bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–01–08
24 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation.
  2. Influence of anti-obesity strategies on brain function in health and review: A review.
  3. Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial.
  4. Possible role of ketone bodies in the generation of burst suppression electroencephalographic pattern.
  5. The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases.
  6. Ablation of NLRP3 inflammasome attenuates muscle atrophy via inhibiting pyroptosis, proteolysis and apoptosis following denervation.
  7. Chronic Kidney Disease-induced Muscle Atrophy: Molecular Mechanisms and Promising Therapies.
  8. Effect of D-β-hydroxybutyrate-(R)-1,3 butanediol on plasma levels of asprosin and leptin: results from a randomised controlled trial.
  9. Brain histone beta-hydroxybutyrylation couples metabolism with gene expression.
  10. NLRP3 inflammasome in traumatic brain injury: Its implication in the disease pathophysiology and potential as a therapeutic target.
  11. An experiment of nature links muscle glycogen unavailability with very high fat oxidation rates despite low aerobic fitness.
  12. Two weeks of high-intensity interval training increases skeletal muscle mitochondrial respiration via complex-specific remodeling in sedentary humans.
  13. Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model.
  14. Increased mitochondrial proton leak and glycolysis in peripheral blood mononuclear cells in type-1-diabetes.
  15. Cardiometabolic health improvements upon dietary intervention are driven by tissue-specific insulin resistance phenotype: A precision nutrition trial.
  16. Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.
  17. Excess lipids on endosomes dictates NLRP3 localization and inflammasome activation.
  18. β-Hydroxybutyric acid upregulated by Suhuang antitussive capsule ameliorates cough variant asthma through GSK3β/AMPK-Nrf2 signal axis.
  19. When aging gets on the way of disposal: Senescent cell suppression of efferocytosis.
  20. The molecular athlete: exercise physiology from mechanisms to medals.
  21. Timed feeding aligns the adipocyte clock to optimize thermogenesis when eating a high-fat diet.
  22. The role of low-carbohydrate diets in the intensive care unit.
  23. Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle.
  24. Low-Carbohydrate and High-Protein Diet Suppresses Working Memory Function in Healthy Mice.
  1. Front Med. 2023 Jan 05.
    Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation.
    Yanhong Xu, Xiaotong Ye, Yang Zhou, Xinyu Cao, Shiqiao Peng, Yue Peng, Xiaoying Zhang, Yili Sun, Haowen Jiang, Wenying Huang, Hongkai Lian, Jiajun Yang, Jia Li, Jianping Ye.
      Ketone bodies have beneficial metabolic activities, and the induction of plasma ketone bodies is a health promotion strategy. Dietary supplementation of sodium butyrate (SB) is an effective approach in the induction of plasma ketone bodies. However, the cellular and molecular mechanisms are unknown. In this study, SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a rate-limiting enzyme in ketogenesis, to promote ketone body production in hepatocytes. SB administrated by gavage or intraperitoneal injection significantly induced blood ß-hydroxybutyrate (BHB) in mice. BHB production was induced in the primary hepatocytes by SB. Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis. However, the alteration was mostly observed in mitochondrial proteins with 41% down- and 65% up-regulation, respectively. Succinylation status of HMGCS2 protein was altered by a reduction at two sites (K221 and K358) without a change in the protein level. The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice. The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver. The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis. The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.
    Keywords:  HMGCS2; SIRT5; ketogenesis; sodium butyrate; succinylation
    DOI:  https://doi.org/10.1007/s11684-022-0943-0
  2. Neurochem Int. 2022 Dec 30. pii: S0197-0186(22)00193-0. [Epub ahead of print]163 105468
    Influence of anti-obesity strategies on brain function in health and review: A review.
    Keila Rufatto de Souza, Nicole Alessandra Engel, Ana Beatriz Costa, Hevylin Jacintho Soares, Catarina Barbosa Chaves Bressan, Mariana Pacheco de Oliveira, Larissa Marques Dela Vedova, Larissa Espindola da Silva, Talita Farias Mendes, Mariella Reinol da Silva, Gislaine Tezza Rezin.
      The aim of this review was to investigate in the literature the application of strategies such as low carbohydrate diet (LCD), ketogenic diet (KD) and intermittent fasting (IF) and their effects on the CNS. We performed a narrative review of the literature. The search was specifically carried out in PubMed, selecting articles in English, which had the following keywords: obesity, central nervous system, low carb diet, ketogenic diet and intermittent fasting, using the narrative review methodology. The studies found show that the benefits of the LCD, KD and IF strategies, at the CNS level, have a strong influence on the mechanisms of hunger and satiety, as well as on the reduction of food reward and show improvement in memory and mood influenced by the interventions.
    Keywords:  Central nervous system; Intermittent fasting; Ketogenic diet; Low carb diet; Obesity
    DOI:  https://doi.org/10.1016/j.neuint.2022.105468
  3. Metabolism. 2022 Dec 30. pii: S0026-0495(22)00274-8. [Epub ahead of print] 155396
    Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial.
    Anna Veelen, Charlotte Andriessen, Yvo Op den Kamp, Edmundo Erazo-Tapia, Marlies de Ligt, Julian Mevenkamp, Johanna A Jörgensen, Esther Moonen-Kornips, Gert Schaart, Russell Esterline, Bas Havekes, Jan Oscarsson, Vera B Schrauwen-Hinderling, Esther Phielix, Patrick Schrauwen.
       AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also reduce the risk for progression of heart failure and chronic kidney disease in patients without diabetes.
    METHODS: Fourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m2; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day) or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate and insulin levels. Hepatic glycogen and lipid content/composition were measured by MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen and lipid content.
    RESULTS: Dapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher 24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic glycogen and lipid content were not significantly changed by dapagliflozin compared to placebo. However, muscle glycogen levels were numerically higher in the afternoon in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg), while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8, afternoon: 340.5 ± 24.3 nmol/mg).
    CONCLUSIONS/INTERPRETATION: Dapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction.
    TRIAL REGISTRATION: ClinicalTrials.gov NCT03721874.
    Keywords:  Energy metabolism; Glycogen; Human(s); Insulin resistance; Mitochondrial function; SGLT2 inhibitor
    DOI:  https://doi.org/10.1016/j.metabol.2022.155396
  4. Front Neurosci. 2022 ;16 1021035
    Possible role of ketone bodies in the generation of burst suppression electroencephalographic pattern.
    Dmitry Chegodaev, Vadim Gusev, Olga Lvova, Polina Pavlova.
      
    Keywords:  EEG; burst-suppression; ketone bodies; mechanism; metabolism
    DOI:  https://doi.org/10.3389/fnins.2022.1021035
  5. Front Cardiovasc Med. 2022 ;9 1059576
    The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases.
    Jiahao Zhao, Junli Li, Guoyong Li, Mao Chen.
      Reactive oxygen species (ROS) metabolism is essential for the homeostasis of cells. Appropriate production of ROS is an important signaling molecule, but excessive ROS production can damage cells. ROS and ROS-associated proteins can act as damage associated molecular pattern molecules (DAMPs) to activate the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in cardiovascular diseases. Previous studies have shown that there are connected sites, termed mitochondria-associated membranes (MAMs), between mitochondria and the endoplasmic reticulum. In cardiovascular disease progression, MAMs play multiple roles, the most important of which is the ability to mediate ROS generation, which further activates the NLPR3 inflammasome, exacerbating the progression of disease. In this review, the following topics will be covered: 1. Molecular structures on MAMs that can mediate ROS generation; 2. Specific mechanisms of molecule-mediated ROS generation and the molecules' roles in cardiovascular disease, 3. The effects of MAMs-mediated ROS on the NLRP3 inflammasome in cardiovascular disease. The purpose of this review is to provide a basis for subsequent clinical treatment development.
    Keywords:  NLRP3 inflammasome; atherosclerosis; mitochondria-associated membranes; myocardial hypertrophy; myocardial infarction; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcvm.2022.1059576
  6. Theranostics. 2023 ;13(1): 374-390
    Ablation of NLRP3 inflammasome attenuates muscle atrophy via inhibiting pyroptosis, proteolysis and apoptosis following denervation.
    Zongqi You, Xinying Huang, Yaoxian Xiang, Junxi Dai, Lei Xu, Junjian Jiang, Jianguang Xu.
      Rationale: The inflammasome has been widely reported to be involved in various myopathies, but little is known about its role in denervated muscle. Here, we explored the role of NLRP3 inflammasome activation in experimental models of denervation in vitro and in vivo. Methods: Employing muscular NLRP3 specific knock-out (NLRP3 cKO) mice, we evaluated the effects of the NLRP3 inflammasome on muscle atrophy in vivo in muscle-specific NLRP3 conditional knockout (cKO) mice subjected to sciatic nerve transection and in vitro in cells incubated with NLRP3 inflammasome activator (NIA). To evaluate the underlying mechanisms, samples were collected at different time points for RNA-sequencing (RNA-seq), and the interacting molecules were comprehensively analysed. Results : In the experimental model, NLRP3 inflammasome activation after denervation led to pyroptosis and upregulation of MuRF1 and Atrogin-1 expression, facilitating ubiquitin-proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knockout of NLRP3 in muscle inhibited pyroptosis-associated protein expression and significantly ameliorated muscle atrophy. Furthermore, cotreatment with shRNA-NLRP3 markedly attenuated NIA-induced C2C12 myotube pyroptosis and atrophy. Intriguingly, inhibition of NLRP3 inflammasome activation significantly suppressed apoptosis. Conclusions: These in vivo and in vitro findings demonstrate that during denervation, the NLRP3 inflammasome is activated and stimulates muscle atrophy via pyroptosis, proteolysis and apoptosis, suggesting that it may contribute to the pathogenesis of neuromuscular diseases.
    Keywords:  NLRP3 inflammasome; apoptosis; denervation; muscle atrophy; proteolysis; pyroptosis
    DOI:  https://doi.org/10.7150/thno.74831
  7. Biochem Pharmacol. 2022 Dec 31. pii: S0006-2952(22)00503-2. [Epub ahead of print] 115407
    Chronic Kidney Disease-induced Muscle Atrophy: Molecular Mechanisms and Promising Therapies.
    Kexin Wang, Qingyuan Liu, Mingyu Tang, Guangdong Qi, Chong Qiu, Yan Huang, Weiran Yu, Wei Wang, Hualin Sun, Xuejun Ni, Yuntian Shen, Xingxing Fang.
      Chronic kidney disease (CKD) is a high-risk chronic catabolic disease due to its high morbidity and mortality. CKD is accompanied by many complications, leading to a poor quality of life, and serious complications may even threaten the life of CKD patients. Muscle atrophy is a common complication of CKD. Muscle atrophy and sarcopenia in CKD patients have complex pathways that are related to multiple mechanisms and related factors. This review not only discusses the mechanisms by which inflammation, oxidative stress, mitochondrial dysfunction promote CKD-induced muscle atrophy but also explores other CKD-related complications, such as metabolic acidosis, vitamin D deficiency, anorexia, and excess angiotensin II, as well as other related factors that play a role in CKD muscle atrophy, such as insulin resistance, hormones, hemodialysis, uremic toxins, intestinal flora imbalance, and miRNA. We highlight potential treatments and drugs that can effectively treat CKD-induced muscle atrophy in terms of complication treatment, nutritional supplementation, physical exercise, and drug intervention, thereby helping to improve the prognosis and quality of life of CKD patients.
    Keywords:  chronic kidney disease; inflammation; molecular mechanisms; muscle atrophy; therapy
    DOI:  https://doi.org/10.1016/j.bcp.2022.115407
  8. Food Funct. 2023 Jan 03.
    Effect of D-β-hydroxybutyrate-(R)-1,3 butanediol on plasma levels of asprosin and leptin: results from a randomised controlled trial.
    Sanjali Charles, Yutong Liu, Wandia Kimita, Juyeon Ko, Sakina H Bharmal, Maxim S Petrov.
      Background: D-β-Hydroxybutyrate-(R)-1,3 butanediol - a non-racemic ketone monoester for ingestion - has emerged as an effective way to achieve acute nutritional ketosis. Whether white adipose tissue plays a role in effects of acute nutritional ketosis is largely unknown. Objective: To investigate the effects of acute nutritional ketosis on plasma levels of asprosin and leptin and if they are affected by abdominal fat phenotypes. Methods: The design was a randomised crossover trial. Participants received either the D-β-hydroxybutyrate-(R)-1,3 butanediol monoester (KEβHB) drink or placebo drink. Blood samples were collected at baseline, 30, 60, 90, 120, and 150 minutes. 3.0 Tesla magnetic resonance imaging was used to measure visceral and subcutaneous fat volumes (VFV and SFV, respectively), intra-hepatic fat deposition (IHFD), and intra-pancreatic fat deposition (IPFD). Results: A total of 18 adults were randomised, with no drop-outs. There were no significant differences in plasma levels of asprosin and leptin (p = 0.808 and p = 0.907, respectively) between the KEβHB and placebo drinks. There was no effect of time, treatment, or interaction between time and treatment on asprosin and leptin. After stratification by the VFV/SFV ratio, IHFD, and IPFD, there were no differences in asprosin and leptin between the KEβHB and placebo drinks. Conclusion: Plasma levels of asprosin and leptin were not significantly affected by acute nutritional ketosis. Abdominal fat phenotypes did not significantly affect circulating levels of the two hormones. White adipose tissue does not appear to play a role in altering hormone levels during acute nutritional ketosis. The clinical trial registry number is NCT03889210 (https://clinicaltrials.gov).
    DOI:  https://doi.org/10.1039/d2fo02405e
  9. Cell Mol Life Sci. 2023 Jan 06. 80(1): 28
    Brain histone beta-hydroxybutyrylation couples metabolism with gene expression.
    Sara Cornuti, Siwei Chen, Leonardo Lupori, Francesco Finamore, Fabrizia Carli, Muntaha Samad, Simona Fenizia, Matteo Caldarelli, Francesca Damiani, Francesco Raimondi, Raffaele Mazziotti, Christophe Magnan, Silvia Rocchiccioli, Amalia Gastaldelli, Pierre Baldi, Paola Tognini.
      Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 h fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms''. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgeber times both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-h fasting. Thus, our results suggest that fasting remarkably impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.
    Keywords:  Beta-hydroxybutyrylation; Cerebral cortex; Epigenome; Fasting; Transcriptome
    DOI:  https://doi.org/10.1007/s00018-022-04673-9
  10. Life Sci. 2022 Dec 30. pii: S0024-3205(22)01052-9. [Epub ahead of print] 121352
    NLRP3 inflammasome in traumatic brain injury: Its implication in the disease pathophysiology and potential as a therapeutic target.
    Rohan Chakraborty, Heena Tabassum, Suhel Parvez.
      Traumatic brain injury (TBI), an acquired brain injury imparted by a mechanical trauma to the head, has significant ramifications in terms of long-term disability and cost of healthcare. TBI is characterized by an initial phase of cell death owing to direct mechanical injury, followed by a secondary phase in which neuroinflammation plays a pivotal role. Activation of inflammasome complexes triggers a cascade that leads to activation of inflammatory mediators such as caspase-1, Interleukin (IL)-18, and IL-1β, eventually causing pyroptosis. NLRP3 inflammasome, a component of the innate immune response, has been implicated in a number of neurodegenerative diseases, including TBI. Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation and improve cognition and motor function in TBI. The NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. Although several therapeutic agents have shown promising results in pre-clinical studies, none of them have been effective in human trials for TBI, to date. Thus, it is imperative that such promising therapeutic candidates are evaluated in clinical trials to assess their efficacy in alleviating neurological impairments in TBI. This review offers an insight into the pathophysiology of TBI, with an emphasis on neuroinflammation in the aftermath of TBI. We highlight the NLRP3 inflammasome and explore its role in the neuroinflammatory cascade in TBI. We also shed light on its potential as a prospective biomarker and therapeutic target for TBI management.
    Keywords:  Caspase-1; Interleukins; NLRP3 inflammasome; Neuroinflammation; Nucleotide-binding oligomerization domain-like receptors; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.lfs.2022.121352
  11. J Physiol. 2023 Jan 04.
    An experiment of nature links muscle glycogen unavailability with very high fat oxidation rates despite low aerobic fitness.
    Joachim Nielsen.
      
    Keywords:  McArdle disease; exercise; fat metabolism; glycogen
    DOI:  https://doi.org/10.1113/JP284098
  12. J Appl Physiol (1985). 2023 Jan 05.
    Two weeks of high-intensity interval training increases skeletal muscle mitochondrial respiration via complex-specific remodeling in sedentary humans.
    Philip M Batterson, Erin M McGowan, Harrison D Stierwalt, Sarah E Ehrlicher, Sean A Newsom, Matthew M Robinson.
      Aerobic training remodels the quantity and quality (function per unit) of skeletal muscle mitochondria to promote substrate oxidation, however, there remain key gaps in understanding the underlying mechanisms during initial training adaptations. We used short-term high-intensity interval training (HIIT) to determine changes to mitochondrial respiration and regulatory pathways that occur early in remodeling. Fifteen normal-weight sedentary adults started seven sessions of HIIT over fourteen days and fourteen participants completed the intervention. We collected vastus lateralis biopsies before and 48-hours after HIIT to determine mitochondrial respiration, RNA sequencing, and western blotting for proteins of mitochondrial respiration and degradation via autophagy. HIIT increased respiration per mitochondrial protein for lipid (+23% P=0.020), complex I (+18%, P=0.0015), complex I+II (+14%, P<0.0001) and complex II (+24% P<0.0001). Transcripts that increased with HIIT identified several gene sets of mitochondrial respiration, particularly for complex I, while transcripts that decreased identified pathways of DNA and chromatin remodeling. HIIT lowered protein abundance of autophagy markers for p62 (-19%, P=0.012) and LC3 II/I (-20%, P=0.004) in whole-tissue lysates but not isolated mitochondria. Meal tolerance testing revealed HIIT increased the change in whole-body respiratory exchange ratio and lowered cumulative plasma insulin concentrations. Gene transcripts and respiratory function indicate remodeling of mitochondria within 2 weeks of HIIT. Overall changes are consistent with increased protein quality driving rapid improvements in substrate oxidation.
    Keywords:  HIIT; exercise; mitochondrial respiration; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00467.2022
  13. J Appl Physiol (1985). 2023 Jan 05.
    Effects of hydroxyurea on skeletal muscle energetics and force production in a sickle cell disease murine model.
    Constance P Michel, David Bendahan, Benoit Giannesini, Christophe Vilmen, Yann Le Fur, Laurent A Messonnier.
      Hydroxyurea (HU) is commonly used as a treatment for Sickle Cell Disease (SCD) patients in order to produce fetal hemoglobin beneficial to compensate anemia (reduced oxygen transport), to reduce abnormal Hb content, which alleviate clinical symptoms such as vaso-occlusives crisis and acute chest syndrome. The effects of HU on skeletal muscle bioenergetics in vivo are still unknown. Due to the beneficial effects of HU upon oxygen delivery, we hypothesized that skeletal muscle might be improved by HU. Muscle energetics and function were analyzed during a standardized rest-exercise-recovery protocol, using 31P-Magnetic resonance spectroscopy in Townes SCD mice. Measurements were performed in three groups of mice i.e. SCD2m (2-month-old, n = 8), SCD4m (4-month-old, n = 8) and SCD4m-HU (4-month-old mice which has been treated from 2 months of age with HU at 50 mg/kg/day, n = 8). The 4-month-old untreated mice (SCD4m) were heavier, developed a lower specific force, displayed lower acidosis and force-normalized PCr decrease during stimulation and demonstrated lower cost of contraction than SCD2m mice. Specific force production (from minute 1 to 5.25 of stimulation) was significantly higher in SCD4m-HU than in SCD4m mice whereas muscle energetics was unchanged. Overall, our results support a beneficial effect of HU on muscle function.
    Keywords:  Hydroxyurea; Sickle Cell Disease; Skeletal muscle bioenergertics; Skeletal muscle function; Spectroscopy
    DOI:  https://doi.org/10.1152/japplphysiol.00333.2022
  14. Heliyon. 2022 Dec;8(12): e12304
    Increased mitochondrial proton leak and glycolysis in peripheral blood mononuclear cells in type-1-diabetes.
    Joana Mendes Lopes de Melo, Jens Christian Laursen, Niels Søndergaard-Heinrich, Ida Kirstine Bull Rasmussen, Christian Stevns Hansen, Marie Frimodt-Møller, Peter Rossing, Joachim Størling.
      Changes in cellular bioenergetics such as mitochondrial respiration and glycolysis may play a role in the pathogenesis of various diseases including type 1 diabetes (T1D). We used Seahorse extracellular flux technology to analyse the efficiency of glycolysis and mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells (PBMCs) obtained from fresh blood samples from fifteen long-term T1D individuals with albuminuria (five females) with an average (±SD) age of 58 (±14) years and 15 age and sex-matched healthy non-diabetic controls. In T1D PBMCs, mitochondrial proton leak was higher (T1D: 21,3 ± 1,46 pmol/min; controls: 17,3 ± 1,24 pmol/min; p = 0,049) and glucose (5 mM) suppressed mitochondrial proton leak more than in healthy controls. Further, PBMCs from T1D individuals had higher glycolysis compared with healthy controls (T1D: 9,68 ± 0,94 mpH/min; controls: 7,07 ± 0,64 mpH/min; p = 0,032). Correlation analysis of circulating inflammatory factors identified Leukaemia Inhibitor factor 1 (LIF) being negatively correlated with PBMC glycolysis. Our results suggest that mitochondrial and glycolytic pathways of PBMCs from long-term T1D individuals with albuminuria might be dysfunctional, possibly due to increased cellular metabolic load and/or oxidative stress in which inflammatory factors could play a role.
    Keywords:  Cellular bioenergetics; Glycolysis; Mitochondrial oxidative phosphorylation; Mitochondrial proton leak; Peripheral blood mononuclear cells (PBMCs); Seahorse extracellular flux technology; Type 1 diabetes (T1D)
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e12304
  15. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00539-3. [Epub ahead of print]35(1): 71-83.e5
    Cardiometabolic health improvements upon dietary intervention are driven by tissue-specific insulin resistance phenotype: A precision nutrition trial.
    Inez Trouwborst, Anouk Gijbels, Kelly M Jardon, Els Siebelink, Gabby B Hul, Lisa Wanders, Balázs Erdos, Szabolcs Péter, Cécile M Singh-Povel, Johan de Vogel-van den Bosch, Michiel E Adriaens, Ilja C W Arts, Dick H J Thijssen, Edith J M Feskens, Gijs H Goossens, Lydia A Afman, Ellen E Blaak.
      Precision nutrition based on metabolic phenotype may increase the effectiveness of interventions. In this proof-of-concept study, we investigated the effect of modulating dietary macronutrient composition according to muscle insulin-resistant (MIR) or liver insulin-resistant (LIR) phenotypes on cardiometabolic health. Women and men with MIR or LIR (n = 242, body mass index [BMI] 25-40 kg/m2, 40-75 years) were randomized to phenotype diet (PhenoDiet) group A or B and followed a 12-week high-monounsaturated fatty acid (HMUFA) diet or low-fat, high-protein, and high-fiber diet (LFHP) (PhenoDiet group A, MIR/HMUFA and LIR/LFHP; PhenoDiet group B, MIR/LFHP and LIR/HMUFA). PhenoDiet group B showed no significant improvements in the primary outcome disposition index, but greater improvements in insulin sensitivity, glucose homeostasis, serum triacylglycerol, and C-reactive protein compared with PhenoDiet group A were observed. We demonstrate that modulating macronutrient composition within the dietary guidelines based on tissue-specific insulin resistance (IR) phenotype enhances cardiometabolic health improvements. Clinicaltrials.gov registration: NCT03708419, CCMO registration NL63768.068.17.
    Keywords:  cardiometabolic health; dietary intervention trial; glucose homeostasis; metabotyping; precision nutrition; tissue-specific insulin resistance
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.002
  16. Proc Natl Acad Sci U S A. 2023 Jan 10. 120(2): e2204750120
    Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics.
    Juliane Cruz Campos, Luiz Henrique Marchesi Bozi, Barbara Krum, Luiz Roberto Grassmann Bechara, Nikolas Dresch Ferreira, Gabriel Santos Arini, Rudá Prestes Albuquerque, Annika Traa, Takafumi Ogawa, Alexander M van der Bliek, Afshin Beheshti, Edward T Chouchani, Jeremy M Van Raamsdonk, T Keith Blackwell, Julio Cesar Batista Ferreira.
      Exercise is a nonpharmacological intervention that improves health during aging and a valuable tool in the diagnostics of aging-related diseases. In muscle, exercise transiently alters mitochondrial functionality and metabolism. Mitochondrial fission and fusion are critical effectors of mitochondrial plasticity, which allows a fine-tuned regulation of organelle connectiveness, size, and function. Here we have investigated the role of mitochondrial dynamics during exercise in the model organism Caenorhabditis elegans. We show that in body-wall muscle, a single exercise session induces a cycle of mitochondrial fragmentation followed by fusion after a recovery period, and that daily exercise sessions delay the mitochondrial fragmentation and physical fitness decline that occur with aging. Maintenance of proper mitochondrial dynamics is essential for physical fitness, its enhancement by exercise training, and exercise-induced remodeling of the proteome. Surprisingly, among the long-lived genotypes we analyzed (isp-1,nuo-6, daf-2, eat-2, and CA-AAK-2), constitutive activation of AMP-activated protein kinase (AMPK) uniquely preserves physical fitness during aging, a benefit that is abolished by impairment of mitochondrial fission or fusion. AMPK is also required for physical fitness to be enhanced by exercise, with our findings together suggesting that exercise may enhance muscle function through AMPK regulation of mitochondrial dynamics. Our results indicate that mitochondrial connectivity and the mitochondrial dynamics cycle are essential for maintaining physical fitness and exercise responsiveness during aging and suggest that AMPK activation may recapitulate some exercise benefits. Targeting mechanisms to optimize mitochondrial fission and fusion, as well as AMPK activation, may represent promising strategies for promoting muscle function during aging.
    Keywords:  C. elegans; aging; exercise; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1073/pnas.2204750120
  17. Nat Immunol. 2023 Jan;24(1): 3-4
    Excess lipids on endosomes dictates NLRP3 localization and inflammasome activation.
    Jonathan C Kagan.
      
    DOI:  https://doi.org/10.1038/s41590-022-01364-2
  18. J Ethnopharmacol. 2022 Dec 28. pii: S0378-8741(22)01052-2. [Epub ahead of print] 116013
    β-Hydroxybutyric acid upregulated by Suhuang antitussive capsule ameliorates cough variant asthma through GSK3β/AMPK-Nrf2 signal axis.
    Hong Jiang, Ziyu Bai, Yongyu Ou, Huiling Liu, Zilin Si, Yafang Liu, Xiaoqiong Liu, Xiaoqing Liu, Zhihao Zhang, Ninghua Tan.
       ETHNOPHARMACOLOGICAL RELEVANCE: Cough variant asthma (CVA) is a chronic inflammatory disease characterized by cough as the main symptom. Suhuang antitussive capsule (Suhuang), one of traditional Chinese patent medicines, mainly treats CVA clinically. Previous studies have shown that Suhuang significantly improved CVA, post-infectious cough (PIC), sputum obstruction and airway remodeling. However, the effect of Suhuang on ovalbumin-induced (OVA-induced) metabolic abnormalities in CVA is unknown.
    AIM OF THE STUDY: This study aimed to identify potential metabolites associated with efficacy of Suhuang in the treatment of CVA, and determined how Suhuang regulates metabolites, and differential metabolites reduce inflammation and oxidative stress.
    MATERIALS AND METHODS: Rats were given 1 mg OVA/100 mg aluminum hydroxide in the 1st and 7th days by intraperitoneal injection and challenged by atomizing inhalation of 1% OVA saline solution after two weeks to establish the CVA model. Rats were intragastrically (i.g.) administrated with Suhuang at 1.4 g/kg and β-hydroxybutyric acid (β-HB) were given with different concentrations (87.5 and 175 mg/kg/day) by intraperitoneal injection for 2 weeks. After 26 days, GC-MS-based metabolomic approach was applied to observe metabolic changes and search differential metabolites. The number of coughs, coughs latencies, enzyme-linked immunosorbent assay (ELISA), histological analysis and quantitative-polymerase chain reaction (Q-PCR) were used to investigate the effects of Suhuang. Then β-HB on CVA rats, NLRP3 inflammasome and GSK3β/AMPK/Nrf2 signalling pathway were detected by western blotting.
    RESULTS: The results showed that Suhuang treatment significantly enhanced the serum level of β-HB. Interestingly, exposure to exogenous β-HB was also protective against OVA-induced CVA. β-HB significantly reduced the number of coughs and lengthened coughs latencies, improved lung injury, reduced the secretion of various cytokines, and directly inhibited the NLRP3 inflammasome. In addition, β-HB increased the nuclear accumulation of Nrf2 by activating the GSK3β/AMPK signaling axis, and then inactivating the NF-κB signaling pathway, effectively protecting OVA-induced CVA from oxidative stress and inflammation.
    CONCLUSIONS: The results of this study shows that β-HB can reduce inflammation and oxidative stress, the increased production of β-HB in serum might be the crucial factor for Suhuang to exert its effect in the treatment of CVA.
    Keywords:  Compound C (PubChem CID: 11524144); Cough variant asthma; Dexamethasone (PubChem CID: 5743); GSK3β/AMPK/Nrf2; Lipopolysaccharide (PubChem CID: 11970143); Metabolomics; Ovalbumin (PubChem CID: 56832351); Pulmonary dysfunction; Sodium nitroprusside (PubChem CID: 11953895); Suhuang antitussive capsule; Trigonelline (PubChem CID: 5570); β-Hydroxybutyric acid; β-Hydroxybutyric acid (PubChem CID: 92135)
    DOI:  https://doi.org/10.1016/j.jep.2022.116013
  19. J Cell Biol. 2023 Feb 06. pii: e202212023. [Epub ahead of print]222(2):
    When aging gets on the way of disposal: Senescent cell suppression of efferocytosis.
    Carla V Rothlin, Sourav Ghosh.
      Chronic senescence can trigger pathological inflammation. In this issue, Schloesser et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202207097) demonstrate that senescent cells employ "don't eat me" signals that inhibit the ability of macrophages to engulf them and additionally prevent macrophages from removing neighboring corpses, revealing a new mechanism by which senescence may contribute to triggering inflammation.
    DOI:  https://doi.org/10.1083/jcb.202212023
  20. Physiol Rev. 2023 Jan 05.
    The molecular athlete: exercise physiology from mechanisms to medals.
    Regula Furrer, John A Hawley, Christoph Handschin.
      Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels of endurance and strength, to elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the signal integration, interpretation and output coordination of the cellular and molecular mechanisms that govern muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite athletes largely rely on a "trial and error" approach with the experience and practices of successful coaches and athletes often providing the bases for "post hoc" scientific enquiry and research. This review provides a synopsis of the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to endurance- and resistance-based training. These traits are placed in the context of innate genetic and inter-individual differences in exercise capacity and performance, with special considerations given to the ageing athletes. Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise, and how such adaptations translate from "molecules to medals".
    Keywords:  athlete; endurance training; exercise; resistance training; skeletal muscle
    DOI:  https://doi.org/10.1152/physrev.00017.2022
  21. Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00545-9. [Epub ahead of print]35(1): 7-9
    Timed feeding aligns the adipocyte clock to optimize thermogenesis when eating a high-fat diet.
    Paramita Pati, Jennifer S Pollock, Karen L Gamble.
      The timing of food intake is vital for metabolic health in obesity. A recent study in mice from Hepler et al. in Science shows the importance of the adipocyte circadian clock in metabolic health, highlighting the creatine pathway and thermogenesis with the alignment of the timing of high-fat feeding.
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.008
  22. Nutr Health. 2023 Jan 02. 2601060221149088
    The role of low-carbohydrate diets in the intensive care unit.
    Julia Hajjar, Claudia Dziegielewski, Sarah Dickson, Allison Simpson, Kwadwo Kyeremanteng.
      Low-carbohydrate, high-fat (LCHF) nutrition therapy is characterized by carbohydrates comprising <26% of the daily caloric intake and a higher proportion of fat. LCHF therapies reduce exogenous glucose load, improve glycemic control, decrease inflammation, and improve clinical outcomes such as respiratory function. Given the altered metabolism in critically ill patients, LCHF nutrition therapy may be especially beneficial as it enables the conservation of protein and glucose for metabolic roles beyond energy use. In critical illness, LCHF diets have the potential to reduce hyperglycemia, improve ventilation, decrease hospital length of stay and reduce hospital costs. The purpose of this commentary piece is to describe LCHF nutrition therapy, summarize its impact on health outcomes, and discuss its role in the intensive care unit (ICU). Additional research on the effects of LCHF nutrition therapy on critically ill patients is warranted, including a focus on COVID-19.
    Keywords:  critical illness; high-fat; inflammation; intensive care unit; low-carbohydrate
    DOI:  https://doi.org/10.1177/02601060221149088
  23. J Cachexia Sarcopenia Muscle. 2023 Jan 05.
    Mitochondria transplant therapy improves regeneration and restoration of injured skeletal muscle.
    Stephen E Alway, Hector G Paez, Christopher R Pitzer, Peter J Ferrandi, Mohammad Moshahid Khan, Junaith S Mohamed, James A Carson, Michael R Deschenes.
       BACKGROUND: Injection of exogenous mitochondria has been shown to improve the ischaemia-damaged myocardium, but the effect of mitochondrial transplant therapy (MTT) to restore skeletal muscle mass and function has not been tested following neuromuscular injury. Therefore, we tested the hypothesis that MTT would improve the restoration of muscle function after injury.
    METHODS: BaCl2 was injected into the gastrocnemius muscle of one limb of 8-12-week-old C57BL/6 mice to induce damage without injury to the resident stem cells. The contralateral gastrocnemius muscle was injected with phosphate-buffered saline (PBS) and served as the non-injured intra-animal control. Mitochondria were isolated from donor mice. Donor mitochondria were suspended in PBS or PBS without mitochondria (sham treatment) and injected into the tail vein of BaCl2 injured mice 24 h after the initial injury. Muscle repair was examined 7, 14 and 21 days after injury.
    RESULTS: MTT did not increase systemic inflammation in mice. Muscle mass 7 days following injury was 21.9 ± 2.1% and 17.4 ± 1.9% lower (P < 0.05) in injured as compared with non-injured intra-animal control muscles in phosphate-buffered saline (PBS)- and MTT-treated animals, respectively. Maximal plantar flexor muscle force was significantly lower in injured as compared with uninjured muscles of PBS-treated (-43.4 ± 4.2%, P < 0.05) and MTT-treated mice (-47.7 ± 7.3%, P < 0.05), but the reduction in force was not different between the experimental groups. The percentage of collagen and other non-contractile tissue in histological muscle cross sections, was significantly greater in injured muscles of PBS-treated mice (33.2 ± 0.2%) compared with MTT-treated mice (26.5 ± 0.2%) 7 days after injury. Muscle wet weight and maximal muscle force from injured MTT-treated mice had recovered to control levels by 14 days after the injury. However, muscle mass and force had not improved in PBS-treated animals by 14 days after injury. The non-contractile composition of the gastrocnemius muscle tissue cross sections was not different between control, repaired PBS-treated and repaired MTT-treated mice 14 days after injury. By 21 days following injury, PBS-treated mice had fully restored gastrocnemius muscle mass of the injured muscle to that of the uninjured muscle, although maximal plantar flexion force was still 19.4 ± 3.7% (P < 0.05) lower in injured/repaired gastrocnemius as compared with uninjured intra-animal control muscles.
    CONCLUSIONS: Our results suggest that systemic mitochondria delivery can enhance the rate of muscle regeneration and restoration of muscle function following injury.
    Keywords:  Mitochondria; Muscle fibre types; Muscle force; Muscle injury; Regeneration
    DOI:  https://doi.org/10.1002/jcsm.13153
  24. J Nutr Sci Vitaminol (Tokyo). 2022 ;68(6): 527-532
    Low-Carbohydrate and High-Protein Diet Suppresses Working Memory Function in Healthy Mice.
    Takeru Shima, Tomonori Yoshikawa, Hayate Onishi.
      Low-carbohydrate and high-protein (LC-HP) diets are acceptable for improving physiological and metabolic parameters. However, the effects of LC-HP diets on the brain are unclear, which depend on glycometabolism for neuronal activity. Since astrocyte-neuron lactate shuttle (ANLS) is an essential pathway for maintaining brain functions, we investigated the changes in hippocampal memory function. In addition, the alteration of lactate transporter constituting ANLS and ANLS-related neurotrophic factors by feeding LC-HP diets was evaluated in healthy mice. C57BL/6 mice were divided into two groups: a group feeding LC-HP diet (24.6% carbohydrate, 57.6% protein, and 17.8% fat as percentages of calories) and a group feeding control diet (58.6% carbohydrate, 24.2% protein, and 17.2% fat as percentages of calories). Here, we found that 4 wk of LC-HP diet feeding suppressed memory function in mice evaluated by Y-maze. Hippocampal mRNA levels of lactate transporters, such as Mct1, Mct4, and Mct2, were unchanged with feeding LC-HP diets; however, LC-HP diets significantly decreased Dcx and Igf-1 receptor mRNA levels in the hippocampus. Bdnf and its related signaling in mice hippocampus exhibited no change by LC-HP diets. Although there was non-influence in the lactate-transport system, LC-HP diets would suppress hippocampal working memory with dysregulation of neuroplasticity. The current data propose the importance of food choices for maintaining hippocampal health.
    Keywords:  carbohydrate; hippocampus; monocarboxylate transporter; neuroplasticity; protein
    DOI:  https://doi.org/10.3177/jnsv.68.527
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