bims-kimdis 2023-04-16 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒04‒16
28 papers selected by
Matías Javier Monsalves Álvarez

Ketone bodies: A double-edged sword for mammalian life span.
Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.
Dietary carbohydrates in the management of epilepsy.
Ketogenic diet alleviates renal fibrosis in mice by enhancing fatty acid oxidation through the free fatty acid receptor 3 pathway.
Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.
Sex-Specific Effects on Total Body Fat Gain with 4-Week Daily Dosing of Raspberry Ketone [4-(4-Hydroxyphenyl)-2-butanone] and Ketogenic Diet in Mice.
Ketogenic diet alleviates hypoglycemia-induced neuroinflammation via modulation the gut microbiota in mice.
Low carbohydrate high fat ketogenic diets on the exercise crossover point and glucose homeostasis.
The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation.
Ketone esters and their effects on carbohydrate metabolism during exercise.
Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.
Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction.
A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development.
Ketone Body β-Hydroxy-Butyrate Sustains Progressive Motility in Capacitated Human Spermatozoa: A Possible Role in Natural Fertility.
Chalcone: A potential scaffold for NLRP3 inflammasome inhibitors.
Low carbohydrate availability impairs hypertrophy and anaerobic performance.
Skeletal muscle dysfunctions in pulmonary arterial hypertension: Effects of aerobic exercise training.
Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex.
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling.
Hyperketonemia: A Marker of Disease, a Sign of a High-Producing Dairy Cow, or Both?
Different Effects of Cyclical Ketogenic vs. Nutritionally Balanced Reduction Diet on Serum Concentrations of Myokines in Healthy Young Males Undergoing Combined Resistance/Aerobic Training.
Myokines: Crosstalk and Consequences on Liver Physiopathology.
Interactions between gut microbes and NLRP3 inflammasome in the gut-brain axis.
Role of NLRP3 in the pathogenesis and treatment of gout arthritis.
Mitochondrial Signaling Pathways Associated with DNA Damage Responses.
Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1.
Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4+/- mice.
Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis.

Aging Cell. 2023 Apr 14. e13833

Ketone bodies: A double-edged sword for mammalian life span.

Issei Tomita, Hiroaki Tsuruta, Mako Yasuda-Yamahara, Kosuke Yamahara, Shogo Kuwagata, Yuki Tanaka-Sasaki, Masami Chin-Kanasaki, Yukihiro Fujita, Eiichiro Nishi, Hideki Katagiri, Hiroshi Maegawa, Shinji Kume.

  Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of β-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.

Keywords:  Hmgcs2; ketone body; longevity; low-carbohydrate ketogenic diet

DOI:  https://doi.org/10.1111/acel.13833
J Alzheimers Dis. 2023 Mar 04.

Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.

Yunlong Xu, Fuxiang Zheng, Qi Zhong, Yingjie Zhu.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.

Keywords:  Alzheimer’s disease; amyloid; dementia; ketogenic diet; ketone bodies therapy; ketone body; neuroinflammation; tau protein

DOI:  https://doi.org/10.3233/JAD-230002
Curr Opin Clin Nutr Metab Care. 2023 Apr 17.

Dietary carbohydrates in the management of epilepsy.

Babitha Haridas.

PURPOSE OF REVIEW: The role of dietary carbohydrates in the management of epilepsy is intrinsically linked to the ketogenic diet. The ketogenic diet has been in use for well over a century now. There have been numerous adaptations to the diet. It is crucial to understand the indications and role of the ketogenic diet in the management of epilepsy.RECENT FINDINGS: There have been new studies that have looked at the role of ketogenic ratios in seizure control. In addition, there has been new evidence in the role of using the ketogenic diet therapy instead of antiseizure medications. These data highlight that the ketogenic diet should be tailored for patients and caregivers. When used appropriately, it can result in a significant improvement in seizure control as well as cognitive and developmental gains.
SUMMARY: The ketogenic diet therapy has undergone numerous revisions and reiterations from its initial reported use in patients a century ago. This has enabled us to tailor the diet specific to each patient's underlying diagnosis.

DOI: https://doi.org/10.1097/MCO.0000000000000938
Front Nutr. 2023 ;10 1127845

Ketogenic diet alleviates renal fibrosis in mice by enhancing fatty acid oxidation through the free fatty acid receptor 3 pathway.

Yang Qiu, Xiaofan Hu, Cong Xu, Chenqi Lu, Rui Cao, Yanan Xie, Jun Yang.

  Introduction: The ketogenic diet (KD), as a dietary intervention, has gained importance in the treatment of solid organ structural remodeling, but its role in renal fibrosis has not been explored.Methods: Male C57BL/6 mice were fed a normal diet or a KD for 6 weeks prior to unilateral ureteral obstruction (UUO), a well-established in vivo model of renal fibrosis in rodents. Seven days after UUO, serum and kidney samples were collected. Serum β-hydroxybutyrate (β-OHB) concentrations and renal fibrosis were assessed. NRK52E cells were treated with TGFβ1, a fibrosis-inducing cytokine, and with or without β-OHB, a ketone body metabolized by KD, to investigate the mechanism underlying renal fibrosis.
Results: KD significantly enhanced serum β-OHB levels in mice. Histological analysis revealed that KD alleviated structural destruction and fibrosis in obstructed kidneys and reduced the expression of the fibrosis protein markers α-SMA, Col1a1, and Col3a1. Expression of the rate-limiting enzymes involved in fatty acid oxidation (FAO), Cpt1a and Acox1, significantly decreased after UUO and were upregulated by KD. However, the protective effect of KD was abolished by etomoxir (a Cpt1a inhibitor). Besides, our study observed that KD significantly suppressed UUO-induced macrophage infiltration and the expression of IL-6 in the obstructive kidneys. In NRK52E cells, fibrosis-related signaling was increased by TGFβ1 and reduced by β-OHB. β-OHB treatment restored the impaired expression of Cpt1a. The effect of β-OHB was blocked by siRNA targeting free fatty acid receptor 3 (FFAR3), suggesting that β-OHB might function through the FFAR3-dependent pathway.
Discussion: Our results highlight that KD attenuates UUO-induced renal fibrosis by enhancing FAO via the FFAR3-dependent pathway, which provides a promising dietary therapy for renal fibrosis.

Keywords:  fatty acid oxidation; free fatty acid receptor 3; ketogenic diet; renal fibrosis; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fnut.2023.1127845
J Neuropsychiatry Clin Neurosci. 2023 ;35(2): 104-109

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Wilfredo López-Ojeda, Robin A Hurley.



Keywords:  Brain Metabolism; Brain energy; Ketogenesis; Ketogenic Diet; Metabolic Diseases; Neuroenergetics; Neurological Diseases

DOI:  https://doi.org/10.1176/appi.neuropsych.20230017
Nutrients. 2023 Mar 28. pii: 1630. [Epub ahead of print]15(7):

Sex-Specific Effects on Total Body Fat Gain with 4-Week Daily Dosing of Raspberry Ketone [4-(4-Hydroxyphenyl)-2-butanone] and Ketogenic Diet in Mice.

Lihong Hao, Nicholas T Bello.

  Background: Raspberry ketone (RK: [4-(4-Hydroxyphenyl)-2-butanone]) is a dietary supplement marketed for weight control. RK is structurally unrelated to the ketone bodies elevated with a ketogenic diet (KD). This study aims to determine whether RK oral supplementation with KD improves the weight loss outcomes in high-fat diet (HFD; 45% fat)-fed mice. Methods: Male and female C57BL/6J mice were HFD-fed for 9 weeks and switched to KD (80% fat) or a control diet (CD; 10% fat) or continued with the HFD for 4 weeks. Coincident with the diet switch, each diet group received oral RK (200 mg/kg/day) or a vehicle. Results: In male KD-fed mice, oral RK reduced body weight by ~6% (KD_Veh: -9.2 ± 1% vs. KD_RK: -15.1 ± 1%) and fat composition by ~18% (KD_Veh: -16.0 ± 4% vs. KD_RK: -34.2 ± 5%). HFD and KD feeding induced glucose intolerance in both male and female mice. Oral RK decreased the glucose area under the curve in female mice by ~6% (KD_Veh: 44,877 ± 957 vs. KD_RK: 42,040 ± 675 mg*min/dl). KD also had gut microbiota alterations with higher alpha diversity in males and more beta diversity with RK. These findings suggest sex-specific weight loss effects with RK and KD in mice.

Keywords:  [4-(4-hydroxyphenyl)-2-butanone]; glucose intolerance; ketogenesis; microbiome; sex effect

DOI:  https://doi.org/10.3390/nu15071630
Mol Nutr Food Res. 2023 Apr 13. e2200711

Ketogenic diet alleviates hypoglycemia-induced neuroinflammation via modulation the gut microbiota in mice.

Cixia Li, Jiarong Pan, Penghao Sun, Shuai Wang, Songlin Wang, Wenyu Feng, Shulin Chen, Xuejun Chai, Shanting Zhao, Xiaoyan Zhu.

  SCOPE: This study aims to investigate the role of gut microbiota regulation with ketogenic diet (KD) in hypoglycemia-induced neuroinflammation.METHODS AND RESULTS: Immunofluorescence staining and western blotting showed that KD alleviated blood-brain barrier injury induced by hypoglycemia by increasing Podxl and ZO-1 levels. KD-fed mice showed reduced brain edema by decreasing AQP4 content and maintaining its polarized expression. 16S rRNA gene amplicon sequencing results showed that KD reduced the Chao 1 index of gut microbiota α-diversity, and significant separation was detected in the β-diversity analysis between the control and KD-fed mice. KD increased the relative abundance of Firmicutes and Proteobacteria and decreased that of Bacteroidetes. Hypoglycemia can reduce SOD and GSH-PX levels while increasing TNF-α, IL-1β, and IL-6 mRNA levels in the brain tissues of mice. KD alleviated hypoglycemia-induced neuroinflammation by inhibiting microglia activation and TLR4/p38MAPK/NF-κB signaling pathway. Importantly, antibiotic cocktail depletion of the gut microbiota weakened anti-inflammatory and antioxidation responses in KD-fed mice.
CONCLUSION: Collectively, these findings suggest that KD alleviates hypoglycemia-induced brain injury via gut microbiota modulation, which may provide novel insights into the therapy for hypoglycemia. This article is protected by copyright. All rights reserved.

Keywords:  gut microbiota; ketogenic diet; microglia cell; neuroinflammation; β-hydroxybutyrate

DOI:  https://doi.org/10.1002/mnfr.202200711
Front Physiol. 2023 ;14 1150265

Low carbohydrate high fat ketogenic diets on the exercise crossover point and glucose homeostasis.

T D Noakes, P J Prins, J S Volek, D P D'Agostino, A P Koutnik.

  In exercise science, the crossover effect denotes that fat oxidation is the primary fuel at rest and during low-intensity exercise with a shift towards an increased reliance on carbohydrate oxidation at moderate to high exercise intensities. This model makes four predictions: First, >50% of energy comes from carbohydrate oxidation at ≥60% of maximum oxygen consumption (VO2max), termed the crossover point. Second, each individual has a maximum fat oxidation capacity (FATMAX) at an exercise intensity lower than the crossover point. FATMAX values are typically 0.3-0.6 g/min. Third, fat oxidation is minimized during exercise ≥85%VO2max, making carbohydrates the predominant energetic substrate during high-intensity exercise, especially at >85%VO2max. Fourth, high-carbohydrate low-fat (HCLF) diets will produce superior exercise performances via maximizing pre-exercise storage of this predominant exercise substrate. In a series of recent publications evaluating the metabolic and performance effects of low-carbohydrate high-fat (LCHF/ketogenic) diet adaptations during exercise of different intensities, we provide findings that challenge this model and these four predictions. First, we show that adaptation to the LCHF diet shifts the crossover point to a higher %VO2max (>80%VO2max) than previously reported. Second, substantially higher FATMAX values (>1.5 g/min) can be measured in athletes adapted to the LCHF diet. Third, endurance athletes exercising at >85%VO2max, whilst performing 6 × 800 m running intervals, measured the highest rates of fat oxidation yet reported in humans. Peak fat oxidation rates measured at 86.4 ± 6.2%VO2max were 1.58 ± 0.33 g/min with 30% of subjects achieving >1.85 g/min. These studies challenge the prevailing doctrine that carbohydrates are the predominant oxidized fuel during high-intensity exercise. We recently found that 30% of middle-aged competitive athletes presented with pre-diabetic glycemic values while on an HCLF diet, which was reversed on LCHF. We speculate that these rapid changes between diet, insulin, glucose homeostasis, and fat oxidation might be linked by diet-induced changes in mitochondrial function and insulin action. Together, we demonstrate evidence that challenges the current crossover concept and demonstrate evidence that a LCHF diet may also reverse features of pre-diabetes and future metabolic disease risk, demonstrating the impact of dietary choice has extended beyond physical performance even in athletic populations.

Keywords:  continuous glucose monitor (CGM); crossover concept; exercise; fat; ketogenic diet (KD); low carbohydrate; oxidation; prediabetes

DOI:  https://doi.org/10.3389/fphys.2023.1150265
Int J Mol Sci. 2023 Mar 24. pii: 6126. [Epub ahead of print]24(7):

The Role of Post-Translational Modifications in Regulation of NLRP3 Inflammasome Activation.

Jing Xia, Songhong Jiang, Shiqi Dong, Yonghong Liao, Yang Zhou.

  Pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) induce NLRP3 inflammasome activation, and subsequent formation of active caspase-1 as well as the maturation of interleukin-1β (IL-1β) and gasdermin D (GSDMD), mediating the occurrence of pyroptosis and inflammation. Aberrant NLRP3 inflammasome activation causes a variety of diseases. Therefore, the NLRP3 inflammasome pathway is a target for prevention and treatment of relative diseases. Recent studies have suggested that NLRP3 inflammasome activity is closely associated with its post-translational modifications (PTMs). This review focuses on PTMs of the components of the NLRP3 inflammasome and the resultant effects on regulation of its activity to provide references for the exploration of the mechanisms by which the NLRP3 inflammasome is activated and controlled.

Keywords:  NLRP3; inflammasome; post-translational modification

DOI:  https://doi.org/10.3390/ijms24076126
J Nutr. 2023 Apr 11. pii: S0022-3166(23)35546-9. [Epub ahead of print]

Ketone esters and their effects on carbohydrate metabolism during exercise.

Javier T Gonzalez.

DOI: https://doi.org/10.1016/j.tjnut.2023.04.003
J Physiol. 2023 Apr 12.

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.

Javier Botella, Camilla T Schytz, Thomas F Pehrson, Rune Hokken, Simon Laugesen, Per Aagaard, Charlotte Suetta, Britt Christensen, Niels Ørtenblad, Joachim Nielsen.

  Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre-type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein responses (UPRmt ). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt ) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes. KEY POINTS: Untrained individuals and strength athletes possess comparable skeletal muscle mitochondrial volume density. In contrast, strength athletes'mitochondria are characterised by increased cristae density, decreased size, and increased surface-to-volume ratio. Type I fibres have an increased number of mitochondrial profiles with minor differences in the mitochondrial morphological characteristics compared to type II fibres. The mitochondrial morphology is distinct across the subcellular compartments in both groups, with subsarcolemmal mitochondria being bigger in size when compared to intermyofibrillar. Acute resistance exercise leads to signs of mild morphological mitochondrial stress accompanied by increased gene expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt). Abstract figure legend: Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. The present study aimed to investigate the mitochondrial structural characteristics of strength athletes when compared to age-matched untrained individuals. Here we show that the mitochondria of strength athletes have an increased mitochondrial cristae density, increased number of profiles, and an increased surface-to-volume ratio; despite similar mitochondrial volumetric density. Furthermore, we show that human type I fibres, when compared to type II fibres, are characterised by an increased number of mitochondrial profiles without differences in their morphological characteristics. Finally, we show that acute resistance exercise leads to mild signs of mitochondrial morphological stress and an increased expression of markers of mitochondrial biogenesis, fission, and mitochondrial unfolded protein response (UPRmt ). This article is protected by copyright. All rights reserved.

Keywords:  Mitochondria; Olympic weightlifting; cristae density; resistance exercise; skeletal muscle; strength

DOI:  https://doi.org/10.1113/JP284394
Circ Cardiovasc Imaging. 2023 Apr 12. e015298

Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction.

Carlos G Santos-Gallego, Juan Antonio Requena-Ibáñez, Belen Picatoste, Brian Fardman, Kiyotake Ishikawa, Renata Mazurek, Michael Pieper, Samantha Sartori, Jorge Rodriguez-Capitán, Valentin Fuster, Juan J Badimon.

  BACKGROUND: SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI).METHODS: We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body beta-hydroxybutyrate BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected.
RESULTS: The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group.
CONCLUSIONS: One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

Keywords:  empagliflozin; glucose; ketone bodies; myocardial infarction; reperfusion

DOI:  https://doi.org/10.1161/CIRCIMAGING.123.015298
PLoS Biol. 2023 Apr;21(4): e3002057

A D-2-hydroxyglutarate dehydrogenase mutant reveals a critical role for ketone body metabolism in Caenorhabditis elegans development.

Olga Ponomarova, Hefei Zhang, Xuhang Li, Shivani Nanda, Thomas B Leland, Bennett W Fox, Alyxandra N Starbard, Gabrielle E Giese, Frank C Schroeder, L Safak Yilmaz, Albertha J M Walhout.

In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Loss of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the up-regulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG or by supplementing either vitamin B12 or the ketone bodies 3-hydroxybutyrate (3HB) and acetoacetate (AA). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low and in which a loss of dhgd-1 causes lethality by limiting ketone body production.

DOI: https://doi.org/10.1371/journal.pbio.3002057
Nutrients. 2023 Mar 27. pii: 1622. [Epub ahead of print]15(7):

Ketone Body β-Hydroxy-Butyrate Sustains Progressive Motility in Capacitated Human Spermatozoa: A Possible Role in Natural Fertility.

Claudia Pappalardo, Federica Finocchi, Federica Pedrucci, Andrea Di Nisio, Alberto Ferlin, Luca De Toni, Carlo Foresta.

  Background Calorie restriction is recognized as a useful nutritional approach to improve the endocrine derangements and low fertility profile associated with increased body weight. This is particularly the case for dietary regimens involving ketosis, resulting in increased serum levels of ketone bodies such as β-hydroxy-butyrate (β-HB). In addition to serum, β-HB is detected in several biofluids and β-HB levels in the follicular fluid are strictly correlated with the reproductive outcome in infertile females. However, a possible direct role of ketone bodies on sperm function has not been addressed so far. Methods Semen samples were obtained from 10 normozoospermic healthy donors attending the University Andrology Unit as participants in an infertility survey programme. The effect of β-HB on cell motility in vitro was evaluated on isolated spermatozoa according to their migratory activity in a swim-up selection procedure. The effect of β-HB on spermatozoa undergone to capacitation was also assessed. Results Two hours of exposure to β-HB, 1 mM or 4 mM, proved to be ineffective in modifying the motility of freshly ejaculated spermatozoa isolated according to the migratory activity in a swim-up procedure (all p values > 0.05). Differently, sperm maintenance in 4 mM β-HB after capacitation was associated with a significantly higher percentage of sperm cells with progressive motility compared to β-HB-lacking control (respectively, 67.6 ± 3.5% vs. 55.3 ± 6.5%, p = 0.0158). Succinyl-CoA transferase inhibitor abolished the effect on motility exerted by β-HB, underpinning a major role for this enzyme. Conclusion Our results suggest a possible physiological role for β-HB that could represent an energy metabolite in support of cell motility on capacitated spermatozoa right before encountering the oocyte.

Keywords:  capacitation; follicular fluid; ketosis; metabolism; succinyl-CoA transferase

DOI:  https://doi.org/10.3390/nu15071622
Eur J Med Chem Rep. 2023 Apr;pii: 100100. [Epub ahead of print]7

Chalcone: A potential scaffold for NLRP3 inflammasome inhibitors.

Pritam Thapa, Sunil P Upadhyay, Vikas Singh, Varun C Boinpelly, Jianping Zhou, David K Johnson, Prajwal Gurung, Eung Seok Lee, Ram Sharma, Mukut Sharma.

  Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions. However, none of the known NLRP3 inhibitors has been approved for clinical use. Sulfonylurea and covalent inhibitors with electrophilic warhead (Michael acceptor) are among the prominent classes of compounds explored for their NLRP3 inhibitory effects. Chalcone, a small molecule with α, β unsaturated carbonyl group (Michael acceptor), has also been studied as a promising scaffold for the development of NLRP3 inhibitors. Low molecular weight, easy to manipulate lipophilicity and cost-effectiveness have attracted many to use chalcone scaffold for drug development. In this review, we highlight chalcone derivatives with NLRP3 inflammasome inhibitory activities. Recent developments and potential new directions summarized here will, hopefully, serve as valuable perspectives for investigators including medicinal chemists and drug discovery researchers to utilize chalcone as a scaffold for developing novel NLRP3 inflammasome inhibitors.

Keywords:  Chalcone; Michael acceptors; NLRP3 inflammasome; NLRP3 inhibitors; Sulfonylureas

DOI:  https://doi.org/10.1016/j.ejmcr.2022.100100
Curr Opin Clin Nutr Metab Care. 2023 Apr 14.

Low carbohydrate availability impairs hypertrophy and anaerobic performance.

Lee M Margolis, Stefan M Pasiakos.

PURPOSE OF REVIEW: Highlight contemporary evidence examining the effects of carbohydrate restriction on the intracellular regulation of muscle mass and anaerobic performance.RECENT FINDINGS: Low carbohydrate diets increase fat oxidation and decrease fat mass. Emerging evidence suggests that dietary carbohydrate restriction increases protein oxidation, thereby limiting essential amino acid availability necessary to stimulate optimal muscle protein synthesis and promote muscle recovery. Low carbohydrate feeding for 24 h increases branched-chain amino acid (BCAA) oxidation and reduces myogenic regulator factor transcription compared to mixed-macronutrient feeding. When carbohydrate restriction is maintained for 8 to 12 weeks, the alterations in anabolic signaling, protein synthesis, and myogenesis likely contribute to limited hypertrophic responses to resistance training. The blunted hypertrophic response to resistance training when carbohydrate availability is low does not affect muscle strength, whereas persistently low muscle glycogen does impair anaerobic output during high-intensity sprint and time to exhaustion tests.
SUMMARY: Dietary carbohydrate restriction increases BCAA oxidation and impairs muscle hypertrophy and anaerobic performance, suggesting athletes who need to perform high-intensity exercise should consider avoiding dietary strategies that restrict carbohydrate.

DOI: https://doi.org/10.1097/MCO.0000000000000934
Front Physiol. 2023 ;14 1148146

Skeletal muscle dysfunctions in pulmonary arterial hypertension: Effects of aerobic exercise training.

Filipe Rios Drummond, Luciano Bernardes Leite, Denise Coutinho de Miranda, Lucas Rios Drummond, Victor Neiva Lavorato, Leôncio Lopes Soares, Clóvis Andrade Neves, Antônio José Natali.

  Pulmonary arterial hypertension is associated with skeletal muscle myopathy and atrophy and impaired exercise tolerance. Aerobic exercise training has been recommended as a non-pharmacological therapy for deleterious effects imposed by pulmonary arterial hypertension. Aerobic physical training induces skeletal muscle adaptations via reduced inflammation, improved anabolic processes, decreased hypoxia and regulation of mitochondrial function. These benefits improve physical exertion tolerance and quality of life in patients with pulmonary arterial hypertension. However, the mechanisms underlying the therapeutic potential of aerobic exercise to skeletal muscle disfunctions in patients with pulmonary arterial hypertension are not well understood yet. This minireview highlights the pathways involved in skeletal muscle adaptations to aerobic exercise training in patients with pulmonary arterial hypertension.

Keywords:  aerobic exercise; effort; myopathy; physical performance; pulmonary hypertension

DOI:  https://doi.org/10.3389/fphys.2023.1148146
Proc Natl Acad Sci U S A. 2023 Apr 18. 120(16): e2217665120

Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex.

Chen-Wei Tsai, Tsung-Yun Liu, Fan-Yi Chao, Yung-Chi Tu, Madison X Rodriguez, Anna M Van Keuren, Zhiwei Ma, John Bankston, Ming-Feng Tsai.

  The mitochondrial calcium uniporter is a Ca2+ channel that imports cytoplasmic Ca2+ into the mitochondrial matrix to regulate cell bioenergetics, intracellular Ca2+ signaling, and apoptosis. The uniporter contains the pore-forming MCU subunit, an auxiliary EMRE protein, and the regulatory MICU1/MICU2 subunits. Structural and biochemical studies have suggested that MICU1 gates MCU by blocking/unblocking the pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block, but instead potentiates MCU via allosteric mechanisms. Here, we address this direct clash of the proposed MICU1 function. Supporting the MICU1-occlusion mechanism, patch-clamp demonstrates that purified MICU1 strongly suppresses MCU Ca2+ currents, and this inhibition is abolished by mutating the MCU-interacting K126 residue. Moreover, a membrane-depolarization assay shows that MICU1 prevents MCU-mediated Na+ flux into intact mitochondria under Ca2+-free conditions. Examining the observations underlying the potentiation model, we found that MICU1 occlusion was not detected in mitoplasts not because MICU1 cannot block, but because MICU1 dissociates from the uniporter complex. Furthermore, MICU1 depletion reduces uniporter transport not because MICU1 can potentiate MCU, but because EMRE is down-regulated. These results firmly establish the molecular mechanisms underlying the physiologically crucial process of uniporter regulation by MICU1.

Keywords:  calcium channels; intracellular calcium signaling; mitochondrial physiology; organellar channels

DOI:  https://doi.org/10.1073/pnas.2217665120
Int J Mol Sci. 2023 Apr 06. pii: 6842. [Epub ahead of print]24(7):

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Ameliorate Metabolic Disorder and Obesity Induced Cardiomyocyte Injury and Mitochondrial Remodeling.

Shih-Jie Jhuo, Yi-Hsiung Lin, I-Hsin Liu, Tsung-Hsien Lin, Bin-Nan Wu, Kun-Tai Lee, Wen-Ter Lai.

  Sodium-glucose transporter 2 inhibitors (SGLT2is) exert significant cardiovascular and heart failure benefits in type 2 diabetes mellitus (DM) patients and can help reduce cardiac arrhythmia incidence in clinical practice. However, its effect on regulating cardiomyocyte mitochondria remain unclear. To evaluate its effect on myocardial mitochondria, C57BL/6J mice were divided into four groups, including: (1) control, (2) high fat diet (HFD)-induced metabolic disorder and obesity (MDO), (3) MDO with empagliflozin (EMPA) treatment, and (4) MDO with glibenclamide (GLI) treatment. All mice were sacrificed after 16 weeks of feeding and the epicardial fat secretome was collected. H9c2 cells were treated with the different secretomes for 18 h. ROS production, Ca2+ distribution, and associated proteins expression in mitochondria were investigated to reveal the underlying mechanisms of SGLT2is on cardiomyocytes. We found that lipotoxicity, mitochondrial ROS production, mitochondrial Ca2+ overload, and the levels of the associated protein, SOD1, were significantly lower in the EMPA group than in the MDO group, accompanied with increased ATP production in the EMPA-treated group. The expression of mfn2, SIRT1, and SERCA were also found to be lower after EMPA-secretome treatment. EMPA-induced epicardial fat secretome in mice preserved a better cardiomyocyte mitochondrial biogenesis function than the MDO group. In addition to reducing ROS production in mitochondria, it also ameliorated mitochondrial Ca2+ overload caused by MDO-secretome. These findings provide evidence and potential mechanisms for the benefit of SGLT2i in heart failure and arrhythmias.

Keywords:  SGLT2 inhibitor; calcium overload; empagliflozin; epicardial fat; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/ijms24076842
Vet Clin North Am Food Anim Pract. 2023 Apr 07. pii: S0749-0720(23)00015-4. [Epub ahead of print]

Hyperketonemia: A Marker of Disease, a Sign of a High-Producing Dairy Cow, or Both?

Sabine Mann, Jessica A A McArt.

  This review covers the history and nomenclature of ketosis, the source and use of ketones in transition cows, and the controversial role of hyperketonemia's association with health and production outcomes in dairy cows. With the goal of assisting veterinarians with on-farm diagnostic and treatment methods, the authors present current and evolving means of direct and indirect hyperketonemia detection as well as a summary of treatment modalities and their efficacy. They encourage veterinarians to include hyperketonemia testing as part of their routine physical examinations and contemplate day in milk at hyperketonemia diagnosis when designing treatment and management strategies.

Keywords:  Epidemiology; Hyperketonemia; Ketone; Transition; Treatment; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.cvfa.2023.02.004
Nutrients. 2023 Mar 31. pii: 1720. [Epub ahead of print]15(7):

Different Effects of Cyclical Ketogenic vs. Nutritionally Balanced Reduction Diet on Serum Concentrations of Myokines in Healthy Young Males Undergoing Combined Resistance/Aerobic Training.

Pavel Kysel, Denisa Haluzíková, Iveta Pleyerová, Kateřina Řezníčková, Ivana Laňková, Zdeňka Lacinová, Tereza Havrlantová, Miloš Mráz, Barbora Judita Kasperová, Viktorie Kovářová, Lenka Thieme, Jaroslava Trnovská, Petr Svoboda, Soňa Štemberková Hubáčková, Zdeněk Vilikus, Martin Haluzík.

  Myokines represent important regulators of muscle metabolism. Our study aimed to explore the effects of a cyclical ketogenic reduction diet (CKD) vs. a nutritionally balanced reduction diet (RD) combined with regular resistance/aerobic training in healthy young males on serum concentrations of myokines and their potential role in changes in physical fitness. Twenty-five subjects undergoing regular resistance/aerobic training were randomized to the CKD (n = 13) or RD (n = 12) groups. Anthropometric and spiroergometric parameters, muscle strength, biochemical parameters, and serum concentrations of myokines and cytokines were assessed at baseline and after 8 weeks of intervention. Both diets reduced body weight, body fat, and BMI. Muscle strength and endurance performance were improved only by RD. Increased musclin (32.9 pg/mL vs. 74.5 pg/mL, p = 0.028) and decreased osteonectin levels (562 pg/mL vs. 511 pg/mL, p = 0.023) were observed in RD but not in the CKD group. In contrast, decreased levels of FGF21 (181 pg/mL vs. 86.4 pg/mL, p = 0.003) were found in the CKD group only. Other tested myokines and cytokines were not significantly affected by the intervention. Our data suggest that changes in systemic osteonectin and musclin levels could contribute to improved muscle strength and endurance performance and partially explain the differential effects of CKD and RD on physical fitness.

Keywords:  adipokines; body composition; cytokines; endurance; ketogenic diet; myokines; strength parameters; training

DOI:  https://doi.org/10.3390/nu15071720
Nutrients. 2023 Mar 31. pii: 1729. [Epub ahead of print]15(7):

Myokines: Crosstalk and Consequences on Liver Physiopathology.

Aurore Dumond Bourie, Jean-Baptiste Potier, Michel Pinget, Karim Bouzakri.

  Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease mainly characterized by the hepatic accumulation of lipid inducing a deregulation of β-oxidation. Its advanced form is non-alcoholic steatohepatitis (NASH), which, in addition to lipid accumulation, induces hepatocellular damage, oxidative stress and fibrosis that can progress to cirrhosis and to its final stage: hepatocellular carcinoma (HCC). To date, no specific therapeutic treatment exists. The implications of organ crosstalk have been highlighted in many metabolic disorders, such as diabetes, metabolic-associated liver diseases and obesity. Skeletal muscle, in addition to its role as a reservoir and consumer of energy and carbohydrate metabolism, is involved in this inter-organs' communication through different secreted products: myokines, exosomes and enzymes, for example. Interestingly, resistance exercise has been shown to have a beneficial impact on different metabolic pathways, such as lipid oxidation in different organs through their secreted products. In this review, we will mainly focus on myokines and their effects on non-alcoholic fatty liver disease, and their complication: non-alcoholic steatohepatitis and HCC.

Keywords:  HCC; NAFLD; NASH; diabetes; inter-organ crosstalk; metabolic disease; myokines

DOI:  https://doi.org/10.3390/nu15071729
Comput Struct Biotechnol J. 2023 ;21 2215-2227

Interactions between gut microbes and NLRP3 inflammasome in the gut-brain axis.

Ding Yang, Zixu Wang, Yaoxing Chen, Qingyun Guo, Yulan Dong.

  The role of the gut-brain axis in maintaining the brain's and gut's homeostasis has been gradually recognized in recent years. The connection between the gut and the brain takes center stage. In this scenario, the nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome promotes inflammatory cell recruitment. It plays a crucial role in coordinating host physiology and immunity. Recent evidence shows how vital the gut-brain axis is for maintaining brain and gut homeostasis. However, more research is needed to determine the precise causal link between changed gut microbiota structure and NLRP3 activation in pathogenic circumstances. This review examines the connection between gut microbiota and the NLRP3 inflammasome. We describe how both dynamically vary in clinical cases and the external factors affecting both. Finally, we suggest that the crosstalk between the gut microbiota and NLRP3 is involved in signaling in the gut-brain axis, which may be a potential pathological mechanism for CNS diseases and intestinal disorders.

Keywords:  Gut microbiota; Gut-brain axis; Inflammation; LPS; NLRP3 inflammasome; Neurological disorders

DOI:  https://doi.org/10.1016/j.csbj.2023.03.017
Front Immunol. 2023 ;14 1137822

Role of NLRP3 in the pathogenesis and treatment of gout arthritis.

Ya-Ru Liu, Jie-Quan Wang, Jun Li.

  Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA.

Keywords:  NLRP3; gout arthritis; natural products; ncRNAs; novel compounds; pathogenesis

DOI:  https://doi.org/10.3389/fimmu.2023.1137822
Int J Mol Sci. 2023 Mar 24. pii: 6128. [Epub ahead of print]24(7):

Mitochondrial Signaling Pathways Associated with DNA Damage Responses.

Tsutomu Shimura.

  Under physiological and stress conditions, mitochondria act as a signaling platform to initiate biological events, establishing communication from the mitochondria to the rest of the cell. Mitochondrial adenosine triphosphate (ATP), reactive oxygen species, cytochrome C, and damage-associated molecular patterns act as messengers in metabolism, oxidative stress response, bystander response, apoptosis, cellular senescence, and inflammation response. In this review paper, the mitochondrial signaling in response to DNA damage was summarized. Mitochondrial clearance via fusion, fission, and mitophagy regulates mitochondrial quality control under oxidative stress conditions. On the other hand, damaged mitochondria release their contents into the cytoplasm and then mediate various signaling pathways. The role of mitochondrial dysfunction in radiation carcinogenesis was discussed, and the recent findings on radiation-induced mitochondrial signaling and radioprotective agents that targeted mitochondria were presented. The analysis of the mitochondrial radiation effect, as hypothesized, is critical in assessing radiation risks to human health.

Keywords:  DNA damage response; inflammation response; mitochondrial signaling; oxidative stress; radiation carcinogenesis

DOI:  https://doi.org/10.3390/ijms24076128
Front Cell Dev Biol. 2023 ;11 1072315

Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1.

César Vásquez-Trincado, Mario Navarro-Márquez, Pablo E Morales, Francisco Westermeier, Mario Chiong, Valentina Parra, Alejandra Espinosa, Sergio Lavandero.

  Introduction: Cardiovascular diseases, especially metabolic-related disorders, are progressively growing worldwide due to high-fat-containing foods, which promote a deleterious response at the cellular level, termed lipotoxicity, or lipotoxic stress. At the cardiac level, saturated fatty acids have been directly associated with cardiomyocyte lipotoxicity through various pathological mechanisms involving mitochondrial dysfunction, oxidative stress, and ceramide production, among others. However, integrative regulators connecting saturated fatty acid-derived lipotoxic stress to mitochondrial and cardiomyocyte dysfunction remain elusive. Methods: Here, we worked with a cardiomyocyte lipotoxicity model, which uses the saturated fatty acid myristate, which promotes cardiomyocyte hypertrophy and insulin desensitization. Results: Using this model, we detected an increase in the mitochondrial E3 ubiquitin ligase, MUL1, a mitochondrial protein involved in the regulation of growth factor signaling, cell death, and, notably, mitochondrial dynamics. In this context, myristate increased MUL1 levels and induced mitochondrial fragmentation, associated with the decrease of the mitochondrial fusion protein MFN2, and with the increase of the mitochondrial fission protein DRP1, two targets of MUL1. Silencing of MUL1 prevented myristate-induced mitochondrial fragmentation and cardiomyocyte hypertrophy. Discussion: These data establish a novel connection between cardiomyocytes and lipotoxic stress, characterized by hypertrophy and fragmentation of the mitochondrial network, and an increase of the mitochondrial E3 ubiquitin ligase MUL1.

Keywords:  MAPL; MUL1; heart; hypertrophy; insulin-desensitization; lipotoxicity; mitochondria

DOI:  https://doi.org/10.3389/fcell.2023.1072315
Cell Mol Life Sci. 2023 Apr 13. 80(5): 122

Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4+/- mice.

Vitor Rosetto Muñoz, José Diego Botezelli, Rafael Calais Gaspar, Alisson L da Rocha, Renan Fudoli Lins Vieira, Barbara Moreira Crisol, Renata Rosseto Braga, Matheus Brandemarte Severino, Susana Castelo Branco Ramos Nakandakari, Gabriel Calheiros Antunes, Sérgio Q Brunetto, Celso D Ramos, Lício Augusto Velloso, Fernando Moreira Simabuco, Leandro Pereira de Moura, Adelino Sanchez Ramos da Silva, Eduardo Rochete Ropelle, Dennys Esper Cintra, José Rodrigo Pauli.

  OBJECTIVE: Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/-) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet.METHODS: Slc2a4+/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line.
RESULTS: When Slc2a4+/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle.
CONCLUSIONS: Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/- mouse model.

Keywords:  Hyperinsulinemia; Mitochondrial adaptations; Physical exercise; Skeletal muscle

DOI:  https://doi.org/10.1007/s00018-023-04771-2
Cells. 2023 Apr 01. pii: 1069. [Epub ahead of print]12(7):

Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis.

Kamrul M Hasan, Meher Parveen, Alondra Pena, Francisco Bautista, Juan Carlos Rivera, Roxana Ramirez Huerta, Erica Martinez, Jorge Espinoza-Derout, Amiya P Sinha-Hikim, Theodore C Friedman.

  CARF (CDKN2AIP) regulates cellular fate in response to various stresses. However, its role in metabolic stress is unknown. We found that fatty livers from mice exhibit low CARF expression. Similarly, overloaded palmitate inhibited CARF expression in HepG2 cells, suggesting that excess fat-induced stress downregulates hepatic CARF. In agreement with this, silencing and overexpressing CARF resulted in higher and lower fat accumulation in HepG2 cells, respectively. Furthermore, CARF overexpression lowered the ectopic palmitate accumulation in HepG2 cells. We were interested in understanding the role of hepatic CARF and underlying mechanisms in the development of NAFLD. Mechanistically, transcriptome analysis revealed that endoplasmic reticulum (ER) stress and oxidative stress pathway genes significantly altered in the absence of CARF. IRE1α, GRP78, and CHOP, markers of ER stress, were increased, and the treatment with TUDCA, an ER stress inhibitor, attenuated fat accumulation in CARF-deficient cells. Moreover, silencing CARF caused a reduction of GPX3 and TRXND3, leading to oxidative stress and apoptotic cell death. Intriguingly, CARF overexpression in HFD-fed mice significantly decreased hepatic steatosis. Furthermore, overexpression of CARF ameliorated the aberrant ER function and oxidative stress caused by fat accumulation. Our results further demonstrated that overexpression of CARF alleviates HFD-induced insulin resistance assessed with ITT and GTT assay. Altogether, we conclude that excess fat-induced reduction of CARF dysregulates ER functions and lipid metabolism leading to hepatic steatosis.

Keywords:  CARF (CDKN2AIP); ER-stress; NAFLD; hepatic steatosis; lipo-toxicity; metabolic stress; oxidative stress

DOI:  https://doi.org/10.3390/cells12071069