

DOI:  https://doi.org/10.7759/cureus.54863
Circulation. 2024 Mar 27.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

Kristoffer Berg-Hansen, Nigopan Gopalasingam, Kristian Hylleberg Christensen, Bertil Ladefoged, Mads Jønsson Andersen, Steen Hvitfeldt Poulsen, Barry A Borlaug, Roni Nielsen, Niels Møller, Henrik Wiggers.

   BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.
METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.
RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes.
CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Keywords:  cardiac output; esters; exercise; heart failure; hemodynamics; hydroxybutyrate dehydrogenase; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067971
Nutrients. 2024 Mar 13. pii: 812. [Epub ahead of print]16(6):

Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.

Dorota Wesół-Kucharska, Milena Greczan, Magdalena Kaczor, Ewa Ehmke Vel Emczyńska-Seliga, Małgorzata Hajdacka, Edyta Czekuć-Kryśkiewicz, Dorota Piekutowska-Abramczuk, Paulina Halat-Wolska, Elżbieta Ciara, Maciej Jaworski, Aleksandra Jezela-Stanek, Dariusz Rokicki.

  Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Keywords:  IPMDS; ketogenic diet; mitochondrial diseases; mtDNA; nDNA

DOI:  https://doi.org/10.3390/nu16060812
Psychiatry Res. 2024 Mar 20. pii: S0165-1781(24)00151-3. [Epub ahead of print]335 115866

Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial.

Shebani Sethi, Diane Wakeham, Terrance Ketter, Farnaz Hooshmand, Julia Bjornstad, Blair Richards, Eric Westman, Ronald M Krauss, Laura Saslow.

  The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy. More recently, this treatment has shown promise in the treatment of psychiatric illness. We conducted a 4-month pilot study to investigate the effects of a KD on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Twenty-three participants were enrolled in a single-arm trial. Results showcased improvements in metabolic health, with no participants meeting metabolic syndrome criteria by study conclusion. Adherent individuals experienced significant reduction in weight (12 %), BMI (12 %), waist circumference (13 %), and visceral adipose tissue (36 %). Observed biomarker enhancements in this population include a 27 % decrease in HOMA-IR, and a 25 % drop in triglyceride levels. In psychiatric measurements, participants with schizophrenia showed a 32 % reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31 %, and the proportion of participants that started with elevated symptomatology improved at least 1-point on CGI (79 %). Psychiatric outcomes across the cohort encompassed increased life satisfaction (17 %) and enhanced sleep quality (19 %). This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness.

Keywords:  Bipolar illness; Clinical trial; Insulin resistance; Ketogenic diet metabolic therapy; Mental health; Metabolic psychiatry; Metabolic syndrome; Obesity; Psychiatric disease; Schizoaffective disorder

DOI:  https://doi.org/10.1016/j.psychres.2024.115866
Curr Issues Mol Biol. 2024 Mar 02. 46(3): 1987-2026

Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.

Sydney Bartman, Giuseppe Coppotelli, Jaime M Ross.

  Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in a variety of cellular processes, such as energy production, calcium buffering and homeostasis, steroid synthesis, cell growth, and apoptosis, as well as inflammation and ROS production. Considering that mitochondria are involved in a multitude of cellular processes, mitochondrial dysfunction has been shown to play a role within several age-related diseases, including cancers, diabetes (type 2), and neurodegenerative diseases, although the underlying mechanisms are not entirely understood. The significant increase in lifespan and increased incidence of age-related diseases over recent decades has confirmed the necessity to understand the mechanisms by which mitochondrial dysfunction impacts the process of aging and age-related diseases. In this review, we will offer a brief overview of mitochondria, along with structure and function of this important organelle. We will then discuss the cause and consequence of mitochondrial dysfunction in the aging process, with a particular focus on its role in inflammation, cognitive decline, and neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease. We will offer insight into therapies and interventions currently used to preserve or restore mitochondrial functioning during aging and neurodegeneration.

Keywords:  aging; mitochondria; mitochondrial dysfunction; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cimb46030130
Am J Physiol Heart Circ Physiol. 2024 Mar 29.

Cardiac Mitochondrial Metabolism During Pregnancy and the Postpartum Period.

Emily B Schulman-Geltzer, Kyle L Fulghum, Richa A Singhal, Bradford G Hill, Helen E Collins.

  The goal of the present study was to characterize changes in mitochondrial respiration in the maternal heart during pregnancy and after birth. Timed pregnancy studies were performed in 12-week-old female FVB/NJ mice, and cardiac mitochondria were isolated from the following groups of mice: non-pregnant (NP), mid-pregnancy (MP), late-pregnancy (LP), and 1-week post-birth (PB). Similar to our previous studies, we observed increased heart size during all stages of pregnancy (e.g., MP and LP) and post-birth (e.g., PB) compared with NP mice. Differential cardiac gene and protein expression analyses revealed changes in several mitochondrial transcripts at LP and PB, including several mitochondrial complex subunits and members of the Slc family, important for mitochondrial substrate transport. Respirometry revealed that pyruvate- and glutamate-supported state 3 respiration was significantly higher in PB versus LP mitochondria, with respiratory control ratio (RCR) values higher in PB mitochondria. In addition, we found that PB mitochondria respired more avidly when given 3-hydroxybutyrate (3-OHB) than mitochondria from NP, MP, and LP hearts, with no differences in RCR. These increases in respiration in PB hearts occurred independent of changes in mitochondrial yield, but were associated with higher abundance of 3-hydroxybutyrate dehydrogenase 1. Collectively, these findings suggest that, after birth, maternal cardiac mitochondria have an increased capacity to use 3-OHB, pyruvate, and glutamate as energy sources; however, increases in mitochondrial efficiency in the postpartum heart appear limited to carbohydrate and amino acid metabolism.

Keywords:  3-hydroxybutyrate; female cardiac biology; mitochondrial subunit complexes; physiological hypertrophy; solute transporters

DOI:  https://doi.org/10.1152/ajpheart.00127.2024
J Clin Endocrinol Metab. 2024 Mar 28. pii: dgae204. [Epub ahead of print]

Enhanced chronic inflammation and increased branched chain amino acids in adrenal disorders: a cross-sectional study.

Annop Kittithaworn A, Prerna Dogra, Jasmine Saini, Eke G Gruppen, Elizabeth Atkinson, Sara Achenbach, Kai Yu, Karthik Thangamuthu, Margery A Connelly, Robin Pf Dullaart, Irina Bancos.

   CONTEXT: Patients with adrenal hormone excess demonstrate increased cardiovascular risk and mortality.
OBJECTIVE: We aimed to determine the impact of adrenal disorders on the inflammation marker GlycA, total branched-chain amino acids (BCAA), ketone bodies and the gut microbiome-derived metabolites trimethylamine N-oxide (TMAO) and betaine.
METHODS: We conducted a single-center cross-sectional study of patients with nonfunctioning adenomas (NFA), mild autonomous cortisol secretion (MACS), primary aldosteronism (PA), Cushing syndrome (CS), pheochromocytoma/paragangliomas (PPGL), other benign or malignant adrenal masses, and adrenocortical carcinoma (ACC) between January 2015 and July 2022 (n=802). Referent subjects included participants of the PREVEND (Prevention of Renal and Vascular End-stage Disease) study (n=5241). GlycA, BCAA, ketone bodies, TMAO, and betaine were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus and statin therapy.
RESULTS: In age-and sex-adjusted comparison to referent subjects, increased GlycA was noted in all patient categories, increased BCAA in NFA, MACS, CS, PA and ACC, increased TMAO in patients with other malignant adrenal masses, increased betaine in NFA and MACS, and increased ketone bodies in NFA, CS and ACC. Essentially similar findings were observed in fully adjusted analysis and after exclusion of subjects with diabetes and cardiovascular disease.
CONCLUSION: Patients with functioning and non-functioning adrenal masses demonstrated increased GlycA and BCAA, biomarkers associated with adverse cardiometabolic disorders and mortality. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS and CS.

Keywords:  Cushing syndrome; MACS; branched chain amino acids; inflammation; mild autonomous cortisol secretion; nuclear magnetic resonance spectroscopy

DOI:  https://doi.org/10.1210/clinem/dgae204
Sports Med. 2024 Mar 25.

Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.

Elizabeth G Reisman, John A Hawley, Nolan J Hoffman.

Exercise perturbs energy homeostasis in skeletal muscle and engages integrated cellular signalling networks to help meet the contraction-induced increases in skeletal muscle energy and oxygen demand. Investigating exercise-associated perturbations in skeletal muscle signalling networks has uncovered novel mechanisms by which exercise stimulates skeletal muscle mitochondrial biogenesis and promotes whole-body health and fitness. While acute exercise regulates a complex network of protein post-translational modifications (e.g. phosphorylation) in skeletal muscle, previous investigations of exercise signalling in human and rodent skeletal muscle have primarily focused on a select group of exercise-regulated protein kinases [i.e. 5' adenosine monophosphate-activated protein kinase (AMPK), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase (CaMK) and mitogen-activated protein kinase (MAPK)] and only a small subset of their respective protein substrates. Recently, global mass spectrometry-based phosphoproteomic approaches have helped unravel the extensive complexity and interconnection of exercise signalling pathways and kinases beyond this select group and phosphorylation and/or translocation of exercise-regulated mitochondrial and nuclear protein substrates. This review provides an overview of recent advances in our understanding of the molecular events associated with acute endurance exercise-regulated signalling pathways and kinases in skeletal muscle with a focus on phosphorylation. We critically appraise recent evidence highlighting the involvement of mitochondrial and nuclear protein phosphorylation and/or translocation in skeletal muscle adaptive responses to an acute bout of endurance exercise that ultimately stimulate mitochondrial biogenesis and contribute to exercise's wider health and fitness benefits.

DOI: https://doi.org/10.1007/s40279-024-02007-2
Endocr Connect. 2024 Mar 01. pii: EC-23-0477. [Epub ahead of print]

MRI quantitative assessment of the effects of low-carbohydrate therapy on Hashimoto's thyroiditis.

Xiao-Shan Huang, Ning Dai, Jian-Xia Xu, Jun-Yi Xiang, Xiao-Zhong Zheng, Tian-Yu Ke, Lin-Ying Ma, Qi-Hao Shi, Shu-Feng Fan.

OBJECTIVE: Hashimoto's thyroiditis is an inflammatory disease, and research suggests that a low-carbohydrate diet may have potential anti-inflammatory effects. This study aims to utilize Dixon-T2-weighted imaging (WI) sequence for semi-quantitative assessment of the impact of a low-carbohydrate diet on the degree of thyroid inflammation in patients with Hashimoto's thyroiditis.
METHODS: Forty patients with Hashimoto's thyroiditis were recruited for this study and randomly divided into two groups: one with a normal diet and the other with a low-carbohydrate diet. Antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) were measured for all participants. Additionally, thyroid water content was semi-quantitatively measured using Dixon-T2WI. The same tests and measurements were repeated for all participants after six months.
RESULTS: After six months of a low-carbohydrate diet, patients with Hashimoto's thyroiditis showed a significant reduction in thyroid water content (94.84±1.57% vs. 93.07±2.05%, P < 0.05). Concurrently, a decrease was observed in levels of TPOAb and TgAb (TPOAb: 211.30 (92.63-614.62) vs. 89.45 (15.9-215.67); TgAb: 17.05 (1.47-81.64) vs. 4.1 (0.51-19.42), P < 0.05). In contrast, there were no significant differences in thyroid water content or TPOAb and TgAb levels for patients with Hashimoto's thyroiditis following a normal diet after six months, P < 0.05.
CONCLUSION: Dixon-T2WI can quantitatively assess the degree of thyroid inflammation in patients with Hashimoto's thyroiditis. Following a low-carbohydrate diet intervention, there is a significant reduction in thyroid water content and a decrease in levels of TPOAb and TgAb. These results suggest that a low-carbohydrate diet may help alleviate inflammation in patients with Hashimoto's thyroiditis.

DOI: https://doi.org/10.1530/EC-23-0477
Mol Cell Biochem. 2024 Mar 25.

Intermittent fasting shifts the diurnal transcriptome atlas of transcription factors.

Min Fu, Siyu Lu, Lijun Gong, Yiming Zhou, Fang Wei, Zhigui Duan, Rong Xiang, Frank J Gonzalez, Guolin Li.

  Intermittent fasting remains a safe and effective strategy to ameliorate various age-related diseases, but its specific mechanisms are not fully understood. Considering that transcription factors (TFs) determine the response to environmental signals, here, we profiled the diurnal expression of 600 samples across four metabolic tissues sampled every 4 over 24 h from mice placed on five different feeding regimens to provide an atlas of TFs in biological space, time, and feeding regimen. Results showed that 1218 TFs exhibited tissue-specific and temporal expression profiles in ad libitum mice, of which 974 displayed significant oscillations at least in one tissue. Intermittent fasting triggered more than 90% (1161 in 1234) of TFs to oscillate somewhere in the body and repartitioned their tissue-specific expression. A single round of fasting generally promoted TF expression, especially in skeletal muscle and adipose tissues, while intermittent fasting mainly suppressed TF expression. Intermittent fasting down-regulated aging pathway and upregulated the pathway responsible for the inhibition of mammalian target of rapamycin (mTOR). Intermittent fasting shifts the diurnal transcriptome atlas of TFs, and mTOR inhibition may orchestrate intermittent fasting-induced health improvements. This atlas offers a reference and resource to understand how TFs and intermittent fasting may contribute to diurnal rhythm oscillation and bring about specific health benefits.

Keywords:  Aging; Circadian rhythm; Every-other-day fasting; Fasting; Intermittent fasting; Transcription factor

DOI:  https://doi.org/10.1007/s11010-024-04928-y
Biol Sport. 2024 Mar;41(2): 57-65

Fasting reduces satiety and increases hunger but does not affect the performance in resistance training.

Marcos D M Drummond, Paula S G Soares, Lucas A Savoi, Ronaldo A D Silva.

  Intermittent fasting (IF) has been suggested to reduce body fat percentage and improve non-communicable chronic diseases. However, little is known about resistance training (RT) and the subjective perception of hunger under fasted conditions. This study aimed to examine the effects of overnight fasting (12 h or 16 h fasting) on the maximum voluntary isometric contraction (MVIC) and countermovement jump (CMJ) performance in resistance-trained young male adults. In RT sessions, the maximum number of repetitions (MNR) and the total volume load (TVL) were evaluated in the back squat and leg press 45°. The volunteers performed all tests and the RT session in 3 different conditions: fed state, 12 and 16 hours of IF. The subjective perception of hunger was applied through an adapted visual analogue scale (adVAS). The results showed that strength and power variables did not change significantly: MVIC (p = 0.960), CMJ (p = 0.986), MNR back squat (p = 0.856), MNR leg press 45° (p = 0.998), TVL (p = 0.954). However, hunger was significantly greater after the 16-hour fasting (p = 0.001) compared to 12 hours of fasting and the fed state. Also, the desire to eat was greater after 16 hours (p = 0.001) compared to 12 hours of fasting and the fed state. This study indicates that IF for 12 or 16 hours does not significantly impair strength and power, but the longer the fasting duration, the greater are the hunger and desire to eat.

Keywords:  Athletic performance; Fasting; Hunger; Resistance training

DOI:  https://doi.org/10.5114/biolsport.2024.131814
Heliyon. 2024 Mar 30. 10(6): e28094

Notopterol mitigates IL-1β-triggered pyroptosis by blocking NLRP3 inflammasome via the JAK2/NF-kB/hsa-miR-4282 route in osteoarthritis.

Ko-Ta Chen, Chi-Tai Yeh, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat-Hang Fong, Wei-Hwa Lee, Yen-Shuo Chiu.

   Objective: Osteoarthritis (OA), the most prevalent form of arthritis, impacts approximately 10% of men and 18% of women aged above 60 years. Currently, a complete cure for OA remains elusive, making clinical management challenging. The traditional Chinese herb Notopterygium incisum, integral to the Juanbi pill for rheumatism, shows promise in safeguarding chondrocytes through its strong anti-inflammatory effects.
Methods: To explore the protective effect of notopterol and miRNA (has-miR-4248) against inflammation, we simulated an inflammatory environment in chondrocytes cell lines C20A4 and C28/12, focusing on inflammasome formation and pyroptosis.
Results: Our finding indicates notopterol significantly reduced interleukin (IL)-18 and tumor necrosis factor (TNF)-alpha levels in inflamed cells, curtailed reactive oxygen species (ROS) production post-inflammation, and inhibited the JAK2/STAT3 signaling pathway, thus offering chondrocytes protection from inflammation. Importantly, notopterol also hindered inflammasome assembly and pyroptosis by blocking the NF-κB/NLRP3 pathway through hsa-miR-4282 modulation. In vivo experiments showed that notopterol treatment markedly decreased Osteoarthritis Research Society International (OARSI) scores in OA mice and boosted hsa-miR-4282 expression compared to control groups.
Conclusions: This study underscores notopterol's potential as a therapeutic agent in OA treatment, highlighting its capacity to shield cartilage from inflammation-induced damage, particularly by preventing pyroptosis.

Keywords:  Interleukin 1 beta; JAK2/NF-κB/hsa-miR-4282 pathway; NLRP3 inflammasome; Notopterol; Osteoarthritis; Pyroptosis

DOI:  https://doi.org/10.1016/j.heliyon.2024.e28094
NPJ Microgravity. 2024 Mar 27. 10(1): 39

Substrate metabolism in male astronauts onboard the International Space Station: the ENERGY study.

Elisa Le Roux, Alexandre Zahariev, Isabelle Chery, Dale A Schoeller, Pierre Bourdier, Alain Maillet, Cecile Thevenot, Maël Garnotel, Guillemette Gauquelin-Koch, Laurie Van Den Berghe, Stéphane Blanc, Chantal Simon, Audrey Bergouignan.

Bedrest shifts fasting and postprandial fuel selection towards carbohydrate use over lipids, potentially affecting astronauts' performance and health. We investigated whether this change occurs in astronauts after at least 3 months onboard the International Space Station (ISS). We further explored the associations with diet, physical activity (PA), and body composition. Before and during spaceflight, respiratory quotient (RQ), carbohydrate, and fat oxidation were measured by indirect calorimetry before and following a standardized meal in 11 males (age = 45.7 [SD 7.7] years, BMI = 24.3 [2.1] kg m-²). Postprandial substrate use was determined by 0-to-260 min postprandial incremental area under the curve (iAUC) of nutrient oxidation and the difference between maximal postprandial and fasting RQ (ΔRQ). Food quotient (FQ) was calculated from diet logs. Fat (FM) and fat-free mass (FFM) were measured by hydrometry and PA by accelerometry and diary logs. Spaceflight increased fasting RQ (P = 0.01) and carbohydrate oxidation (P = 0.04) and decreased fasting lipid oxidation (P < 0.01). An increase in FQ (P < 0.001) indicated dietary modifications onboard the ISS. Spaceflight-induced RQ changes adjusted for ground RQ correlated with inflight FQ (P < 0.01). In postprandial conditions, nutrient oxidation and ΔRQ were unaffected on average. Lipid oxidation changes negatively correlated with FFM changes and inflight aerobic exercise and positively with FM changes. The opposite was observed for carbohydrate oxidation. ΔRQ changes were negatively and positively related to FM and FFM changes, respectively. In conclusion, fasting substrate oxidation shift observed during spaceflight may primarily result from dietary modifications. Between-astronaut variability in postprandial substrate oxidation depends on body composition changes and inflight PA.

DOI: https://doi.org/10.1038/s41526-024-00360-0
Elife. 2024 Mar 27. pii: RP91060. [Epub ahead of print]12

Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.

Hong Chen, Lijun Sun, Lu Feng, Xue Han, Yunhua Zhang, Wenbo Zhai, Zehe Zhang, Michael Mulholland, Weizhen Zhang, Yue Yin.

  Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

Keywords:  adipocytes; adipose tissue; immune; innate lymphoid cells; intestine; medicine; metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.91060
Biomolecules. 2024 Mar 07. pii: 316. [Epub ahead of print]14(3):

Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model.

Mikhail V Dubinin, Irina B Mikheeva, Anastasia E Stepanova, Anastasia D Igoshkina, Alena A Cherepanova, Alena A Semenova, Vyacheslav A Sharapov, Igor I Kireev, Konstantin N Belosludtsev.

  Duchenne muscular dystrophy is caused by loss of the dystrophin protein. This pathology is accompanied by mitochondrial dysfunction contributing to muscle fiber instability. It is known that mitochondria-targeted in vivo therapy mitigates pathology and improves the quality of life of model animals. In the present work, we applied mitochondrial transplantation therapy (MTT) to correct the pathology in dystrophin-deficient mdx mice. Intramuscular injections of allogeneic mitochondria obtained from healthy animals into the hind limbs of mdx mice alleviated skeletal muscle injury, reduced calcium deposits in muscles and serum creatine kinase levels, and improved the grip strength of the hind limbs and motor activity of recipient mdx mice. We noted normalization of the mitochondrial ultrastructure and sarcoplasmic reticulum/mitochondria interactions in mdx muscles. At the same time, we revealed a decrease in the efficiency of oxidative phosphorylation in the skeletal muscle mitochondria of recipient mdx mice accompanied by a reduction in lipid peroxidation products (MDA products) and reduced calcium overloading. We found no effect of MTT on the expression of mitochondrial signature genes (Drp1, Mfn2, Ppargc1a, Pink1, Parkin) and on the level of mtDNA. Our results show that systemic MTT mitigates the development of destructive processes in the quadriceps muscle of mdx mice.

Keywords:  Duchenne muscular dystrophy; lipid peroxidation; mitochondrial dysfunction; mitochondrial transplantation; muscle force; skeletal muscle

DOI:  https://doi.org/10.3390/biom14030316
J Biol Chem. 2024 Mar 27. pii: S0021-9258(24)01730-7. [Epub ahead of print] 107233

SLC25A3 negatively regulates NLRP3 inflammasome activation by restricting the function of NLRP3.

Feng Xiao, Yaling Jia, Simeng Zhang, Nanfang Liu, Xuelong Zhang, Tianci Wang, Jialu Qiao, Ge Yang, Xu Che, Keli Chen, Pan Pan, Lingli Zhou, Binlian Sun, Jun Chen, Pin Wan.

  The NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome activation plays a critical role in innate immune and pathogenic microorganism infections. However, excessive activation of NLRP3 inflammasome will lead to cellular inflammation and tissue damage, and naturally it must be precisely controlled in the host. Here, we discovered that solute carrier family 25 member 3 (SLC25A3), a mitochondrial phosphate carrier protein, plays an important role in negatively regulating NLRP3 inflammasome activation. We found that SLC25A3 could interact with NLRP3, overexpression of SLC25A3 and knockdown of SLC25A3 could regulate NLRP3 inflammasome activation, and the interaction of NLRP3 and SLC25A3 is significantly boosted in the mitochondria when the NLRP3 inflammasome is activated. Our detailed investigation demonstrated that the interaction between NLRP3 and SLC25A3 disrupted the interaction of NLRP3-NEK7, promoted ubiquitination of NLRP3, and negatively regulated NLRP3 inflammasome activation. Thus, these findings uncovered a new regulatory mechanism of NLRP3 inflammasome activation, which provides a new perspective for the therapy of NLRP3 inflammasome-associated inflammatory diseases.

Keywords:  Innate immune response; Mitochondria; NLRP3 inflammasome activation; SLC25A3

DOI:  https://doi.org/10.1016/j.jbc.2024.107233
Front Aging. 2024 ;5 1356954

Endurance exercise preserves physical function in adult and older male C57BL/6 mice: high intensity interval training (HIIT) versus voluntary wheel running (VWR).

Megan L Pajski, Chris Byrd, Nainika Nandigama, Emily Seguin, Anna Seguin, Alyssa Fennell, Ted G Graber.

  Exercise has been shown to improve physical function, mitigate aspects of chronic disease and to potentially alter the trajectory of age-related onset of frailty and sarcopenia. Reliable and valid preclinical models are necessary to elucidate the underlying mechanisms at the intersection of age, exercise, and functional decline. The purpose of this study was to compare, head to head, the effects of two common pre-clinical models of endurance exercise: high intensity interval training (HIIT) and voluntary wheel running (VWR). The hypothesis was that a prescribed and regimented exercise program, HIIT, would prove to be a superior training method to unregulated voluntary exercise, VWR. To investigate this hypothesis, we evaluated adult (n = 24, designated 10 m, aged 6 months at the beginning of the study, 10 months at its completion) and older adult (n = 18, designated 26 m, aging from 22 months to 26 months over the course of the study) C57BL/6 male mice. These mice were randomly assigned (with selection criteria) to a 13-week program of voluntary wheel running (VWR), high intensity interval training (HIIT), or sedentary control (SED). The functional aptitude of each mouse was determined pre- and post-training using our composite CFAB (comprehensive functional assessment battery) scoring system consisting of voluntary wheel running (volitional exercise and activity rate), treadmill (endurance), rotarod (overall motor function), grip meter (forelimb strength), and inverted cling (whole body strength/endurance). To measure sarcopenia, we tracked body mass, body composition (with EchoMRI), plantar flexor torque (in 10 m), and measured muscle wet mass post-training. Overall, adult CFAB scores decreased while body mass and percent body fat increased as they matured; however, exercise significantly mitigated the changes (p < 0.05) compared to SED. Older adults demonstrated preservation of function (CFAB) and reduced body fat (p < 0.05) compared to SED. To conclude, both types of exercise maintained physical function equally in older mice.

Keywords:  aging; endurance training; exercise; mice; sarcopenia

DOI:  https://doi.org/10.3389/fragi.2024.1356954
J Cell Mol Med. 2024 Apr;28(8): e18126

Mitochondrial respiration in peripheral arterial disease depends on stage severity.

Fiona Speichinger, Alexandra Gratl, Ben Raude, Larissa Schawe, Jan Carstens, Nina A Hering, Andreas Greiner, Dominik Pesta, Jan Paul Frese.

  Peripheral arterial disease (PAD) is an increasing cause of morbidity and its severity is graded based on clinical manifestation. To investigate the influence of the different stages on myopathy of ischemic muscle we analysed severity-dependent effects of mitochondrial respiration in PAD. Eighteen patients with severe PAD, defined as chronic limb-threatening ischemia, 47 patients with intermittent claudication (IC) and 22 non-ischemic controls were analysed. High-resolution respirometry (HRR) was performed on muscle biopsies of gastrocnemius and vastus lateralis muscle of patients in different PAD stages to investigate different respiratory states. Results from HRR are given as median and interquartile range and were normalized to citrate synthase activity (CSA), a marker for mitochondrial content. In order to account for inter-individual differences between patients and controls, we calculated the ratio of O₂-flux in gastrocnemius muscle over vastus muscle ('GV ratio'). CSA of the gastrocnemius muscle as a proxy for mitochondrial content was significantly lower in critical ischemia compared to controls. Mitochondrial respiration normalized to CSA was higher in IC compared to controls. Likewise, the GV ratio was significantly higher in IC compared to control. Mitochondrial respiration and CSA of PAD patients showed stage-dependent modifications with greater changes in the mild PAD stage group (IC).

Keywords:  PAD; chronic limb‐threatening ischemia; intermittent claudication; mitochondrial function; mitochondrial respiration; myopathy; peripheral arterial disease

DOI:  https://doi.org/10.1111/jcmm.18126