bims-kimdis 2022-12-04 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–12–04
33 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.
Dietary Changes Leading to Euglycemic Diabetic Ketoacidosis in Sodium-Glucose Cotransporter-2 Inhibitor Users: A Challenge for Primary Care Physicians?
Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.
Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer.
Corrigendum: Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study.
Comparison of a pre-bariatric surgery very low-calorie ketogenic diet and the Mediterranean diet effects on weight loss, metabolic parameters, and liver size reduction.
Ketone monoester ingestion increases post-exercise serum erythropoietin concentrations in healthy men.
β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation.
Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice.
Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.
Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects.
Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.
What about hybrids? Supplemental methods for skeletal muscle fibre typing.
[Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?]
Ketone Body β-Hydroxybutyric Acid Ameliorates Dopaminergic Neuron Injury Through Modulating Zinc Finger Protein 36/Acyl-CoA Synthetase Long-Chain Family Member Four Signaling Axis-Mediated Ferroptosis.
SIRT3 Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Activation of the NLRP3 Inflammasome via Autophagy.
Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.
Mitochondria and cell death-associated inflammation.
Effect of fasting on short-term visual plasticity in adult humans.
ChemR23 signaling ameliorates cognitive impairments in diabetic mice via dampening oxidative stress and NLRP3 inflammasome activation.
The role of the NLRP3 inflammasome in chronic inflammation in asthma and chronic obstructive pulmonary disease.
Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses.
Upregulation of TXNIP contributes to granulosa cell dysfunction in polycystic ovary syndrome via activation of the NLRP3 inflammasome.
Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson's disease: mechanisms and therapeutic implications.
All Fiber is Not Fiber.
Low aerobic capacity in McArdle disease: a role for mitochondrial network impairment?
HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24.
The lysosomal Ragulator complex activates NLRP3 inflammasome in vivo via HDAC6.
Effects of protein intake from an energy-restricted diet on the skeletal muscle composition of overweight and obese rats.
Editorial: Clinical prospective of SGLT2 inhibitors in atherosclerosis.
Aerobic exercise alleviates ventilator-induced lung injury by inhibiting NLRP3 inflammasome activation.
Targeting Mitochondrial Calcium Handling to Treat Atrial Fibrillation.
Mitochondria-associated niches in health and disease.

Front Nutr. 2022 ;9 947567

Ketogenic diets and Ketone suplementation: A strategy for therapeutic intervention.

Christiaan G J Saris, Silvie Timmers.

  Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.

Keywords:  ketogenic diet; ketone bodies; ketone supplementation; nutritional ketosis; precision nutrition

DOI:  https://doi.org/10.3389/fnut.2022.947567
Korean J Fam Med. 2022 Nov;43(6): 361-366

Dietary Changes Leading to Euglycemic Diabetic Ketoacidosis in Sodium-Glucose Cotransporter-2 Inhibitor Users: A Challenge for Primary Care Physicians?

Manoj Kumar Reddy Somagutta, Utkarsha Uday, Nishat Shama, Narayana Reddy Bathula, Siva Pendyala, Ashwini Mahadevaiah, Greta Mahmutaj, Ngaba Negumadji Ngardig.

   BACKGROUND: The use of euglycemic diabetic ketoacidosis (EDKA) related to sodium-glucose cotransporter 2 inhibitors (SGLT2i) use in people with diabetes has been increasingly reported. The causes are multifactorial, and dietary changes in SGLT2i users were observed to trigger EDKA. A ketogenic diet or very low-carbohydrate diet (VLCD) enhances body ketosis by breaking down fats into energy sources, causing EDKA. This study aimed to understand the patient specific risk factors and clinical characteristics of this cohort.
METHODS: Several databases were carefully analyzed to understand the patients' symptoms, clinical profile, laboratory results, and safety of dietary changes in SGLT2i's. Thirteen case reports identifying 14 patients on a ketogenic diet and SGLT2i's diagnosed with EDKA were reviewed.
RESULTS: Of the 14 patients, 12 (85%) presented with type-2 diabetes mellitus (DM) and 2 (15%) presented with type-1 DM. The duration of treatment with SGLT2i before the onset of EDKA varies from 1 to 365 days. The duration of consuming a ketogenic diet or VLCD before EDKA onset varies from 1 to 90 days, with over 90% of patients hospitalized <4 weeks after starting the diet. At presentation, average blood glucose was 167.50±41.80 mg/dL, pH 7.10±0.10, HCO3 8.1±3.0 mmol/L, potassium 4.2±1.1 mEq/L, anion-gap 23.6±3.5 mmol/L, and the average hemoglobin A1c was 10%±2.4%. The length of hospital stay ranged from 1 to 15 days. None of the patients were reinitiated on SGLT2i's, and 50% (2/4) of the patients reported were on the ketogenic diet or VLCD upon patient questioning.
CONCLUSION: Despite the popularity of the ketogenic diet and VLCD for weight loss, their use in diabetics taking SGLT2i's is associated with EDKA. Physicians should educate patients with diabetes taking SGLT2i's about the risk of EDKA. In addition, patients should be encouraged to include their physicians in any decision related to significant changes in diet or exercise routines. Further research is needed to address if SGLT2i's should be permanently discontinued in patients with diabetes on SGLT2i and whether the ketogenic diet developed EDKA.

Keywords:  Carbohydrate-Restricted Diet; Diabetes Mellitus; Diabetic Ketoacidosis; Ketogenic Diet; Sodium-Glucose Transporter 2 Inhibitors

DOI:  https://doi.org/10.4082/kjfm.22.0003
Sci Transl Med. 2022 Nov 30. 14(673): eabn9061

Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.

Sisi Xie, Chenyu Jiang, Meng Wu, Ying Ye, Biying Wu, Xiaoting Sun, Xue Lv, Ruibo Chen, Wen Yu, Qi Sun, Yuting Wu, Rongliang Que, Huilan Li, Ling Yang, Wen Liu, Ji Zuo, Lasse D Jensen, Guichun Huang, Yihai Cao, Yunlong Yang.

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating β-hydroxybutyrate (β-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-β-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked β-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.

DOI: https://doi.org/10.1126/scitranslmed.abn9061
DNA Cell Biol. 2022 Nov 29.

Ketogenic Diet and Beta-Hydroxybutyrate in Colorectal Cancer.

Svetlana Khoziainova, Galina Rozenberg, Maayan Levy.

  Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the United States. Although certain genetic predispositions may contribute to one's risk for developing CRC, dietary and lifestyle factors may play an important role as well. In a recent study in Nature, Dmitrieva-Posocco et al, reveal a potential protective role of the ketogenic diet in colorectal cancer growth and progression. Administration of a ketogenic diet to CRC-bearing mice demonstrated a tumor-suppressive effect. Specifically, the ketone body β-hydroxybutyrate (BHB) exhibited the ability to suppress epithelial cell proliferation and inhibit tumor growth. BHB acts on cancer cells through regulation of homeodomain-only protein Hopx, known regulator of CRC. Furthermore, BHB requires a surface receptor Hcar to induce Hopx expression and suppress proliferation of intestinal epithelial cells. Taken together, these results describe a new therapeutic approach of using dietary intervention for the prevention and treatment of colorectal cancer.

Keywords:  BHB; colorectal cancer; ketogenic diet; metabolites

DOI:  https://doi.org/10.1089/dna.2022.0486
Front Nutr. 2022 ;9 1076667

Corrigendum: Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study.

Elisabetta Camajani, Alessandra Feraco, Stefania Proietti, Sabrina Basciani, Luigi Barrea, Andrea Armani, Mauro Lombardo, Lucio Gnessi, Massimiliano Caprio.

  [This corrects the article DOI: 10.3389/fnut.2022.955024.].

Keywords:  VLCKD; fat free mass; fat mass; physical activity; sarcopenia

DOI:  https://doi.org/10.3389/fnut.2022.1076667
Sci Rep. 2022 Nov 30. 12(1): 20686

Comparison of a pre-bariatric surgery very low-calorie ketogenic diet and the Mediterranean diet effects on weight loss, metabolic parameters, and liver size reduction.

Nihal Zekiye Erdem, Demet Ozelgun, Halit Eren Taskin, Fatih Mehmet Avsar.

This study compared the effects on weight as well as on metabolic parameters and liver size of a very low-calorie ketogenic diet versus a Mediterranean diet in patients with morbid obesity preparing to undergo bariatric surgery. This prospective comparison study evaluated patients 18-65 years of age who enrolled for bariatric surgery. Study duration was limited to an immediate preoperative period of 15 days. The very low-calorie ketogenic diet incorporated 10-12 kcal/kg/day of energy and 1-1.2 g/kg of protein using Kalibra (Societa Dietetica Medica) (VLCKD-SDM). The Mediterranean diet (MD) included 15-20% protein, 45-50% carbohydrate, and 25-35% fat. Changes in body mass index (BMI), liver size, and anthropometric and metabolic measurements were assessed. Between January 2016 and March 2017, of 45 patients enrolled, 30 completed the study (VLCKD-SDM, n = 15; MD, n = 15). Respective median BMI loss after VLCKD-SDM was 2.7 kg/m2 versus MD 1.4 kg/m2 (p < 0.05); median fat percentage reduction was 3.2 units versus 1.7 units (p < 0.05). Median liver size decreased 5.5% in the VLCKD-SDM group versus 1.7% in the MD group (p < 0.05). Median total cholesterol, and LDL levels decreased in both groups (p < 0.05), with greater relative decreases in the VLCKD-SDM group. Short-term preoperative diet-based weight loss in patients with morbid obesity preparing for bariatric surgery was significantly greater following a very low-calorie ketogenic diet versus a Mediterranean diet. The very low-calorie diet also significantly improved anthropometric and metabolic parameters and reduced preoperative liver size above that of the MD.

DOI: https://doi.org/10.1038/s41598-022-24959-z
Am J Physiol Endocrinol Metab. 2022 Nov 30.

Ketone monoester ingestion increases post-exercise serum erythropoietin concentrations in healthy men.

Eric Evans, Jean-Philippe Walhin, Aaron Hengist, James A Betts, David J Dearlove, Javier T Gonzalez.

  Intravenous ketone body infusion can increase erythropoietin (EPO) concentrations, but responses to ketone monoester ingestion post-exercise are currently unknown. The purpose of this study was to assess the effect of ketone monoester ingestion on post-exercise erythropoietin (EPO) concentrations. Nine healthy men completed two trials in a randomized, crossover design (one-week washout). During trials, participants performed a one-hour of cycling (initially alternating between 50% and 90% of maximal aerobic capacity for 2 min each interval, and then 50% and 80%, and 50% and 70% when the higher intensity was unsustainable). Participants ingested 0.8 g·kg-1 sucrose with 0.4 g·kg-1 protein immediately after exercise, and at 1, 2, and 3 hours post-exercise. During the control trial (CONTROL), no further nutrition was provided, whereas on the ketone monoester trial (KETONE), participants also ingested 0.29 g·kg-1 of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate immediately post-exercise and at 1 and 2 hours post-exercise. Blood was sampled immediately post-exercise, every 15 min in the first hour, and hourly thereafter for 4 hours. Serum EPO concentrations increased to a greater extent in KETONE than CONTROL (time x condition interaction: p = 0.046). Peak serum EPO concentrations were higher with KETONE (mean ± SD: 9.0 ± 2.3 IU·L-1) compared with CONTROL (7.5 ± 1.5 IU·L-1, p < 0.01). Serum beta-hydroxybutyrate concentrations were also higher, and glucose concentrations lower, with KETONE vs CONTROL (both p < 0.01). In conclusion, ketone monoester ingestion increases post-exercise erythropoietin concentrations, revealing a new avenue for orally ingestible ketone monoesters to potentially alter haemoglobin mass.

Keywords:  Erythropoeisis; Exercise; Ketones; Metabolism; Recovery

DOI:  https://doi.org/10.1152/ajpendo.00264.2022
Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01602-3. [Epub ahead of print]41(9): 111724

β-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α β-hydroxybutyrylation.

Hongchun Li, Xuemei Wan, Zhixiang Wu, Yuanyi Zhou, Rong Chen, Wei Xu, Jiamei Zhang, Zhen Yang, Lin Bai, Jie Zhang, Feng Qin, Liang Wang, Yaxing Chen, Linhong Jiang, Yuman He, Xiaojie Wang, Qingfan Wei, Shu Li, Yanping Dai, Yuanyuan Chen, Yonghai Wang, Hongbo Wang, Jingwei Tian, Yinglan Zhao, Xiaobo Cen.

  Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of β-hydroxybutyrate (β-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that β-OHB posttranslationally modifies CaMKII-α with β-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that β-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.

Keywords:  CP: Neuroscience; CaMKII-α; cocaine relapse; hippocampus; ketogenic diet; β-hydroxybutyrate; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.celrep.2022.111724
Front Nutr. 2022 ;9 1041026

Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice.

Brandon M Roberts, Sarah E Deemer, Daniel L Smith, James A Mobley, Nicolas Musi, Eric P Plaisance.

  Exogenous ketone ester supplementation provides a means to increase circulating ketone concentrations without the dietary challenges imposed by ketogenic diets. Our group has shown that oral R,S-1,3, butanediol diacetoacetate (BD-AcAc2) consumption results in body weight loss or maintenance with moderate increases in circulating ketones. We have previously shown a diet consisting of 25% BD-AcAc2 can maintain lean body mass (LBM) and induce fat mass (FM) loss in young, healthy male mice, but the underlying mechanisms are still unknown. Therefore, the purpose of this study was to determine if a diet consisting of 25% BD-AcAc2 (ketone ester, KE) would alter body composition, transcriptional regulation, the proteome, and the lipidome of skeletal muscle in aged mice. We hypothesized that the KE group would remain weight stable with improvements in body composition compared to controls, resulting in a healthy aging phenotype. Male C57BL/6J mice (n = 16) were purchased from Jackson Laboratories at 72 weeks of age. After 1 week of acclimation, mice were weighed and randomly assigned to one of two groups (n = 8 per group): control (CON) or KE. A significant group by time interaction was observed for body weight (P < 0.001), with KE fed mice weighing significantly less than CON. FM increased over time in the control group but was unchanged in the KE group. Furthermore, LBM was not different between CON and KE mice despite KE mice weighing less than CON mice. Transcriptional analysis of skeletal muscle identified 6 genes that were significantly higher and 21 genes that were significantly lower in the KE group compared to CON. Lipidomic analysis of skeletal muscle identified no differences between groups for any lipid species, except for fatty acyl chains in triacylglycerol which was 46% lower in the KE group. Proteomics analysis identified 44 proteins that were different between groups, of which 11 were lower and 33 were higher in the KE group compared to CON. In conclusion, 72-week-old male mice consuming the exogenous KE, BD-AcAc2, had lower age-related gains in body weight and FM compared to CON mice. Furthermore, transcriptional and proteomics data suggest a signature in skeletal muscle of KE-treated mice consistent with markers of improved skeletal muscle regeneration, improved electron transport chain utilization, and increased insulin sensitivity.

Keywords:  ketone ester; lipidomics; nutrition; proteomics; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fnut.2022.1041026
J Biol Chem. 2022 Oct 28. pii: S0021-9258(22)01091-2. [Epub ahead of print]298(12): 102648

Requirement of hepatic pyruvate carboxylase during fasting, high fat, and ketogenic diet.

Ebru S Selen, Susana Rodriguez, Kyle S Cavagnini, Han-Byeol Kim, Chan Hyun Na, Michael J Wolfgang.

  Pyruvate has two major fates upon entry into mitochondria, the oxidative decarboxylation to acetyl-CoA via the pyruvate decarboxylase complex or the biotin-dependent carboxylation to oxaloacetate via pyruvate carboxylase (Pcx). Here, we have generated mice with a liver-specific KO of pyruvate carboxylase (PcxL-/-) to understand the role of Pcx in hepatic mitochondrial metabolism under disparate physiological states. PcxL-/- mice exhibited a deficit in hepatic gluconeogenesis and enhanced ketogenesis as expected but were able to maintain systemic euglycemia following a 24 h fast. Feeding a high-fat diet to PcxL-/- mice resulted in animals that were resistant to glucose intolerance without affecting body weight. However, we found that PcxL-/- mice fed a ketogenic diet for 1 week became severely hypoglycemic, demonstrating a requirement for hepatic Pcx for long-term glycemia under carbohydrate-limited diets. Additionally, we determined that loss of Pcx was associated with an induction in the abundance of lysine-acetylated proteins in PcxL-/- mice regardless of physiologic state. Furthermore, liver acetyl-proteomics revealed a biased induction in mitochondrial lysine-acetylated proteins. These data show that Pcx is important for maintaining the proper balance of pyruvate metabolism between oxidative and anaplerotic pathways.

Keywords:  Pyruvate Carboxylase; acetylation; fasting; gluconeogenesis; mitochondria

DOI:  https://doi.org/10.1016/j.jbc.2022.102648
Andrology. 2022 Dec 02.

Very low-calorie ketogenic diet rapidly augments testosterone levels in non-diabetic obese subjects.

Angelo Cignarelli, Daniele Santi, Valentina Annamaria Genchi, Eleonora Conte, Fiorella Giordano, Simona Di Leo, Annalisa Natalicchio, Luigi Laviola, Francesco Giorgino, Sebastio Perrini.

   BACKGROUND: The very low-calorie ketogenic diet (VLCKD) represents an opportunity to attain clinically relevant weight loss in obese patients. Functional hypogonadism represents a frequent hormonal disorder associated with obesity and visceral fat accumulation characterized by low testosterone levels and subnormal LH levels.
AIM: To evaluate the early effects of VLCKD on serum total testosterone (TT) levels in non-diabetic obese patients.
METHODS: Twenty-two obese male patients (mean age 39.3 ± 11.7 years, mean BMI 38.2 ± 6.4 kg/m2 ) were enrolled and treated for 28 days with VLCKD. Anthropometric and hormonal variables were assessed before, during and after diet intervention.
RESULTS: After 7 and 28 days on a VLCKD, a significant and persistent reduction in body weight, BMI, fat mass, blood glucose, insulin, and HOMA index was observed compared with baseline. TT significantly increased after 7 days (+35 ± 64 ng/dl) and 28 days (+74 ± 97 ng/dl) on a VLCKD. In addition to TT, a significant increase in serum sex hormone-binding globulin (SHBG) levels was observed after 7 (+2.1 ± 4.1) and 28 days (+7.7 ± 10.0). However, both calculated free testosterone and LH did not change after 7 or 28 days of VLCKD. Following cessation of VLCKD, hypogonadal subjects achieved a higher percentage of total weight loss (8.5 ± 1.5%), a greater reduction in weight (-9.94 ± 1.66 kg), fat mass (-7 ± 2.1 kg), and waist circumference (-6.31 ± 2.65 cm), and a greater improvement in glycaemia (-8.75 ± 10.92 mg/dl) as compared with eugonadal subjects. Furthermore, hypogonadal subjects exhibited a trend of higher TT increase (+98.12 ± 71.51 ng/dl) as compared with eugonadal subjects.
CONCLUSIONS: VLCKD results in rapid improvements in TT levels associated with weight loss in male obese non-diabetic subjects, particularly in the presence of obesity-related hypogonadism. This article is protected by copyright. All rights reserved.

Keywords:  VLCKD; hypogonadism; obesity

DOI:  https://doi.org/10.1111/andr.13357
Diabetologia. 2022 Dec 01.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

Rafael C Gaspar, Kun Lyu, Brandon T Hubbard, Brooks P Leitner, Panu K Luukkonen, Sandro M Hirabara, Ikki Sakuma, Ali Nasiri, Dongyan Zhang, Mario Kahn, Gary W Cline, José Rodrigo Pauli, Rachel J Perry, Kitt F Petersen, Gerald I Shulman.

   AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content.
METHODS: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle.
RESULTS: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively.
CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.

Keywords:  Athlete’s paradox; Insulin resistance; PKCε; PKCθ; Physical exercise; Skeletal muscle

DOI:  https://doi.org/10.1007/s00125-022-05838-8
J Physiol. 2022 Nov 30.

What about hybrids? Supplemental methods for skeletal muscle fibre typing.

Omar B El-Kurd, Patrick Bialy, Maty Kirkes.



Keywords:  hybrid muscle fibre; myosin heavy chain; skeletal muscle fibre

DOI:  https://doi.org/10.1113/JP284038
Laeknabladid. 2022 Dec;108(12): 553-557

[Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?]

Astridur Palsdottir, Asbjorg Osk Snorradottir, Hakon Hakonarson.

  Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease caused by a mutation (L68Q) in the cystatin C gene, CST3. Mutant cystatin C protein accumulates as amyloid in arterioles in the brain leading to repeated brain hemorrhages and death of young carriers. Recently a possible treatment option was reported for HCCAA carriers involving an oral treatment with N-acetyl-cysteine in order to increase glutathione which was found to dissolve aggregates of mutant cystatin C. An earlier study described how the life span of carriers of the L68Q mutation shortened in the latter half of the 19th century. During the same decades a drastic change occured in the diet in Iceland. In the beginning of the century the diet was simple and low in carbohydrates, which mostly came from milk products. Import of grains and sugar was limited, but increased greatly according to import records. Due to lack of salt, food was preserved in acid whey, but gradually salt replaced whey as means of preserving food. This study aims to explore if changes in the diet of Icelanders during the same decades could possibly affect the amount of glutathione in people.

Keywords:  HCCAA; L68Q; amyloid; cystatin C; glutathione; n-acetylcystein

DOI:  https://doi.org/10.17992/lbl.2022.12.721
Neuroscience. 2022 Nov 23. pii: S0306-4522(22)00574-7. [Epub ahead of print]

Ketone Body β-Hydroxybutyric Acid Ameliorates Dopaminergic Neuron Injury Through Modulating Zinc Finger Protein 36/Acyl-CoA Synthetase Long-Chain Family Member Four Signaling Axis-Mediated Ferroptosis.

Xiaorong Yu, Yunpeng Yang, Bo Zhang, Guangyu Han, Junxing Yu, Qi Yu, Lei Zhang.

  β-hydroxybutyrate (BHB) is one of main component of ketone body, which plays an important protective role in various tissues and organs. Whereas, its exact regulatory roles and mechanisms in Parkinson's disease (PD) have not been full elucidated. In this study, SN4741 cells and C57BL/6 mice were treated with 1-methyl-4-phenylpyridinium ion (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish the PD model in vitro and in vivo. Cell viability and damage to dopaminergic neurons were measured by cell counting kit 8, Calcein-AM/PI staining, terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and hematoxylin & eosin staining. Corresponding assay kits and BODIPY 581/591 C11 probe evaluated oxidative stress and intracellular iron levels. Western blot examined the ferroptosis-related proteins. MPTP/MPP+-treatment reduced cell viability but triggered oxidative stress and ferroptosis in SNA4741 cells and brain tissues of mice. However, these effects were dramatically reversed by BHB and Fer-1 treatment. Mechanistically, Zinc finger protein 36 (ZFP36) was a target of BHB, and its depletion could reverse the anti-oxidative stress and anti-ferroptosis roles of BHB. Moreover, ZFP36 could directly bound to acyl-CoA synthetase long-chain family member 4 (ACSL4) mRNA to decay its expression, thus negatively modulating ACSL4-mediated oxidative stress and ferroptosis. Summary, BHB alleviated oxidative stress and ferroptosis of dopaminergic neurons in PD via modulating ZFP36/ACSL4 axis, which provided some new understanding for PD prevention and treatment.

Keywords:  ACSL4; Parkinson's disease; ZFP36; ferroptosis; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.neuroscience.2022.11.018
Biochem Pharmacol. 2022 Nov 23. pii: S0006-2952(22)00449-X. [Epub ahead of print] 115354

SIRT3 Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Activation of the NLRP3 Inflammasome via Autophagy.

Zhengzhu Sun, Chongfeng Fang, Shasha Xu, Bin Wang, Danlei Li, Xiaoman Liu, Yafei Mi, Hangyuan Guo, Jianjun Jiang.

  Doxorubicin (DOX) is a highly effective and extensively used chemotherapeutic drug but is limited by its cardiotoxicity. In our previous study, we showed that DOX-induced cardiotoxicity (DIC) triggers autophagy and pyroptosis. Sirtuin 3(SIRT3) is an NAD+-dependent deacetylase of the mitochondria that regulates autophagy. However, it is unknown if the protective effects of SIRT3 on DOX-induced cardiotoxicity involve the inhibition of NLRP3 inflammasome activation. In this study, we constructed in vivo and in vitro DIC models to investigate the effects and potential mechanisms of SIRT3 on DIC. We found that the overexpression of SIRT3 remarkably attenuated DIC through inhibition of the NLRP3 inflammasome. Moreover, we found that the overexpression of SIRT3 restored the dynamic balance of autophagosome/autolysosomes by targeting the mTOR/ULK1 signaling pathway. Application of the mTOR agonist MHY1485 further demonstrated that SIRT3 inhibited NLRP3 inflammasome activation by regulating autophagy. Collectively, the results suggest that SIRT3 effectively attenuates the cardiotoxicity of DOX and provides a theoretical foundation for further exploration of DIC.

Keywords:  Cardiotoxicity; Doxorubicin; NLRP3 Inflammasome; SIRT3; autophagy

DOI:  https://doi.org/10.1016/j.bcp.2022.115354
Front Cell Dev Biol. 2022 ;10 1049653

Nicotinamide riboside kinases regulate skeletal muscle fiber-type specification and are rate-limiting for metabolic adaptations during regeneration.

Tanja Sonntag, Sara Ancel, Sonia Karaz, Paulina Cichosz, Guillaume Jacot, Maria Pilar Giner, José Luis Sanchez-Garcia, Alice Pannérec, Sofia Moco, Vincenzo Sorrentino, Carles Cantó, Jérôme N Feige.

  Nicotinamide riboside kinases (NRKs) control the conversion of dietary Nicotinamide Riboside (NR) to NAD+, but little is known about their contribution to endogenous NAD+ turnover and muscle plasticity during skeletal muscle growth and remodeling. Using NRK1/2 double KO (NRKdKO) mice, we investigated the influence of NRKs on NAD+ metabolism and muscle homeostasis, and on the response to neurogenic muscle atrophy and regeneration following muscle injury. Muscles from NRKdKO animals have altered nicotinamide (NAM) salvage and a decrease in mitochondrial content. In single myonuclei RNAseq of skeletal muscle, NRK2 mRNA expression is restricted to type IIx muscle fibers, and perturbed NAD+ turnover and mitochondrial metabolism shifts the fiber type composition of NRKdKO muscle to fast glycolytic IIB fibers. NRKdKO does not influence muscle atrophy during denervation but alters muscle repair after myofiber injury. During regeneration, muscle stem cells (MuSCs) from NRKdKO animals hyper-proliferate but fail to differentiate. NRKdKO also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and extracellular matrix remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling. Altogether, we demonstrate that NAD+ synthesis controls mitochondrial metabolism and fiber type composition via NRK1/2 and is rate-limiting for myogenic commitment and mitochondrial maturation during skeletal muscle repair.

Keywords:  NAD+; NRK; fiber type; mitochondria; muscle regeneration; muscle stem cell (satellite cell); nicotinamide riboside; skeletal muscle

DOI:  https://doi.org/10.3389/fcell.2022.1049653
Cell Death Differ. 2022 Nov 29.

Mitochondria and cell death-associated inflammation.

Esmee Vringer, Stephen W G Tait.

Mitochondria have recently emerged as key drivers of inflammation associated with cell death. Many of the pro-inflammatory pathways activated during cell death occur upon mitochondrial outer membrane permeabilization (MOMP), the pivotal commitment point to cell death during mitochondrial apoptosis. Permeabilised mitochondria trigger inflammation, in part, through the release of mitochondrial-derived damage-associated molecular patterns (DAMPs). Caspases, while dispensable for cell death during mitochondrial apoptosis, inhibit activation of pro-inflammatory pathways after MOMP. Some of these mitochondrial-activated inflammatory pathways can be traced back to the bacterial ancestry of mitochondria. For instance, mtDNA and bacterial DNA are highly similar thereby activating similar cell autonomous immune signalling pathways. The bacterial origin of mitochondria suggests that inflammatory pathways found in cytosol-invading bacteria may be relevant to mitochondrial-driven inflammation after MOMP. In this review, we discuss how mitochondria can initiate inflammation during cell death highlighting parallels with bacterial activation of inflammation. Moreover, we discuss the roles of mitochondrial inflammation during cell death and how these processes may potentially be harnessed therapeutically, for instance to improve cancer treatment.

DOI: https://doi.org/10.1038/s41418-022-01094-w
Eur J Neurosci. 2022 Nov 28.

Effect of fasting on short-term visual plasticity in adult humans.

Silvia Animali, Cecilia Steinwurzel, Angela Dardano, Veronica Sancho-Bornez, Stefano Del Prato, Maria Concetta Morrone, Giuseppe Daniele, Paola Binda.

  Brain plasticity and function is impaired in conditions of metabolic dysregulation, such as obesity. Less is known on whether brain function is also affected by transient and physiological metabolic changes, such as the alternation between fasting and fed state. Here we asked whether these changes affect the transient shift of ocular dominance that follows short-term monocular deprivation, a form of homeostatic plasticity. We further asked whether variations in three of the main metabolic and hormonal pathways affected in obesity (glucose metabolism, leptin signaling and fatty acid metabolism) correlate with plasticity changes. We measured the effects of 2h monocular deprivation in three conditions: post-absorptive state (fasting), after ingestion of a standardized meal, and during infusion of glucagon-like peptide-1 (GLP-1), an incretin physiologically released upon meal ingestion that plays a key role in glucose metabolism. We found that short-term plasticity was less manifest in fasting than in fed state, while GLP-1 infusion did not elicit reliable changes compared to fasting. While we confirmed a positive association between plasticity and supraphysiological GLP-1 levels, achieved by GLP-1 infusion, we found that none of the parameters linked to glucose metabolism could predict the plasticity reduction in the fasting versus fed state. Instead, this was selectively associated with the increase in plasma Beta-Hydroxybutyrate (B-OH) levels during fasting, which suggests a link between neural function and energy substrates alternative to glucose. These results reveal a previously unexplored link between homeostatic brain plasticity and the physiological changes associated with the daily cycle of fasting and fed state.

Keywords:  binocular rivalry; glucose metabolism; ketone metabolism; ocular-dominance plasticity; psychophysics

DOI:  https://doi.org/10.1111/ejn.15873
Redox Biol. 2022 Nov 24. pii: S2213-2317(22)00326-3. [Epub ahead of print]58 102554

ChemR23 signaling ameliorates cognitive impairments in diabetic mice via dampening oxidative stress and NLRP3 inflammasome activation.

Jiawei Zhang, Lan Liu, Yaxuan Zhang, Yuan Yuan, Zhijuan Miao, Kaili Lu, Xiaojie Zhang, Ruiqing Ni, Haibing Zhang, Yuwu Zhao, Xiuzhe Wang.

  Diabetes mellitus is associated with cognitive impairment characterized by memory loss and cognitive inflexibility. Recent studies have revealed that ChemR23 is implicated in both diabetes mellitus and Alzheimer's disease. However, the impact of ChemR23 on diabetes-associated cognitive impairment remains elusive. In this study, we explored the longitudinal changes of ChemR23 expression and cognitive function in STZ-induced type 1 diabetic mice and leptin receptor knockout type 2 diabetic mice at different ages. We also treated diabetic mice with ChemR23 agonists RvE1 or chemerin-9 to explore whether ChemR23 activation could alleviate diabetes-associated cognitive impairment. The underlying mechanism was further investigated in diabetic mice with genetic deletion of ChemR23. The results showed that ChemR23 expression was decreased along with aging and the progression of diabetes, suggesting that abnormal ChemR23 signaling may be involved in diabetes-associated cognitive impairment. Administration of RvE1 or chemerin-9 ameliorated oxidative stress and inhibited NLRP3 inflammasome activation through Nrf2/TXNIP pathway, and ultimately alleviated cognitive impairment in diabetic mice. Depletion of ChemR23 in diabetic mice abolished the beneficial effects of RvE1 and chemerin-9, and exacerbated cognitive impairment via increasing oxidative stress and activating NLRP3 inflammasome. Collectively, our data highlight the crucial role of ChemR23 signaling in diabetes-associated cognitive impairment via regulating oxidative stress and NLRP3 inflammasome, and targeting ChemR23 may serve as a promising novel strategy for the treatment of diabetes-associated cognitive impairment.

Keywords:  ChemR23; Cognitive impairment; Diabetes mellitus; NLRP3 inflammasome; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2022.102554
Immun Inflamm Dis. 2022 Dec;10(12): e750

The role of the NLRP3 inflammasome in chronic inflammation in asthma and chronic obstructive pulmonary disease.

Yaxin Wu, Xin Di, Min Zhao, Haoran Li, Li Bai, Ke Wang.

  Asthma and chronic obstructive pulmonary disease (COPD) are lung diseases characterized by airflow limitation and chronic inflammation. More and more studies have shown that the occurrence and development of asthma and COPD are related to abnormal immune responses caused by dysregulation of many genetic and environmental factors. The exact pathogenesis of the disease is still unclear. A large number of studies have shown that the NLRP3 inflammasome is involved in the process of chronic airway inflammation in asthma and COPD. Here, we summarize recent advances in the mechanism of NLRP3 inflammasome activation and regulation and its role in the pathogenesis of inflammatory lung diseases such as asthma and COPD. Meanwhile we propose possible therapeutic targets in asthma and COPD.

Keywords:  COPD; NLRP3; asthma; chronic inflammation; inflammasome

DOI:  https://doi.org/10.1002/iid3.750
Oxid Med Cell Longev. 2022 ;2022 8803404

Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses.

Qing Yuan, Z L Zeng, Shiqi Yang, Anqi Li, Xuyu Zu, Jianghua Liu.

Energy intake and metabolic balance are the pillars of health preservation. Overnutrition causes nonspecific, persistently low inflammatory state known as metabolic inflammation. This condition contributes to the pathophysiology of various metabolic disorders, such as atherosclerosis, obesity, diabetes mellitus, and metabolic syndrome. The mitochondria maintain the balance of energy metabolism. Excessive energy stress can lead to mitochondrial dysfunction, which promotes metabolic inflammation. The inflammatory environment further impairs mitochondrial function. Accordingly, excellent organism design keeps the body metabolically healthy in the context of mitochondrial dysfunction, and moderate mitochondrial stress can have a beneficial effect. This review summarises the research progress on the multifaceted characterisation of mitochondrial dysfunction and its role in metabolic inflammation.

DOI: https://doi.org/10.1155/2022/8803404
Mol Cell Endocrinol. 2022 Nov 27. pii: S0303-7207(22)00272-6. [Epub ahead of print] 111824

Upregulation of TXNIP contributes to granulosa cell dysfunction in polycystic ovary syndrome via activation of the NLRP3 inflammasome.

Ying Wang, Jiyu Yang, Yu Wang, Yao Chen, Yiran Wang, Hongying Kuang, Xiaoling Feng.

  Polycystic ovary syndrome (PCOS) is a complex endocrine disease. Thioredoxin-interacting protein (TXNIP) promotes oxidative stress and triggers inflammation. Herein, we investigated the role and potential mechanism of TXNIP in PCOS. In a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS, we found that TXNIP was upregulated in the ovaries, especially in granulosa cells (GCs). TXNIP was also upregulated in testosterone (T)-treated GCs in vitro. Knockdown of TXNIP by lentivirus-constructed shRNA attenuated T-induced GC injury and oxidative stress, as well as inflammation and the NLRP3 inflammasome. The mechanism by which TXNIP promotes inflammation may involve TXNIP dissociation from the TXNIP-TRX complex and binding to NLRP3 to form the inflammasome. Additionally, we verified that knockdown of TXNIP ameliorated ovarian injury and inflammation in mice with DHEA-induced PCOS in vivo. Collectively, we demonstrated that TXNIP is involved in GC inflammation by promoting NLRP3 inflammasome activation in PCOS.

Keywords:  Granulosa cells; NLRP3 inflammasome; PCOS; TXNIP

DOI:  https://doi.org/10.1016/j.mce.2022.111824
J Neurol. 2022 Dec 03.

Toll-like receptors and NLRP3 inflammasome-dependent pathways in Parkinson's disease: mechanisms and therapeutic implications.

Luca Soraci, Maria Elsa Gambuzza, Leonardo Biscetti, Pasqualina Laganà, Carmela Lo Russo, Annamaria Buda, Giada Barresi, Andrea Corsonello, Fabrizia Lattanzio, Giuseppe Lorello, Gianfranco Filippelli, Silvia Marino.

  Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and damage to dopaminergic neurons. All these phenomena are mediated by the translocation of nuclear factor kappa-B (NF-κB) and enhanced by reactive oxygen species (ROS). To date, drugs to treat PD are mainly aimed at relieving clinical symptoms and there are no disease-modifying options to reverse or stop disease progression. This review outlines the role of the TLR/NLRP3/Cas-1 pathway in PD-related immune dysfunction, also focusing on specific therapeutic options that might be used since the early stages of the disease to counteract neuroinflammation and immune dysfunction.

Keywords:  Inflammation; Innate immunity; Parkinson’s disease; TLR/NLRP3/Caspase-1 pathway; Toll-like receptors; α-synuclein

DOI:  https://doi.org/10.1007/s00415-022-11491-3
Curr Gastroenterol Rep. 2022 Dec 03.

All Fiber is Not Fiber.

Shahrose Rahman, Kristin Trone, Caleb Kelly, Andrea Stroud, Robert Martindale.

   PURPOSE OF REVIEW: Epidemiologic studies and clinical trials have demonstrated the benefits of dietary fiber. This occurs through a combination of the physiochemical properties of fiber and through microbial fermentation that occurs in the colon which result in the production of short-chain fatty acids (SCFA). The purpose of this review is to highlight the physiochemical properties of fiber that result in the range of physiologic effects and to review the literature on the health benefits of acetate, propionate, and butyrate.
RECENT FINDINGS: Of the variety of properties and functions exerted by dietary fibers, the fermentability and production of SCFA's are emphasized in this review. Studies done in both animal and humans reveal the anti-obesity, anti-inflammatory, and possible anti-neoplastic roles SCFAs exert at the mucosal level. Many clinical questions remain regarding the optimal dose, type, and method of delivery of fiber to exert the desired beneficial effects. It has the potential to be used in the management of clinical symptoms, prevention of disease, and improvement in human health. Further studies to address this novel use of fiber has the potential to make a large impact in clinical practice.

Keywords:  Acetate; Butyrate; Constipation; Dietary fiber; Propionate; Short chain fatty acids

DOI:  https://doi.org/10.1007/s11894-022-00858-1
Mol Metab. 2022 Nov 28. pii: S2212-8778(22)00217-4. [Epub ahead of print] 101648

Low aerobic capacity in McArdle disease: a role for mitochondrial network impairment?

M Villarreal-Salazar, A Santalla, A Real-Martínez, G Nogales-Gadea, P L Valenzuela, C Fiuza-Luces, A L Andreu, J C Rodríguez-Aguilera, M A Martín, J Arenas, J Vissing, A Lucia, T O Krag, T Pinós.

   BACKGROUND: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation.
METHODS: We analyzed in depth mitochondrial characteristics--content, biogenesis, ultrastructure--and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N=145) and healthy controls (N=133).
RESULTS: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components--actin microfilaments, microtubules and intermediate filaments--thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin--with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected.
CONCLUSIONS: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.

Keywords:  McArdle disease; aerobic capacity; cytoskeleton and mitochondrial network; glycogen; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2022.101648
J Alzheimers Dis. 2022 Nov 22.

HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24.

Li-Tian Hu, Xiao-Yong Xie, Gui-Feng Zhou, Qi-Xin Wen, Li Song, Biao Luo, Xiao-Juan Deng, Qiu-Ling Pan, Guo-Jun Chen.

   BACKGROUND: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer's disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive.
OBJECTIVE: The present study was to investigate the role of HMGCS2 in Tau/p degradation.
METHODS: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy.
RESULTS: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau.
CONCLUSION: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Keywords:  ANKRD24; Alzheimer’s disease; HMGCS2; Tau; autophagy; ketone body

DOI:  https://doi.org/10.3233/JAD-220640
EMBO J. 2022 Nov 29. e111389

The lysosomal Ragulator complex activates NLRP3 inflammasome in vivo via HDAC6.

Kohei Tsujimoto, Tatsunori Jo, Daiki Nagira, Hachiro Konaka, Jeong Hoon Park, Shin-Ichiro Yoshimura, Akinori Ninomiya, Fuminori Sugihara, Takehiro Hirayama, Eri Itotagawa, Yusei Matsuzaki, Yuki Takaichi, Wataru Aoki, Shotaro Saita, Shuhei Nakamura, Andrea Ballabio, Shigeyuki Nada, Masato Okada, Hyota Takamatsu, Atsushi Kumanogoh.

  The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting in NLRP3 inflammasome activation. DL-all-rac-α-tocopherol, a synthetic form of vitamin E, inhibited the Lamtor1-HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. Further, DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. These results provide novel insights into the role of lysosomes in the activation of NLRP3 inflammasomes by the Ragulator complex.

Keywords:  HDAC6; NLRP3 inflammasome; Ragulator complex; α-tocopherol

DOI:  https://doi.org/10.15252/embj.2022111389
Sci Rep. 2022 Nov 27. 12(1): 20396

Effects of protein intake from an energy-restricted diet on the skeletal muscle composition of overweight and obese rats.

Ying Tian, Yuping Huan, Lihong Chen, Suwen Peng, Zhiyan He, Qian Wang.

Excess weight and obesity are often associated with ectopic adipose tissue accumulation in skeletal muscles. Intermuscular adipose tissue (IMAT) impairs muscle quality and reduces insulin-stimulated skeletal muscle glucose uptake. Although energy restriction and high protein intake can decrease IMAT, the effects and mechanisms of protein intake from an energy-restricted diet on protein and fat masses in skeletal muscle have received little attention. After establishing a diet-induced overweight and obese Sprague-Dawley rat model (half male and half female), rats were divided into five groups: normal control (NC; normal weight, general maintenance diet), model control (MC; overweight and obesity, high-fat diet), energy-restricted low protein (LP; overweight and obesity, 60% energy intake of NC, general maintenance diet), energy-restricted normal protein (NP; overweight and obesity, 60% energy intake of NC, high-protein diet 1), and energy-restricted high protein (HP; overweight and obesity, 60% energy intake of NC, high-protein diet 2). After 8 weeks, plasma and skeletal muscle (quadriceps femoris and gastrocnemius) samples were collected. Plasma levels of glucose, triglycerides, and hormones were analyzed, while contents of protein, fat, and factors associated with their synthesis and degradation were evaluated in skeletal muscles. Plasma concentrations of hormones contrasted protein and fat contents in skeletal muscles. Fat weights and contents of quadriceps femoris and gastrocnemius muscles in the NP group were significantly lower compared with LP and HP groups (P < 0.05). Moreover, concentrations of factors associated with the degradation of muscle fat were significantly higher in the NP group compared with LP and HP groups (P < 0.05). During energy restriction, protein intake equal to that of a normal protein diet increased lipolysis of quadriceps femoris and gastrocnemius muscles in rats of both sexes.

DOI: https://doi.org/10.1038/s41598-022-24961-5
Front Cardiovasc Med. 2022 ;9 1040649

Editorial: Clinical prospective of SGLT2 inhibitors in atherosclerosis.

Annalisa Capuano, Emilio Clementi, Giuseppe Paolisso.



Keywords:  SGLT2 inhibitors; acute myocardial infarction; atherosclerosis; cardiovascular diseases; heart failure; peripheral artery diseases

DOI:  https://doi.org/10.3389/fcvm.2022.1040649
BMC Anesthesiol. 2022 Dec 01. 22(1): 369

Aerobic exercise alleviates ventilator-induced lung injury by inhibiting NLRP3 inflammasome activation.

Mengjie Liu, Yaqiang Zhang, Jie Yan, Yuelan Wang.

   BACKGROUND: Ventilator-induced lung injury (VILI) is caused by stretch stimulation and other factors related to mechanical ventilation (MV). NOD-like receptor protein 3 (NLRP3), an important innate immune component, is strongly associated with VILI. This study aimed to investigate the effect and mechanisms of aerobic exercise (EX) on VILI.
METHODS: To test the effects of the PKC inhibitor bisindolylmaleimide I on PKC and NLRP3, male C57BL/6 mice (7 weeks old, 19 ~ 23 g) were randomly divided into four groups: control group(C), bisindolylmaleimide I-pretreated group(B), MV group, and bisindolylmaleimide I-pretreated + MV (B + MV) group. The mice were pretreated with bisindolylmaleimide I through intraperitoneal injection (0.02 mg/kg) 1 h before MV. MV was performed at a high tidal volume (30 ml/kg). To explore the ameliorative effect of EX on VILI, the mice were randomly divided into C group, MV group, EX group and EX + MV group and subjected to either MV or 5 weeks of EX training. After ventilation, haematoxylin-eosin (HE) staining and wet/dry weight ratio was used to assess lung pathophysiological changes. PKCɑ, P-PKCɑ, ASC, procaspase-1, caspase-1, pro-IL-1β, IL-1β, NLRP3 and occludin (tight junction protein) expression in lung tissues was determined by Western blotting. The level of IL-6 in alveolar lavage fluid was determined by ELISA.
RESULTS: NLRP3, P-PKCɑ, and PKCɑ levels were inceased in MV group, but bisindolylmaleimide I treatment reversed these changes. Inhibition of PKC production prevented NLRP3 activation. Moreover, MV increased ASC, procaspase-1, caspase-1, pro-IL-1β, and IL1β levels and decreased occludin levels, but EX alleviated these changes. HE staining and lung injury scoring confirmed an absence of obvious lung injury in C group and EX group. Lung injury was most severe in MV group but was improved in EX + MV group. Overall, these findings suggest that MV activates the NLRP3 inflammasome by activating PKCɑ and inducing occludin degradation, while Exercise attenuates NLRP3 inflammasome and PKCɑ activation. Besides, exercise improves cyclic stretch-induced degradation of occludin.
CONCLUSION: PKC activation can increase the level of NLRP3, which can lead to lung injury. Exercise can reduce lung injury by inhibiting PKCɑ and NLRP3 activation. Exercise maybe a potential measure for clinical prevention of VILI.

Keywords:  Aerobic exercise; NLRP3 inflammasome; Ventilator-induced lung injury

DOI:  https://doi.org/10.1186/s12871-022-01874-4
J Am Coll Cardiol. 2022 Dec 06. pii: S0735-1097(22)07044-9. [Epub ahead of print]80(23): 2220-2223

Targeting Mitochondrial Calcium Handling to Treat Atrial Fibrillation.

Niels Voigt, Christoph Maack, Julius Ryan D Pronto.



Keywords:  atrial arrhythmias; atrial fibrillation; calcium; diabetic cardiomyopathy; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.jacc.2022.09.043
J Cell Sci. 2022 Dec 01. pii: jcs259634. [Epub ahead of print]135(23):

Mitochondria-associated niches in health and disease.

Mateus Milani, Philippe Pihán, Claudio Hetz.

  The appreciation of the importance of interorganelle contacts has steadily increased over the past decades. Advances in imaging, molecular biology and bioinformatic techniques allowed the discovery of new mechanisms involved in the interaction and communication between organelles, providing novel insights into the inner works of a cell. In this Review, with the mitochondria under the spotlight, we discuss the most recent findings on the mechanisms mediating the communication between organelles, focusing on Ca2+ signaling, lipid exchange, cell death and stress responses. Notably, we introduce a new integrative perspective to signaling networks that is regulated by interorganelle interactions - the mitochondria-associated niches - focusing on the link between the molecular determinants of contact sites and their functional outputs, rather than simply physical and structural communication. In addition, we highlight the neuropathological and metabolic implications of alterations in mitochondria-associated niches and outline how this concept might improve our understanding of multi-organelle interactions.

Keywords:  Apoptosis; Bioenergetics; MAMs; Mitochondria; Mitochondria-associated membranes; Stress responses

DOI:  https://doi.org/10.1242/jcs.259634