bims-kimdis 2023-07-23 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–07–23
thirty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Neuroprotective effect of a medium-chain triglyceride ketogenic diet on MPTP-induced Parkinson's disease mice: a combination of transcriptomics and metabolomics in the substantia nigra and fecal microbiome.
Very low-calorie ketogenic diet: A valuable and fashionable nutritional therapy. When could it become dangerous?
Can the ketogenic diet improve our dreams? Effect of very low-calorie ketogenic diet (VLCKD) on sleep quality.
Does Ketogenic Diet Used in Pregnancy Affect the Nervous System Development in Offspring?─FTIR Microspectroscopy Study.
The Mechanism of the NLRP3 Inflammasome Activation and Pathogenic Implication in the Pathogenesis of Gout.
Jump Starting the Heart: Ketone Esters Improve Cardiac Function in Patients With Cardiogenic Shock.
A Patent Review of NLRP3 Inhibitors to Treat Autoimmune Diseases.
Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation.
Effects of a low-carbohydrate-high-protein pre-exercise meal in type 1 diabetes - a randomised, crossover trial.
Beneficial Effects of Ketone Ester in Patients With Cardiogenic Shock: A Randomized, Controlled, Double-Blind Trial.
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.
An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™).
Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through C-C Chemokine Receptor Type 2 Downregulation and Enhanced MMP Balance.
Modified Atkins diet in children with epilepsy with eyelid myoclonia (Jeavons syndrome).
Role of NLRP3 inflammasome and oxidative stress in hepatic insulin resistance and the ameliorative effect of phytochemical intervention.
Medium-chain fatty acid oxidation is independent of L-carnitine in liver and kidney but not in heart and skeletal muscle.
Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity.
Exercise-Induced Changes to the Fiber Type Specific Redox State in Human Skeletal Muscle are Associated with Aerobic Capacity.
Intermittent fasting reduces mouse body fat while maintaining muscle mass by regulating protein synthesis and autophagy.
Intermittent feeding with an overnight fast versus 24-h feeding in critically ill neonates, infants, and children: An open-label, single-centre, randomised controlled trial.
Skeletal muscle proteins involved in fatty acid transport influence fatty acid oxidation rates observed during exercise.
Preventing Iatrogenic Euglycemic Diabetic Ketoacidosis in Cardiac Surgery: The Role of Sodium-Glucose Cotransporter 2 Inhibitors.
Critical role of the mTOR pathway in poultry skeletal muscle physiology and meat quality: an opinion paper.
Resistance training diminishes mitochondrial adaptations to subsequent endurance training in healthy untrained men.
What is really known about the effects of nicotinamide riboside supplementation in humans.
Body mass dependence of oxidative phosphorylation efficiency in liver mitochondria from mammals.
In vivo Electroporation of Skeletal Muscle Fibers in Mice.
Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.
Exercise prevents obesity by reducing gut-derived inflammatory signals to brown adipocytes in mice.
Mitochondrial reactive oxygen species: double agents in Mycobacterium tuberculosis infection.
Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.

Cell Death Discov. 2023 Jul 17. 9(1): 251

Neuroprotective effect of a medium-chain triglyceride ketogenic diet on MPTP-induced Parkinson's disease mice: a combination of transcriptomics and metabolomics in the substantia nigra and fecal microbiome.

Wenlong Zhang, Shiyu Chen, Xingting Huang, Huichun Tong, Hongxin Niu, Lingli Lu.

The ketogenic diet (KD) is a low carbohydrate and high-fat protein diet. It plays a protective role in neurodegenerative diseases by elevating the levels of ketone bodies in blood, regulating central and peripheral metabolism and mitochondrial functions, inhibiting neuroinflammation and oxidative stress, and altering the gut microbiota. However, studies on ketogenic therapy for Parkinson's disease (PD) are still in their infancy. Therefore, we examined the possible protective effect of KD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, examined the mouse gut microbiota and its metabolites, and performed transcriptomics and metabolomics on the substantia nigra of mice. Our results showed that a long-term medium-chain triglyceride KD (MCT-KD) significantly reduced MPTP-induced damage to dopaminergic (DA) neurons, exerted antioxidant stress through the PI3K/Akt/Nrf2 pathway, and reversed oxidative stress in DA neurons. The MCT-KD also reduced mitochondrial loss, promoted ATP production, and inhibited the activation of microglia to protect DA neurons in MPTP-induced PD mice. MCT-KD altered the gut microbiota and consequently changed the metabolism of substantia nigra neurons through gut microbiota metabolites. Compared to the MPTP group, MCT-KD increased the abundance of gut microbiota, including Blautia and Romboutsia. MCT-KD also affects purine metabolism in the substantia nigra pars compacta (SNpc) by altering fecal metabolites. This study shows that MCT-KD has multiple protective effects against PD.

DOI: https://doi.org/10.1038/s41420-023-01549-0
Diabetes Metab Res Rev. 2023 Jul 19. e3698

Very low-calorie ketogenic diet: A valuable and fashionable nutritional therapy. When could it become dangerous?

Stefania Gorini, Andrea Armani, Massimiliano Caprio.



Keywords:  carbohydrate restriction; cardiometabolic risk; metabolic rehabilitation; precision nutrition; weight cycling; weight loss

DOI:  https://doi.org/10.1002/dmrr.3698
J Transl Med. 2023 Jul 18. 21(1): 479

Can the ketogenic diet improve our dreams? Effect of very low-calorie ketogenic diet (VLCKD) on sleep quality.

Luigi Barrea, Ludovica Verde, Cherubino Di Lorenzo, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri.

   BACKGROUND: Obesity is a condition that is often associated with sleep disorders, including reduced sleep quality (SQ). Very low calorie ketogenic diet (VLCKD) has proven to be effective in the management of obesity and associated metabolic disorders. However, little is still known about the effects of this promising nutritional protocol on SQ. Thus, the purpose of this study was to investigate the short-term effect of VLCKD on SQ in women with overweight/obesity and if any changes, to identify the predictive factor that through VLCKD modified SQ.
METHODS: Were consecutively enrolled a total of 324 subjects, who met the inclusion criteria and accepted to adhere to VLCKD. Assessment of nutritional status, including anthropometric measurements (height, weight, and waist circumference), bioelectrical impedance analysis (phase-sensitive system, 50 kHz BIA 101 RJL, Akern Bioresearch, Florence, Italy Akern), high sensitivity C reactive protein levels (hs-CRP), and SQ were carried out at baseline and after 31 days of active stage of VLCKD. SQ was evaluated using the validated questionnaire Pittsburgh Sleep Quality Index (PSQI).
RESULTS: In addition to the expected general improvement of anthropometric parameters and body composition, VLCKD improved significantly SQ, as demonstrated by the improvement of all parameters included in the PSQI questionnaire (p < 0.001). Both at baseline and after 31 days of active stage of VLCKD, the PSQI score was significantly associated with BMI, waist circumference, fat mass, fat free mass (p < 0.001 for all) and hs-CRP (p = 0.023). PhA was negatively associated with PSQI score only at baseline (p < 0.001). ∆% PSQI positively correlated with ∆% BMI, ∆% fat mass, ∆% hs-CRP (p < 0.001 for all) and negatively correlated with ∆% fat free mass (p < 0.001), and ∆% PhA (p = 0.031). In the multiple regression analysis ∆% fat mass represented the only predictor of changes in SQ after VLCKD. Finally, in the ROC analysis, a threshold value of ∆% fat mass > - 8.4% predicted improvement in SQ (p < 0.001).
CONCLUSION: In conclusion, VLCKD determines an improvement of SQ in women with overweight and obesity, that was mostly mediated by the reduction of fat mass related to this nutritional protocol.

Keywords:  Diet; Fat mass; Ketogenic diet; Nutrition; Obesity; Sleep management; Sleep quality; VLCKD; Very low-calorie ketogenic diet

DOI:  https://doi.org/10.1186/s12967-023-04280-7
ACS Chem Neurosci. 2023 Jul 20.

Does Ketogenic Diet Used in Pregnancy Affect the Nervous System Development in Offspring?─FTIR Microspectroscopy Study.

Marzena Rugiel, Zuzanna Setkowicz-Janeczko, Wojciech Kosiek, Zuzanna Rauk, Kamil Kawon, Joanna Chwiej.

  Anti-seizure medications used during pregnancy may have transient or long-lasting impact on the nervous system of the offspring. Therefore, there is a great need to search for alternative therapies for pregnant women suffering from seizures. One of the solutions may be the use of the ketogenic diet (KD), which has been successfully applied as a treatment of drug-resistant epilepsy in children and adults. However, the risks associated with the use of this dietary therapy during pregnancy are unknown and more investigation in this area is needed. To shed some light on this problem, we attempted to determine the potential abnormalities in brain biomolecular composition that may occur in the offspring after the prenatal exposure to KD. To achieve this, the female Wistar rats were, during pregnancy, fed with either ketogenic or standard laboratory diet, and for further studies, their male offspring at 2, 6, or 14 days of age were used. Fourier transform infrared microspectroscopy was applied for topographic and quantitative analysis of main biological macromolecules (proteins, lipids, compounds containing phosphate and carbonyl groups, and cholesterol) in brain samples. Performed chemical mapping and further semi-quantitative and statistical analysis showed that the use of the KD during pregnancy, in general, does not lead to the brain biochemical anomalies in 2 and 6 days old rats. The exception from this rule was increased relative (comparing to proteins) content of compounds containing phosphate groups in white matter and cortex of 2 days old rats exposed prenatally to KD. Greater number of abnormalities was found in brains of the 14 days old offspring of KD-fed mothers. They included the increase of the relative level of compounds containing carbonyl groups (in cortex as well as multiform and molecular cells of the hippocampal formation) as well as the decrease of the relative content of lipids and their structural changes (in white matter). What is more, the surface of the internal capsule (structure of the white matter) determined for this age group was smaller in animals subjected to prenatal KD exposure. The observed changes seem to arise from the elevated exposition to ketone bodies during a fetus life and the disturbance of lipid metabolism after prenatal exposure to the KD. These changes may be also associated with the processes of compensation of mother organism, which slowly began to make up for the deficiencies in carbohydrates postpartum.

Keywords:  Fourier transform infrared microspectroscopy; biochemical analysis; brain development; ketogenic diet; pregnancy; principal component analysis (PCA)

DOI:  https://doi.org/10.1021/acschemneuro.3c00331
J Rheum Dis. 2022 Jul 01. 29(3): 140-153

The Mechanism of the NLRP3 Inflammasome Activation and Pathogenic Implication in the Pathogenesis of Gout.

Seong-Kyu Kim.

  The NACHT, LRR, and PYD-domains-containing protein 3 (NLRP3) inflammasome is an intracellular multi-protein signaling platform that is activated by cytosolic pattern-recognition receptors such as NLRs against endogenous and exogenous pathogens. Once it is activated by a variety of danger signals, recruitment and assembly of NLRP3, ASC, and pro-caspase-1 trigger the processing and release of pro-inflammatory cytokines including interleukin-1β (IL-1β) and IL-18. Multiple intracellular and extracellular structures and molecular mechanisms are involved in NLRP3 inflammasome activation. Gout is an autoinflammatory disease induced by inflammatory response through production of NLRP3 inflammasome-mediated proinflammatory cytokines such as IL-1β by deposition of monosodium urate (MSU) crystals in the articular joints and periarticular structures. NLRP3 inflammasome is considered a main therapeutic target in MSU crystal-induced inflammation in gout. Novel therapeutic strategies have been proposed to control acute flares of gouty arthritis and prophylaxis for gout flares through modulation of the NLRP3/IL-1 axis pathway. This review discusses the basic mechanism of NLRP3 inflammasome activation and the IL-1-induced inflammatory cascade and explains the NLRP3 inflammasome-induced pathogenic role in the pathogenesis of gout.

Keywords:  Gout; Inflammasome; Interleukin-1; Monosodium urate; NLRP3

DOI:  https://doi.org/10.4078/jrd.2022.29.3.140
JACC Heart Fail. 2023 Jul 03. pii: S2213-1779(23)00305-0. [Epub ahead of print]

Jump Starting the Heart: Ketone Esters Improve Cardiac Function in Patients With Cardiogenic Shock.

Gary D Lopaschuk, Qutuba G Karwi.



Keywords:  energy production; heart failure; ketone oxidation; ketones

DOI:  https://doi.org/10.1016/j.jchf.2023.06.006
Expert Opin Ther Pat. 2023 Jul 20.

A Patent Review of NLRP3 Inhibitors to Treat Autoimmune Diseases.

Yiming Xu, Savannah Biby, Baljit Kaur, Shijun Zhang.

   INTRODUCTION: NOD-like receptor family pyrin domain containing 3 (NLRP3) can sense a plethora of exogenous and endogenous dangers. Upon activation, a multimeric protein complex, the NLRP3 inflammasome, is formed to initiate the innate immune responses. Emerging studies have implicated the pathophysiological roles of this protein complex in human disorders, highlighting that it represents a druggable target for therapeutics development.
AREAS COVERED: The current review summarizes the functional facets of the NLRP3 inflammasome, its association with autoimmune diseases, and recent patents on the development of NLRP3 inhibitors. Literature search was conducted using SciFinder and Google Patents with the key word NLRP3 and NLRP3 inhibitors.
EXPERT OPINION: Although significant advances have been made in understanding the NLRP3 inflammasome, more studies are still needed to elucidate the molecular mechanisms underlying its roles in autoimmune diseases. A number of NLRP3 inhibitors have been patented, however, none of them have been approved for clinical use. Due to the complex nature of the NLRP3 inflammasome, novel screening assays along with target engagement methods could benefit the drug discovery and clinical translation. In addition, clinical trials on NLRP3 inhibitors are still in their early stages, and continuous investigations are needed to fully assess their safety and effectiveness.

Keywords:  NLRP3 inflammasome; SAR; autoimmune diseases; small molecule inhibitors

DOI:  https://doi.org/10.1080/13543776.2023.2239502
Food Funct. 2023 Jul 19.

Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation.

Wei Sun, Qingpeng Wang, Ruiyan Zhang, Ning Zhang.

Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system (CNS); severe symptoms lead MS patients to use complementary treatments. Ketogenic diet (KD) shows wide neuroprotective effects, but the precise mechanisms underlying the therapeutic activity of KD in MS are unclear. The present study established a continuous 24 days experimental autoimmune encephalomyelitis (EAE) mouse model with or without KD. The changes in motor function, pathological hallmarks of EAE, the status of microglia, neuroinflammatory response and intracellular signaling pathways in mice were detected by the rotarod test, histological analysis, real-time PCR (RT-PCR) and western blotting. Our results showed that KD could prevent motor deficiency, reduce clinical scores, inhibit demyelination, improve pathological lesions and suppress microglial activation in the spinal cord of EAE mice. Meanwhile, KD shifted microglial polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, as well as upregulating the release of anti-inflammatory cytokines such as TGF-β. Furthermore, KD decreased the expression levels of CCL2, CCR2, CCL3, CCR1, CCR5, CXCL10 and CXCR3 in the spinal cord and spleen with reduced monocyte/macrophage infiltration in the CNS. In addition, KD inhibits NLRP3 activation in the microglia, as revealed by the significantly decreased co-expression of NLRP3+ and Iba-1+ in the KD + EAE group. Further studies demonstrated that KD suppresses inflammatory response and M1 microglial polarization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway, the JAK1/STAT1 pathway, HDAC3 and P2X7R activation, as well as up-regulation of JAK3/STAT6.

DOI: https://doi.org/10.1039/d3fo00122a
J Clin Endocrinol Metab. 2023 Jul 18. pii: dgad427. [Epub ahead of print]

Effects of a low-carbohydrate-high-protein pre-exercise meal in type 1 diabetes - a randomised, crossover trial.

Kasper B Kristensen, Ajenthen G Ranjan, Olivia M McCarthy, Jens J Holst, Richard M Bracken, Kirsten Nørgaard, Signe Schmidt.

   CONTEXT: Current guidelines for exercise-related glucose management focus on reducing bolus and/or basal insulin doses and considering carbohydrate intake. Yet far less attention has been paid to the potential role of other macronutrients alongside carbohydrates on glucose dynamics around exercise.
OBJECTIVE: To investigate the effects of a low-carbohydrate-high-protein (LCHP) compared to a high-carbohydrate-low-protein (HCLP) pre-exercise meal on the metabolic, hormonal, and physiological responses to exercise in adults with insulin pump-treated type 1 diabetes.
METHODS: Fourteen adults with insulin pump-treated type 1 diabetes (11 females with a median [range] HbA1c of 50 [43-59] mmol/mol (6.7 [6.1-7.5] %), age of 49 [25-65] years, and BMI of 24.0 [19.3-27.1] kg/m2) completed an unblinded, two-arm, randomised, crossover study. Participants ingested isocaloric meals that were either LCHP (carbohydrate 21%, protein 52%, fat 27%) or HCLP (carbohydrate 52%, protein 21%, fat 27%) 90 min prior to undertaking 45 min of cycling at moderate intensity. Meal insulin bolus was dosed according to meal carbohydrate content but reduced by 25%. Basal insulin rates were reduced by 35% from meal ingestion to end of exercise.
RESULTS: Around exercise the coefficient of variability was lower during LCHP (LCHP:14.5±5.3 vs. HCLP: 24.9±7.7%, p=0.001). Over exercise, LCHP was associated with a lesser drop (LCHP: Δ-1.49±1.89 vs. HCLP: Δ-3.78±1.95 mmol/L, p=0.001). Mean insulin concentration was 30% lower during exercise for LCHP compared to HCLP (LCHP: 25.5±11.0 vs. HCLP: 36.5±15.9 mU/L, p<0.001).
CONCLUSIONS: Ingesting a LCHP pre-exercise meal lowered plasma glucose variability around exercise and diminished the drop in plasma glucose over exercise.

Keywords:  Exercise; Glucose management; Insulin pump; Low carbohydrate; Meal composition; Type 1 diabetes

DOI:  https://doi.org/10.1210/clinem/dgad427
JACC Heart Fail. 2023 Jul 01. pii: S2213-1779(23)00306-2. [Epub ahead of print]

Beneficial Effects of Ketone Ester in Patients With Cardiogenic Shock: A Randomized, Controlled, Double-Blind Trial.

Kristoffer Berg-Hansen, Kristian Hylleberg Christensen, Nigopan Gopalasingam, Roni Nielsen, Hans Eiskjær, Niels Møller, Thomas Birkelund, Steffen Christensen, Henrik Wiggers.

   BACKGROUND: Cardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown.
OBJECTIVES: The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS.
METHODS: In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period.
RESULTS: KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: -5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered.
CONCLUSIONS: Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768).

Keywords:  3-hydroxybutyrate; cardiac output; cardiogenic shock; invasive hemodynamics; ketone ester; metabolism

DOI:  https://doi.org/10.1016/j.jchf.2023.05.029
bioRxiv. 2023 Jul 03. pii: 2023.07.03.547547. [Epub ahead of print]

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

S S Madhavan, S Roa Diaz, S Peralta, M Nomura, C D King, A Lin, D Bhaumik, S Shah, T Blade, W Gray, M Chamoli, B Eap, O Panda, D Diaz, T Y Garcia, B J Stubbs, G J Lithgow, B Schilling, E Verdin, A R Chaudhuri, J C Newman.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate βHB-induced protein insolubility across in vitro , ex vivo , and in vivo mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We have generated a comprehensive atlas of the βHB-induced protein insolublome ex vivo and in vivo using mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

DOI: https://doi.org/10.1101/2023.07.03.547547
Front Physiol. 2023 ;14 1195702

An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™).

James Lowder, Shafagh Fallah, Carolina Venditti, Kathy Musa-Veloso, Vassili Kotlov.

  Introduction: A study was undertaken to determine the acute effects of a beverage made with Avela™ (R)-1,3-butanediol, on blood beta-hydroxybutyrate (BHB) levels (using the Keto-Mojo monitor), gastrointestinal (GI) tolerability (using the modified visual analogue scale GI Symptoms Tool), and sleepiness (using the Stanford Sleepiness Scale). Methods: Following a 12-h overnight fast, 26 healthy adults consumed one beverage containing 11.5 g of (R)-1,3-butanediol at each of 0, 30, and 60 min, culminating in a total intake of 34.5 g of (R)-1,3-butanediol. Blood BHB levels, GI tolerability, and sleepiness were assessed at baseline (0 min), and at 30, 60, 90, 120, 180, 240, and 300 min. At 240 min, a protein bar was consumed. Results: The mean (±SD) BHB fasting baseline level, maximal concentration, time at maximal concentration, and incremental area under the curve over 300 min were 0.23 ± 0.21 mmol/L, 2.10 ± 0.97 mmol/L, 133.85 ± 57.07 min, and 376.73 ± 156.76 mmol/L*min, respectively. BHB levels at each time point were significantly increased relative to baseline. In females, BHB Tmax was significantly greater (p = 0.046), and BHB iAUC0-300 min nearly significantly greater (p = 0.06) than in males. Discussion: The beverage formulated with Avela™ had no impact on sleepiness and was generally well-tolerated, with no or mild GI symptoms reported in most participants. Mild headaches were reported as an adverse event by five participants and judged possibly related to the study product in two of the participants.

Keywords:  BHB; beta-hydroxybutyrate; butanediol; ketones; ketosis

DOI:  https://doi.org/10.3389/fphys.2023.1195702
Res Sq. 2023 Jun 29. pii: rs.3.rs-3054767. [Epub ahead of print]

Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through C-C Chemokine Receptor Type 2 Downregulation and Enhanced MMP Balance.

Mohamed Zayed, Sergio Sastriques-Dunlop, Santiago Elizondo-Benedetto, Batool Arif, Rodrigo Meade, Mohamed Zaghloul, Hannah Luehmann, Gyu Heo, Sean English, Yongjian Liu.

Abdominal aortic aneurysms (AAAs) are prevelant with aging, and AAA rupture is associated with high mortality. There is currently no effective medical therapy for AAA rupture. Previous work demonstrated that the monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. Here we similarly observed that Ccr2-/- mice have significantly reduced AAA expansion and rupture. We therefore hypothesized that a dietary modulation of the CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we specifically evaluated whether systemic ketosis in vivo can reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA formation using porcine pancreatic elastase (PPE), and received daily β-aminopropionitrile (BAPN) to promote AAA rupture. Animals with AAAs received either a standard diet (SD), ketogenic diet (KD), or exogenous KBs (EKB). Animals recieving KD and EKB reached a state of ketosis, and had significant reduction in AAA expansion and incidence of rupture. Ketosis also led to significantly reduced aortic CCR2 content, improved MMP balance, and reduced ECM degradation. In summary, this study demonstrates that ketosis plays a crucial role in AAA pathobiology, and provides the impetus for future clinical studies investigating the potential benefit of ketosis for prevention of AAA expansion and rupture.

DOI: https://doi.org/10.21203/rs.3.rs-3054767/v1
Epilepsy Behav. 2023 Jul 15. pii: S1525-5050(23)00266-4. [Epub ahead of print]145 109347

Modified Atkins diet in children with epilepsy with eyelid myoclonia (Jeavons syndrome).

Watuhatai Paibool, Stephanie Schimpf, Douglas R Nordli, Chalongchai Phitsanuwong.

   BACKGROUND: Epilepsy with eyelid myoclonia(EEM) or Jeavons syndrome is considered a genetic generalized epilepsy with a typical age of onset in childhood. Many types of seizures can be observed, including eyelid myoclonia, absence, generalized tonic-clonic, and myoclonic seizures. Seizures tend to be difficult to control requiring polypharmacy treatment or become drug-resistant. Dietary therapy, particularly with Modified Atkins Diet (MAD), as a treatment of seizures in this syndrome has rarely been studied. We report efficacy and tolerability of MAD in children with epilepsy with eyelid myoclonia.
METHODS: We reviewed medical records of children with EEM treated at the University of Chicago Ketogenic Diet program from 2017 to 2022. Patient's demography, seizure characteristics, EEG findings, response to treatment, and adverse effects were reviewed.
RESULT: Six patients with EEM were identified. Average age of seizure onset was 6 (2-11) years and an average age when the MAD started was 10.7 (6-15) years. All patients were started on MAD and completed at least 6 months on the diet at the time of report. An average of 4 (0-9) anti-seizure medications (ASM) had been tried prior to the MAD. All patients achieved ketosis with an average level of serum beta-hydroxybutyrate of 1.9 (1.03-3.61) mmol/L. At the 6-month follow-up visit, all patients (100%) experienced a greater than 50% seizure reduction, 3/6 patients (50%) had more than 90% seizure reduction, 1/6 patients (17%) became seizure-free. All seizure types demonstrated a greater than 80% reduction in frequency.Absence and myoclonic seizures showed the greatest reduction with 100% seizure reduction. Eyelid myoclonia and generalized tonic-clonic seizures showed more than 80% seizure reduction.Moreover, all patients reported improvement in alertness, mood, and concentration. Initial weight loss and mild gastrointestinal disturbances were reported in 2/6 patients (33%) and corrected with dietary adjustment.
CONCLUSION: The Modified Atkins Diet has shown to be effective and welltolerated for children with EEM in our study. Cognitive improvement has also been subjectively reported in all patients. Adverse effects are tolerable and correctable. The MAD, therefore, may be considered as a treatment option for patients with epilepsy with eyelid myoclonia.

Keywords:  Dietary therapy; Epilepsy with eyelid myoclonia; Jeavons syndrome; Ketogenic diet; modified Atkins diet

DOI:  https://doi.org/10.1016/j.yebeh.2023.109347
Front Pharmacol. 2023 ;14 1188829

Role of NLRP3 inflammasome and oxidative stress in hepatic insulin resistance and the ameliorative effect of phytochemical intervention.

Isabela Jesus de Deus, Ana Flávia Martins-Silva, Miliane Martins de Andrade Fagundes, Sílvia Paula-Gomes, Fernanda Guimarães Drummond E Silva, Larissa Leandro da Cruz, Aline Rezende Ribeiro de Abreu, Karina Barbosa de Queiroz.

  NLRP3 inflammasome has a key role in chronic low-grade metabolic inflammation, and its excessive activation may contribute to the beginning and progression of several diseases, including hepatic insulin resistance (hIR). Thus, this review aims to highlight the role of NLRP3 inflammasome and oxidative stress in the development of hIR and evidence related to phytochemical intervention in this context. In this review, we will address the hIR pathogenesis related to reactive oxygen species (ROS) production mechanisms, involving oxidized mitochondrial DNA (ox-mtDNA) and thioredoxin interacting protein (TXNIP) induction in the NLRP3 inflammasome activation. Moreover, we discuss the inhibitory effect of bioactive compounds on the insulin signaling pathway, and the role of microRNAs (miRNAs) in the phytochemical target mechanism in ameliorating hIR. Although most of the research in the field has been focused on evaluating the inhibitory effect of phytochemicals on the NLRP3 inflammasome pathway, further investigation and clinical studies are required to provide insights into the mechanisms of action, and, thus, encourage the use of these bioactive compounds as an additional therapeutic strategy to improve hIR and correlated conditions.

Keywords:  bioactive compounds; inflammasome; insulin resistance; lowgrade inflammation; microRNA; oxidative stress; phytochemicals; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2023.1188829
Am J Physiol Gastrointest Liver Physiol. 2023 Jul 18.

Medium-chain fatty acid oxidation is independent of L-carnitine in liver and kidney but not in heart and skeletal muscle.

Andrea S Pereyra, Kelsey L McLaughlin, Katherine A Buddo, Jessica M Ellis.

  Medium-chain fatty acid (MCFA) consumption confers a wide range of health benefits that are highly distinct from long-chain fatty acids (LCFA). A major difference between the metabolism of LCFAs compared to MCFAs is that mitochondrial LCFA oxidation depends on the carnitine shuttle, whereas MCFA mitochondrial oxidation is not. Although MCFAs are said to range from 6 to 14 carbons long based on physicochemical properties in vitro, the biological cut-off length of acyl chains that can bypass the carnitine shuttle in different mammalian tissues is unknown. To define the range of acyl chain length that can be oxidized in the mitochondria independent of carnitine, we determined the oxidative metabolism of free fatty acids (FFAs) from 6 to 18 carbons long in the liver, kidney, heart, and skeletal muscle. The liver oxidized FFAs 6 to 14 carbons long, while the kidney oxidized FFAs from 6 to 10 carbons in length. Heart and skeletal muscle were unable to oxidize FFAs of any chain length. These data show that while the liver and kidney can oxidize MCFAs in the free form, the heart and skeletal muscle require carnitine for the oxidative metabolism of MCFAs. Together these data demonstrate that MCFA oxidation independent of carnitine is tissue-specific.

Keywords:  carnitine; liver; medium-chain fatty acids; mitochondrial fatty acid oxidation; skeletal muscle

DOI:  https://doi.org/10.1152/ajpgi.00105.2023
Inflammation. 2023 Jul 21.

Regulation of NLRP3 Inflammasome Activation and Inflammatory Exosome Release in Podocytes by Acid Sphingomyelinase During Obesity.

Dandan Huang, Jason M Kidd, Yao Zou, Xiaoyuan Wu, Todd W B Gehr, Pin-Lan Li, Guangbi Li.

  The activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been reported to importantly contribute to glomerular inflammation and injury under different pathological conditions such as obesity. However, the mechanism mediating NLRP3 inflammasome activation in podocytes and subsequent glomerular injury remains poorly understood. Given that the ceramide signaling pathway has been reported to be implicated in obesity-related glomerulopathy (ORG), the present study was designed to test whether the ceramide-producing enzyme, acid sphingomyelinase (ASM), determines NLRP3 inflammasome activation and inflammatory exosome release in podocytes leading to glomerular inflammation and injury during ORG. In Smpd1trg/Podocre mice, podocyte-specific overexpression of Smpd1 gene which encodes ASM significantly exaggerated high-fat diet (HFD)-induced NLRP3 inflammasome activation in podocytes and immune cell infiltration in glomeruli compared to WT/WT mice. Smpd1 gene deletion, however, blocked these pathological changes induced by HFD in Smpd1-/- mice. Accompanied with NLRP3 inflammasome activation and glomerular inflammation, urinary excretion of exosomes containing podocyte marker and NLRP3 inflammasome products (IL-1β and IL-18) in Smpd1trg/Podocre mice on the HFD was much higher than that in WT/WT mice. In contrast, Smpd1-/- mice on the HDF had significantly lower urinary exosome excretion than WT/WT mice. Correspondingly, HFD-induced podocyte injury, glomerular sclerosis, and proteinuria were more severe in Smpd1trg/Podocre mice, but milder in Smpd1-/- mice compared to WT/WT mice. Using podocytes isolated from these mice, we demonstrated that visfatin, a prototype pro-inflammatory adipokine, induced NLRP3 inflammasome activation and enrichment of multivesicular bodies (MVBs) containing IL-1β in podocytes, which was much stronger in podocytes from Smpd1trg/Podocre mice, but weaker in those from Smpd1-/- mice than WT/WT podocytes. By quantitative analysis of exosomes, it was found that upon visfatin stimulation, podocytes from Smpd1trg/Podocre mice released much more exosomes containing NLRP3 inflammasome products, but podocytes from Smpd1-/- mice released much less exosomes compared to WT/WT podocytes. Super-resolution microscopy demonstrated that visfatin inhibited lysosome-MVB interaction in podocytes, indicating impaired MVB degradation by lysosome. The inhibition of lysosome-MVB interaction by visfatin was amplified by Smpd1 gene overexpression but attenuated by Smpd1 gene deletion. Taken together, our results suggest that ASM in podocytes is a crucial regulator of NLRP3 inflammasome activation and inflammatory exosome release that instigate glomerular inflammation and injury during obesity.

Keywords:  NLRP3 inflammasome; exosome.; obesity-related glomerulopathy; podocyte

DOI:  https://doi.org/10.1007/s10753-023-01861-y
J Appl Physiol (1985). 2023 Jul 20.

Exercise-Induced Changes to the Fiber Type Specific Redox State in Human Skeletal Muscle are Associated with Aerobic Capacity.

James Shadiow, Edwin R Miranda, Ryan K Perkins, Corey E Mazo, Zhen Lin, Kendell N Lewis, Jacob T Mey, Thomas P J Solomon, Jacob M Haus.

  The benefits of exercise involve skeletal muscle redox state alterations of nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). We determined the fiber-specific effects of acute exercise on the skeletal muscle redox state in healthy adults. Muscle biopsies were obtained from 19 (11 M, 8 F; 26±4 yrs) at baseline (fasted), and 30-min and 3h after treadmill exercise at 80% VO2max. Muscle samples were fiber typed probed for autofluorescence of NADH (excitation at 340-360nm) and oxidized flavoproteins (Fp; excitation at 440-470nm) to quantify the redox signatures of individual muscle fibers. Redox state was calculated as the oxidation-to-reduction redox ratio: Fp/(Fp+NADH). At baseline, the redox ratio of MHC I fibers was 7.2% higher than MHC IIa (p = 0.023, 95% CI: 5.2, 9.2%) and the redox ratio of MHC IIa was 8.0% higher than MHC IIx (p = 0.035, 95% CI: 6.8, 9.2%). MHC I fibers also displayed greater NADH intensity than MHC IIx (p = 0.007) and greater Fp intensity than both MHC IIa (p = 0.019) and MHC IIx (p < 0.0001). Fp intensities increased in all fiber types (p = 0.039) but redox ratios did not change (p = 0.483) 30 min after exercise. The change in redox ratio was positively correlated with VO2max (ml/min/kg) in MHC I (rho = 0.809, p = 0.004) and MHC IIa (rho = 0.782, p = 0.006) but not MHC IIx fibers (rho = 0.571, p = 0.151). These findings support the use of redox autofluorescence to interrogate skeletal muscle metabolism.

Keywords:  NAD/NADH; autofluorescence; exercise physiology; flavoproteins; oxygen delivery

DOI:  https://doi.org/10.1152/japplphysiol.00662.2022
Nutrition. 2023 Jun 15. pii: S0899-9007(23)00159-4. [Epub ahead of print]115 112130

Intermittent fasting reduces mouse body fat while maintaining muscle mass by regulating protein synthesis and autophagy.

Rikako Yoshii, Kazuhiko Higashida, Naoya Nakai.

   OBJECTIVES: The aim of this study is to investigate the effect of intermittent fasting (IF) on the regulation of skeletal muscle protein metabolism in response to nutrient supplementation during fasting.
METHODS: Twelve-week-old male C57BL/6J mice were assigned to two groups: ad libitum and IF, with the latter having access to food for only 3 h/d. After 6 wk of experimental periods, an oral glucose tolerance test was performed. One week later, phosphate-buffered saline or a glucose and branched-chain amino acid mixture was administered orally, and blood and tissues were collected 30 min later.
RESULTS: The oral glucose tolerance test results revealed that the IF group had better insulin sensitivity. They also had lower body and fat weights while maintaining the same level of skeletal muscle mass as the ad libitum group. The phosphorylation of ribosomal protein S6 in the skeletal muscle, a marker for the activation of protein translation, was greater in the IF group after glucose and branched-chain amino acid mixture administration. Microtubule-associated protein light chain 3-II-to-light chain 3-I ratio, a marker for autophagosome formation, in skeletal muscle during fasting was significantly lower in the IF group than that in the ad libitum group.
CONCLUSIONS: Our findings suggest that adaptation to IF regulates protein synthesis and breakdown, leading to the maintenance of skeletal muscle mass while reducing body fat.

Keywords:  Insulin sensitivity; LC3; Ribosomal protein S6; mTOR

DOI:  https://doi.org/10.1016/j.nut.2023.112130
Clin Nutr. 2023 Jul 15. pii: S0261-5614(23)00229-7. [Epub ahead of print]42(9): 1569-1580

Intermittent feeding with an overnight fast versus 24-h feeding in critically ill neonates, infants, and children: An open-label, single-centre, randomised controlled trial.

Karlien Veldscholte, Arnout B G Cramer, Rogier C J de Jonge, Dimitris Rizopoulos, Koen F M Joosten, Sascha C A T Verbruggen.

   BACKGROUND & AIMS: Critically ill children are fed day and night, assuming this improves enteral tolerance and the probability of achieving nutritional goals. It was previously shown that a fasting response, reflected by increased ketosis, at least partly explained the beneficial outcome of delayed initiation of supplemental parenteral nutrition. This study aims to investigate whether an overnight fast increases ketosis and is feasible and safe in critically ill children.
METHODS: The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48 h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12 h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients' highest daily ketone (3-β-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877).
RESULTS: Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n = 67) or continuous feeding (n = 73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p < 0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group.
CONCLUSION: Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.

Keywords:  Chrononutrition; Critically ill children; Fasting responsee; Intermittent feeding; Ketones; Pediatric intensive care unit

DOI:  https://doi.org/10.1016/j.clnu.2023.07.010
Pflugers Arch. 2023 Jul 18.

Skeletal muscle proteins involved in fatty acid transport influence fatty acid oxidation rates observed during exercise.

Ed Maunder, Jeffrey A Rothschild, Andreas M Fritzen, Andreas B Jordy, Bente Kiens, Matthew J Brick, Warren B Leigh, Wee-Leong Chang, Andrew E Kilding.

  Several proteins are implicated in transmembrane fatty acid transport. The purpose of this study was to quantify the variation in fatty acid oxidation rates during exercise explained by skeletal muscle proteins involved in fatty acid transport. Seventeen endurance-trained males underwent a (i) fasted, incremental cycling test to estimate peak whole-body fatty acid oxidation rate (PFO), (ii) resting vastus lateralis microbiopsy, and (iii) 2 h of fed-state, moderate-intensity cycling to estimate whole-body fatty acid oxidation during fed-state exercise (FO). Bivariate correlations and stepwise linear regression models of PFO and FO during 0-30 min (early FO) and 90-120 min (late FO) of continuous cycling were constructed using muscle data. To assess the causal role of transmembrane fatty acid transport in fatty acid oxidation rates during exercise, we measured fatty acid oxidation during in vivo exercise and ex vivo contractions in wild-type and CD36 knock-out mice. We observed a novel, positive association between vastus lateralis FATP1 and PFO and replicated work reporting a positive association between FABPpm and PFO. The stepwise linear regression model of PFO retained CD36, FATP1, FATP4, and FABPpm, explaining ~87% of the variation. Models of early and late FO explained ~61 and ~65% of the variation, respectively. FATP1 and FATP4 emerged as contributors to models of PFO and FO. Mice lacking CD36 had impaired whole-body and muscle fatty acid oxidation during exercise and muscle contractions, respectively. These data suggest that substantial variation in fatty acid oxidation rates during exercise can be explained by skeletal muscle proteins involved in fatty acid transport.

Keywords:  Cycling; Fat metabolism; Muscle; Transporters

DOI:  https://doi.org/10.1007/s00424-023-02843-7
J Cardiothorac Vasc Anesth. 2023 Jun 24. pii: S1053-0770(23)00410-X. [Epub ahead of print]

Preventing Iatrogenic Euglycemic Diabetic Ketoacidosis in Cardiac Surgery: The Role of Sodium-Glucose Cotransporter 2 Inhibitors.

DOI: https://doi.org/10.1053/j.jvca.2023.06.029
Front Physiol. 2023 ;14 1228318

Critical role of the mTOR pathway in poultry skeletal muscle physiology and meat quality: an opinion paper.

Jiahui Xu, Sandra G Velleman.



Keywords:  mTOR; meat quality; muscle growth; poultry; satellite cells; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1228318
J Physiol. 2023 Jul 20.

Resistance training diminishes mitochondrial adaptations to subsequent endurance training in healthy untrained men.

Paulo H C Mesquita, Joshua S Godwin, Bradley A Ruple, Casey L Sexton, Mason C McIntosh, Breanna J Mueller, Shelby C Osburn, C Brooks Mobley, Cleiton A Libardi, Kaelin C Young, L Bruce Gladden, Michael D Roberts, Andreas N Kavazis.

  We investigated the effects of performing a period of resistance training (RT) on the performance and molecular adaptations to a subsequent period of endurance training (ET). Twenty-five young adults were divided into an RT+ET group (n = 13), which underwent 7 weeks of RT followed by 7 weeks of ET, and an ET-only group (n = 12), which performed 7 weeks of ET. Body composition, endurance performance and muscle biopsies were collected before RT (T1, baseline for RT+ET), before ET (T2, after RT for RT+ET and baseline for ET) and after ET (T3). Immunohistochemistry was performed to determine fibre cross-sectional area (fCSA), myonuclear content, myonuclear domain size, satellite cell number and mitochondrial content. Western blots were used to quantify markers of mitochondrial remodelling. Citrate synthase activity and markers of ribosome content were also investigated. RT improved body composition and strength, increased vastus lateralis thickness, mixed and type II fCSA, myonuclear number, markers of ribosome content, and satellite cell content (P < 0.050). In response to ET, both groups similarly decreased body fat percentage (P < 0.0001) and improved endurance performance (e.g. V̇O2max${\dot V_{{{\mathrm{O}}_2}\max }}$ , and speed at which the onset of blood lactate accumulation occurred, P < 0.0001). Levels of mitochondrial complexes I-IV in the ET-only group increased 32-66%, while those in the RT+ET group increased 1-11% (time, P < 0.050). Additionally, mixed fibre relative mitochondrial content increased 15% in the ET-only group but decreased 13% in the RT+ET group (interaction, P = 0.043). In conclusion, RT performed prior to ET had no additional benefits to ET adaptations. Moreover, prior RT seemed to impair mitochondrial adaptations to ET. KEY POINTS: Resistance training is largely underappreciated as a method to improve endurance performance, despite reports showing it may improve mitochondrial function. Although several concurrent training studies are available, in this study we investigated the effects of performing a period of resistance training on the performance and molecular adaptations to subsequent endurance training. Prior resistance training did not improve endurance performance and impaired most mitochondrial adaptations to subsequent endurance training, but this effect may have been a result of detraining from resistance training.

Keywords:  HIIT; aerobic training; mitochondrial remodelling; skeletal muscle; strength training

DOI:  https://doi.org/10.1113/JP284822
Sci Adv. 2023 Jul 21. 9(29): eadi4862

What is really known about the effects of nicotinamide riboside supplementation in humans.

Mads V Damgaard, Jonas T Treebak.

Nicotinamide riboside is a precursor to the important cofactor nicotinamide adenine dinucleotide and has elicited metabolic benefits in multiple preclinical studies. In 2016, the first clinical trial of nicotinamide riboside was conducted to test the safety and efficacy of human supplementation. Many trials have since been conducted aiming to delineate benefits to metabolic health and severe diseases in humans. This review endeavors to summarize and critically assess the 25 currently published research articles on human nicotinamide riboside supplementation to identify any poorly founded claims and assist the field in elucidating the actual future potential for nicotinamide riboside. Collectively, oral nicotinamide riboside supplementation has displayed few clinically relevant effects, and there is an unfortunate tendency in the literature to exaggerate the importance and robustness of reported effects. Even so, nicotinamide riboside may play a role in the reduction of inflammatory states and has shown some potential in the treatment of diverse severe diseases.

DOI: https://doi.org/10.1126/sciadv.adi4862
Comp Biochem Physiol A Mol Integr Physiol. 2023 Jul 19. pii: S1095-6433(23)00123-X. [Epub ahead of print] 111490

Body mass dependence of oxidative phosphorylation efficiency in liver mitochondria from mammals.

Boël Mélanie, Voituron Yann, Roussel Damien.

  In eukaryotes, the performances of an organism are dependent on body mass and chemically supported by the mitochondrial production of ATP. Although the relationship between body mass and mitochondrial oxygen consumption is well described, the allometry of the transduction efficiency from oxygen to ATP production (ATP/O) is still poorly understood. Using a comparative approach, we investigated the oxygen consumption and ATP production of liver mitochondria from twelve species of mammals ranging from 5 g to 600 kg. We found that both oxygen consumption and ATP production are mass dependent but not the ATP/O at the maximal phosphorylating state. The results also showed that for sub-maximal phosphorylating states the ATP/O value positively correlated with body mass, irrespective of the metabolic intensity. This result contrasts with previous data obtained in mammalian muscles, suggesting a tissue-dependence of the body mass effect on mitochondrial efficiency.

Keywords:  Bioenergetics; Liver; Mitochondria; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.cbpa.2023.111490
Bio Protoc. 2023 Jul 05. 13(13): e4759

In vivo Electroporation of Skeletal Muscle Fibers in Mice.

Steven J Foltz, Criss H Hartzell, Hyojung J Choo.

  In vitro models are essential for investigating the molecular, biochemical, and cell-biological aspects of skeletal muscle. Still, models that utilize cell lines or embryonic cells do not fully recapitulate mature muscle fibers in vivo. Protein function is best studied in mature differentiated tissue, where biological context is maintained, but this is often difficult when reliable detection reagents, such as antibodies, are not commercially available. Exogenous expression of tagged proteins in vivo solves some of these problems, but this approach can be technically challenging because either a mouse must be engineered for each protein of interest or viral vectors are required for adequate levels of expression. While viral vectors can infect target cells following local administration, they carry the risk of genome integration that may interfere with downstream analyses. Plasmids are another accessible expression system, but they require ancillary means of cell penetration; electroporation is a simple physical method for this purpose that requires minimal training or specialized equipment. Here, we describe a method for in vivo plasmid expression in a foot muscle following electroporation.

Keywords:  Imaging; In vivo transfection; Muscle biology; Muscular dystrophy; Skeletal muscle

DOI:  https://doi.org/10.21769/BioProtoc.4759
J Neurotrauma. 2023 Jul 21.

Mitochondrial dysfunction following repeated mild blast traumatic brain injury is attenuated by a mild mitochondrial uncoupling prodrug.

William Brad Hubbard, Hemendra Vekaria, Gopal Velmurugan, Olivia Kalimon, Paresh Prajapati, Emily Brown, John Geisler, Patrick G Sulllivan.

  Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2d post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared to its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. While there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

Keywords:  METABOLISM; MILITARY INJURY; MITOCHONDRIA; OXIDATIVE STRESS; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2023.0102
J Endocrinol. 2023 Jul 01. pii: JOE-23-0123. [Epub ahead of print]

Exercise prevents obesity by reducing gut-derived inflammatory signals to brown adipocytes in mice.

Daiana Araujo Santana-Oliveira, Henrique Souza-Tavares, Aline Fernandes-da-Silva, Flávia Maria Silva-Veiga, Gustavo Casimiro-Lopes, Patricia Lisboa, Carlos Alberto Mandarim-de-Lacerda, Vanessa Souza-Mello.

Gut dysbiosis impairs nonshivering thermogenesis (NST) in obesity. The anti-obesogenic effects of exercise training might involve the modulation of gut microbiota and its inflammatory signals to the brown adipose tissue (BAT). This study evaluated whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) prevent overweight through reduced gut-derived inflammatory signals to BAT in high-fat-fed mice. Sixty male C57BL/6 mice (3 months old) comprised six experimental groups, Control diet (C), C + HIIT (C-HIIT), C+ MICT (C-MICT), High-fat diet (HF), HF + HIIT (HF-HIIT), HF + MICT (HF-MICT). The protocols lasted for ten weeks. HIIT and MICT restored body mass, mitigated glucose intolerance, and prevented hyperinsulinemia in HF-trained groups. A chronic HF diet caused dysbiosis, but HIIT and MICT prevented gut dysbiosis and preserved tight junction (TJ) gene expression. HF-HIIT and HF-MICT exhibited a similar pattern of goblet cell distribution, agreeing with the decreased plasma LPS concentrations and iBAT Lbp-Cd14-Tlr4 expression. The lowered Nlrp3 and Il1β in the HF-HITT and HF-MICT groups complied with iBAT thermogenic capacity maintenance. This study shows reliable evidence that HIIT and MICT prevented overweight by restoring the diversity of the gut microbiota phyla and TJ gene expression, thereby reducing inflammatory signals to brown adipocytes with preserved thermogenic capacity. Both exercise modalities prevented overweight, but HIIT rescued Zo-1 and Jam-a gene expression, exerting more potent anti-inflammatory effects than MICT (reduced LPS concentrations), providing a sustained increase in thermogenesis with 78 % less distance traveled.

DOI: https://doi.org/10.1530/JOE-23-0123
Curr Opin Immunol. 2023 Jul 12. pii: S0952-7915(23)00085-7. [Epub ahead of print]84 102366

Mitochondrial reactive oxygen species: double agents in Mycobacterium tuberculosis infection.

Lily M Ellzey, Kristin L Patrick, Robert O Watson.

In addition to housing the major energy-producing pathways in cells, mitochondria are active players in innate immune responses. One critical way mitochondria fulfill this role is by releasing damage-associated molecular patterns (mtDAMPs) that are recognized by innate sensors to activate pathways including, but not limited to, cytokine expression, selective autophagy, and cell death. Mitochondrial reactive oxygen species (mtROS) is a multifunctional mtDAMP linked to pro- and antimicrobial immune outcomes. Formed as a by-product of energy generation, mtROS links mitochondrial metabolism with downstream innate immune responses. As a result, altered cellular metabolism can change mtROS levels and impact downstream antimicrobial responses in a variety of ways. MtROS has emerged as a particularly important mediator of pathogenesis during infection with Mycobacterium tuberculosis (Mtb), an intracellular bacterial pathogen that continues to pose a significant threat to global public health. Here, we will summarize how Mtb modulates mtROS levels in infected macrophages and how mtROS dictates Mtb infection outcomes by controlling inflammation, lipid peroxidation, and cell death. We propose that mtROS may serve as a biomarker to predict tuberculosis patient outcomes and/or a target for host-directed therapeutics.

DOI: https://doi.org/10.1016/j.coi.2023.102366
Autophagy. 2023 Jul 16.

Mitofissin: a novel mitochondrial fission protein that facilitates mitophagy.

Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Nobuo N Noda, Tomotake Kanki.

  Mitophagy is a selective form of autophagy that targets dysfunctional or superfluous mitochondria for degradation. During mitophagy, specific selective autophagy receptors (SARs) mark a portion of mitochondria to recruit the autophagy-related (Atg) machinery and nucleate a phagophore. The phagophore expands and surrounds the mitochondrial cargo, forming an autophagosome. Fission plays a crucial role in separating the targeted portion of mitochondria from the main body to sequester it within the autophagosome. Our recent study, utilizing fission and budding yeasts as model systems, has identified Atg44 as a mitochondrial fission factor that generates mitochondrial fragments suitable for phagophore engulfment. Atg44 resides in the mitochondrial intermembrane space (IMS) and interacts with lipid membranes, with the capacity of mediating membrane fragility and fission. Based on our findings, we propose the term mitofissin to refer to Atg44 and its homologous proteins, which might participate in diverse cellular processes requiring membrane remodeling across various species.

Keywords:  Atg44; autophagy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast

DOI:  https://doi.org/10.1080/15548627.2023.2237343