bims-kimdis 2023-02-19 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–02–19
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

The effect of the ketogenic diet on Acne: Could it be a therapeutic tool?
Update on Measuring Ketones.
Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis.
Role of Ketogenic Diets in Multiple Sclerosis and Related Animal Models: An Updated Review.
On the interdependence of ketone body oxidation,glycogen content, glycolysis and energy metabolism in the heart.
Synergy between ketamine and ketogenic diet in anorexia nervosa, and other neurobehavioral disorders.
NLRP3 inflammasome activation, metabolic danger signals and protein binding partners.
Metabolomic, Proteomic, and Transcriptomic Changes in Adults with Epilepsy on Modified Atkins Diet.
Exercise suppresses NLRP3 inflammasome activation in mice with diet-induced NASH: a plausible role of adropin.
Probing protein-ketone body interaction to elucidate the function of putative ABC transporters.
Mitochondrial function in macrophages controls cardiac repair after myocardial infarction.
Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.
Branched chain amino acids alter cellular redox to induce lipid oxidation and reduce de novo lipogenesis in the liver.
Indirect regulation of HIPPO pathway by miRNA mediates high-intensity intermittent exercise to ameliorate aging skeletal muscle function.
Sustained activation of NLRP3 inflammasome contributes to delayed wound healing in aged mice.
Contribution of High-Intensity Interval Exercise in the Fasted State to Fat Browning: Potential Roles of Lactate and β-hydroxybutyrate.
Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.
Diallyl trisulfide inhibits monosodium urate-induced NLRP3 inflammasome activation via NOX3/4-dependent mitochondrial oxidative stress in RAW 264.7 and bone marrow-derived macrophages.
Bioengineering approaches to promote maturity in human skeletal muscle constructs.
Sodium-glucose cotransporter 2 inhibitors in obese patients with heart failure.
The role of the mechanistic target of rapamycin complex 1 in the regulation of mitochondrial adaptation during skeletal muscle atrophy under denervation or calorie restriction in mice.
Acute hypoxia attenuates resistance exercise-induced ribosome signaling but does not impact satellite cell pool expansion in human skeletal muscle.
Butyrate limits human natural killer cell effector function.
Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery.
Sodium butyrate inhibits high glucose-induced inflammation by controlling the acetylation of NF-κB p65 in human monocytes.

Crit Rev Food Sci Nutr. 2023 Feb 13. 1-20

The effect of the ketogenic diet on Acne: Could it be a therapeutic tool?

Luigi Barrea, Sara Cacciapuoti, Matteo Megna, Ludovica Verde, Claudio Marasca, Rosa Vono, Elisabetta Camajani, Annamaria Colao, Silvia Savastano, Gabriella Fabbrocini, Giovanna Muscogiuri.

  Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production, altered keratinization, inflammation, and bacterial colonization of the hair follicles of the face, neck, chest and back by Propionibacterium acnes. Overall, inflammation and immune responses are strongly implicated in the pathogenesis of acne. Although early colonization with Propionibacterium acnes and family history may play an important role in the disease, it remains unclear exactly what triggers acne and how treatment affects disease progression. The influence of diet on acne disease is a growing research topic, yet few studies have examined the effects of diet on the development and clinical severity of acne disease, and the results have often been contradictory. Interestingly, very low-calorie ketogenic diet (VLCKD) has been associated with both significant reductions in body weight and inflammatory status through the production of ketone bodies and thus it has been expected to reduce the exacerbation of clinical manifestations or even block the trigger of acne disease. Given the paucity of studies regarding the implementation of VLCKD in the management of acne, this review aims to provide evidence from the available scientific literature to support the speculative use of VLCKD in the treatment of acne.

Keywords:  Ketogenic diet; VLCKD; acne; diet; inflammation; microbiota; nutrition; obesity; oxidation; skin disease

DOI:  https://doi.org/10.1080/10408398.2023.2176813
J Diabetes Sci Technol. 2023 Feb 16. 19322968231152236

Update on Measuring Ketones.

Jingtong Huang, Andrea M Yeung, Richard M Bergenstal, Kristin Castorino, Eda Cengiz, Ketan Dhatariya, Isabella Niu, Jennifer L Sherr, Guillermo E Umpierrez, David C Klonoff.

  Ketone bodies are an energy substrate produced by the liver and used during states of low carbohydrate availability, such as fasting or prolonged exercise. High ketone concentrations can be present with insulin insufficiency and are a key finding in diabetic ketoacidosis (DKA). During states of insulin deficiency, lipolysis increases and a flood of circulating free fatty acids is converted in the liver into ketone bodies-mainly beta-hydroxybutyrate and acetoacetate. During DKA, beta-hydroxybutyrate is the predominant ketone in blood. As DKA resolves, beta-hydroxybutyrate is oxidized to acetoacetate, which is the predominant ketone in the urine. Because of this lag, a urine ketone test might be increasing even as DKA is resolving. Point-of-care tests are available for self-testing of blood ketones and urine ketones through measurement of beta-hydroxybutyrate and acetoacetate and are cleared by the US Food and Drug Administration (FDA). Acetone forms through spontaneous decarboxylation of acetoacetate and can be measured in exhaled breath, but currently no device is FDA-cleared for this purpose. Recently, technology has been announced for measuring beta-hydroxybutyrate in interstitial fluid. Measurement of ketones can be helpful to assess compliance with low carbohydrate diets; assessment of acidosis associated with alcohol use, in conjunction with SGLT2 inhibitors and immune checkpoint inhibitor therapy, both of which can increase the risk of DKA; and to identify DKA due to insulin deficiency. This article reviews the challenges and shortcomings of ketone testing in diabetes treatment and summarizes emerging trends in the measurement of ketones in the blood, urine, breath, and interstitial fluid.

Keywords:  SGLT2 inhibitors; continuous ketone monitor; diabetes; diabetic ketoacidosis; insulin; ketones

DOI:  https://doi.org/10.1177/19322968231152236
Adv Nutr. 2022 Sep;pii: S2161-8313(23)00034-0. [Epub ahead of print]13(5): 1697-1714

Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis.

Kaja Falkenhain, Ali Daraei, Scott C Forbes, Jonathan P Little.

  Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect of exogenous ketones. This study aimed to systematically review available evidence and conduct meta-analyses of studies reporting on exogenous ketones and blood glucose. We searched 6 electronic databases on 13 December 2021 for randomized and nonrandomized trials of any length that reported on the use of exogenous ketones. We calculated raw mean differences (MDs) in blood BHB and glucose in 2 main analyses: 1) after compared with before acute ingestion of exogenous ketones and 2) following acute ingestion of exogenous ketones compared with a comparator supplement. We pooled effect sizes using random-effects models and performed prespecified subgroup analyses to examine the effect of potential explanatory factors, including study population, exercise, blood BHB, and supplement type, dosing, and timing. Risk of bias was examined using Cochrane's risk-of-bias tools. Studies that could not be meta-analyzed were summarized narratively. Forty-three trials including 586 participants are summarized in this review. Following ingestion, exogenous ketones increased blood BHB (MD = 1.73 mM; 95% CI: 1.26, 2.21 mM; P < 0.001) and decreased mean blood glucose (MD = -0.54 mM; 95% CI: -0.68, -0.40 mM; P < 0.001). Similarly, when compared with placebo, blood BHB increased (MD = 1.98 mM; 95% CI: 1.52, 2.45 mM; P < 0.001) and blood glucose decreased (MD = -0.47 mM; 95% CI: -0.57, -0.36 mM; P < 0.001). Across both analyses, significantly greater effects were seen with ketone monoesters compared with salts (P < 0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.

Keywords:  blood glucose; exercise; glycemia; heart failure; ketosis; meta-analysis; prediabetes; systematic review; type 2 diabetes; β-hydroxybutyrate

DOI:  https://doi.org/10.1093/advances/nmac036
Adv Nutr. 2022 Sep;pii: S2161-8313(23)00053-4. [Epub ahead of print]13(5): 2002-2014

Role of Ketogenic Diets in Multiple Sclerosis and Related Animal Models: An Updated Review.

Wei-Sheng Lin, Shan-Ju Lin, Pei-Yin Liao, Divya Suresh, Ting-Rong Hsu, Pei-Yu Wang.

  Prescribing a ketogenic diet (KD) is a century-old dietary intervention mainly used in the context of intractable epilepsy. The classic KD and its variants regained popularity in recent decades, and they are considered potentially beneficial in a variety of neurological conditions other than epilepsy. Many patients with multiple sclerosis (MS) have attempted diet modification for better control of their disease, although evidence thus far remains insufficient to recommend a specific diet for these patients. The results of 3 pilot clinical trials of KD therapy for MS, as well as several related studies, have been reported in recent years. The preliminary findings suggest that KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with MS. Research on corresponding rodent models has also lent support to the efficacy of KD in the prevention and treatment of experimental autoimmune encephalomyelitis and toxin-induced inflammatory demyelinating conditions in the brain. Furthermore, the animal studies have yielded mechanistic insights into the molecular mechanisms of KD action in relevant situations, paving the way for precision nutrition. Herein we review and synthesize recent advances and also identify unresolved issues, such as the roles of adipokines and gut microbiota, in this field. Hopefully this panoramic view of current understanding can inform future research directions and clinical practice with regard to KD in MS and related conditions.

Keywords:  decanoic acid; demyelination; experimental autoimmune encephalomyelitis; ketogenic diet; multiple sclerosis; neuroinflammation; β-hydroxybutyrate

DOI:  https://doi.org/10.1093/advances/nmac065
J Physiol. 2023 Feb 17.

On the interdependence of ketone body oxidation,glycogen content, glycolysis and energy metabolism in the heart.

Azrul Abdul Kadir, Brianna J Stubbs, Cher-Rin Chong, Henry Lee, Mark Cole, Carolyn Carr, David Hauton, James McCullagh, Rhys D Evans, Kieran Clarke.

  In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-beta-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]-glucose and/or 4mM [14 C]-βHB to measure glycolytic rates or βHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reactions, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations were measured using 31 P-NMR spectroscopy. Rates of βHB oxidation in LG hearts were half that in HG hearts, with βHB oxidation directly proportional to glycogen content. βHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with βHB alone was twice that of hearts perfused with βHB and glucose, which had significantly higher levels of the glycolytic intermediates, fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. βHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total nicotinamide adenine dinucleotide phosphate (NADP/H) pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although βHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. βHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac βHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (D-β-hydroxybutyrate; acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Kreb's cycle intermediates; therefore their utilisation requires anaplerotic supplementation. Intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. We demonstrate here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate β-hydroxybutyrate oxidation in isolated perfused rat heart, and utilising a novel pulse-chase metabolic approach, quantify this contribution. Further, using metabolomics and 31 P-MR, we show that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise βHB, and βHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis. Abstract figure legend Overview of relationship of glycogen to ketone body oxidation and cardiac energetics in isolated perfused rat hearts. Myocardial glycogen was pre-labelled with tritium and its metabolic fate tracked using a pulse-chase technique. Increased glycolytic flux from glycogen facilitated increased exogenous β-hydroxybutyrate (βHB) oxidation through anaplerosis, and the increased βHB oxidation increased mitochondrial redox potential, and hence increased free energy of ATP hydrolysis. This article is protected by copyright. All rights reserved.

Keywords:  d-β-hydroxybutyrate oxidation; glycogen; glycolysis; metabolomics; redox states

DOI:  https://doi.org/10.1113/JP284270
Eat Weight Disord. 2023 Feb 14. 28(1): 8

Synergy between ketamine and ketogenic diet in anorexia nervosa, and other neurobehavioral disorders.

Barbara Scolnick, Caroline Beckwith.

Through serendipity, we observed an apparent synergy between adopting a ketogenic diet and receiving ketamine infusions that led to complete and durable remission in two patients with chronic enduring anorexia nervosa. Both patients had struggled with the disorder for over a decade. We offer a hypothesis, based on glutamate to explain this synergy, and hope it stimulates further research.

DOI: https://doi.org/10.1007/s40519-023-01528-5
J Endocrinol. 2023 Feb 01. pii: JOE-22-0184. [Epub ahead of print]

NLRP3 inflammasome activation, metabolic danger signals and protein binding partners.

Sy-Ying Leu, Yi-Ling Tsang, Li-Chun Ho, Ching-Chun Yang, Ai-Ning Shao, Chia-Yu Chang, Hui-Kuan Lin, Pei-Jane Tsai, Junne-Ming Sung, Yau-Sheng Tsai.

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich-repeat domain. Protein-protein interactions act as a "pedal or brake" to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via the protein-protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.

DOI: https://doi.org/10.1530/JOE-22-0184
Epilepsia. 2023 Feb 12.

Metabolomic, Proteomic, and Transcriptomic Changes in Adults with Epilepsy on Modified Atkins Diet.

Dominique F Leitner, Yik Siu, Aryeh Korman, Ziyan Lin, Evgeny Kanshin, Daniel Friedman, Sasha Devore, Beatrix Ueberheide, Aristotelis Tsirigos, Drew R Jones, Thomas Wisniewski, Orrin Devinsky.

   OBJECTIVE: High fat and low carbohydrate diets can reduce seizure frequency in some treatment-resistant epilepsy patients, including the more flexible Modified Atkins Diet (MAD) that is more palatable, mimicking fasting and inducing high ketone body levels. Low carbohydrate diets may shift brain energy production, particularly impacting neuron and astrocyte linked metabolism.
METHODS: We evaluated the effect of short-term MAD on molecular mechanisms in adult epilepsy patients from surgical brain tissue and plasma compared to Control participants consuming a non-modified higher carbohydrate diet (n = 6 MAD, mean age 43.7 years, range 21-53, diet average 10 days; n = 10 Control, mean age 41.9 years, range 28-64).
RESULTS: By metabolomics, there were 13 increased metabolites in plasma (n = 15 participants with available specimens) that included 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex (n = 16), and 11 decreased metabolites in hippocampus (n = 6) that had top associations with mitochondrial functions. Cortex and plasma 3-hydroxybutyric acid levels had a positive correlation (p = 0.0088, R2 = 0.48). Brain proteomics and RNAseq identified few differences, including 2.75-fold increased hippocampal MT-ND3 and trends (p < 0.01, FDR > 5%) in hippocampal NADH related signaling pathways (activated oxidative phosphorylation and inhibited sirtuin signaling).
SIGNIFICANCE: Short-term MAD was associated with metabolic differences in plasma and resected epilepsy brain tissue when compared to Control participants, in combination with trending expression changes observed in hippocampal NADH related signaling pathways. Future studies should evaluate how brain molecular mechanisms are altered with long-term MAD in a larger cohort of epilepsy patients, with correlations to seizure frequency, epilepsy syndrome, and other clinical variables.

Keywords:  metabolomics; proteomics; transcriptomics

DOI:  https://doi.org/10.1111/epi.17540
Lab Invest. 2021 Mar;pii: S0023-6837(22)00301-4. [Epub ahead of print]101(3): 369-380

Exercise suppresses NLRP3 inflammasome activation in mice with diet-induced NASH: a plausible role of adropin.

Wenqi Yang, Ling Liu, Yuan Wei, Chunlu Fang, Shujing Liu, Fu Zhou, Yaping Li, Ge Zhao, Ziyi Guo, Yuan Luo, Liangming Li.

NLRP3 inflammasome activation, which can be triggered by reactive oxygen species (ROS), contributes to nonalcoholic steatohepatitis (NASH) progression. Exercise is an effective therapeutic strategy for NASH. However, whether exercise prevents NLRP3 activation in NASH has not been investigated. Here, we investigated the effect of exercise on NLRP3 inflammasome in mice with high-fat diet (HFD)-induced or methionine and choine-deficient (MCD) diet-induced NASH and explored whether adropin, a metabolic peptide hormone shown to inhibit inflammation, mediates an exercise-induced benefit against NLRP3 inflammasome activation. Exercise alleviated diet-induced hepatic steatosis, inflammation, and fibrosis. Importantly, exercise significantly reduced the expression of NLRP3 inflammasome components, decreased Caspase-1 enzymatic activity, normalized IL-1β production, and suppressed ROS overproduction in HFD-fed and MCD diet-fed mice. The exercise-elicited NLRP3 inflammasome inhibition was accompanied by increased adropin levels. Moreover, serum adropin levels were negatively correlated with serum IL-1β levels. We further explored the effect of adropin on the NLRP3 inflammasome in palmitic acid (PA)-treated hepatocytes and Kupffer cells. Although adropin treatment did not significantly decrease the levels of all inflammasome components, it reduced the active Caspase-1 level, decreased Caspase-1 activity and downregulated IL-1β expression in hepatocytes and Kupffer cells (KCs) treated with PA. Moreover, ROS levels in PA-stimulated hepatocytes and Kupffer cells were reduced upon adropin treatment. In summary, we demonstrated that the inhibitory effect of exercise on NLRP3 inflammasome activation was associated with adropin induction, resulting in NASH improvement. This study shows that exercise increases adropin levels and inhibits NLRP3 inflammasome activation in mice with diet-induced nonalcoholic steatohepatitis (NASH). Furthermore, adropin suppresses palmitic acid-induced NLRP3 inflammasome activation in hepatocytes and Kupffer cells. These results indicate that exercise may inhibit NLRP3 inflammasome activation via adropin induction, resulting in NASH improvement.

DOI: https://doi.org/10.1038/s41374-020-00508-y
Biophys J. 2023 Feb 10. pii: S0006-3495(22)02811-9. [Epub ahead of print]122(3S1): 340a

Probing protein-ketone body interaction to elucidate the function of putative ABC transporters.

Bryant J Kane, Junko Okuda-Shimazaki, Koji Sode.

DOI: https://doi.org/10.1016/j.bpj.2022.11.1895
J Clin Invest. 2023 Feb 15. pii: e167079. [Epub ahead of print]133(4):

Mitochondrial function in macrophages controls cardiac repair after myocardial infarction.

David Weissman, Christoph Maack.

Cardiac healing following acute myocardial infarction (MI) involves the mobilization and activation of immune cells, including macrophages. In the early phase after MI, macrophages adopt a proinflammatory phenotype, while polarizing toward a reparative one in the late stage. Although metabolic reprogramming has been observed during this transition, the mechanistic links to macrophage differentiation are still poorly understood. In this issue of the JCI, Cai, Zhao and colleagues demonstrate that mitochondrial function in macrophages governed the resolution of inflammation and tissue repair by modulating the phagocytic removal of apoptotic cells (so-called efferocytosis) as well as myofibroblast activation. These findings provide important mechanistic insights into the potential relevance of metabolic modulation of macrophage functions following MI, which might lead to alternative therapeutic strategies for MI.

DOI: https://doi.org/10.1172/JCI167079
Lab Invest. 2022 09;pii: S0023-6837(22)00274-4. [Epub ahead of print]102(9): 979-988

Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.

Baoxiang Li, Limin Liu.

Abnormal Drp1 activation and subsequent excessive mitochondrial fission play a critical role in ischemia-reperfusion injury (I/RI). Although fibroblast growth factor 21 (FGF21) protects organs against I/RI and regulates metabolism, which indicates that FGF21 is involved in mitochondria homeostasis, the detailed mechanism remains unclear. Herein, we investigated whether FGF21 had an effect on Drp1 activation during skeletal muscle I/RI. Drp1 phosphorylation and its translocation to mitochondria, as regulated by FGF21, was examined in mouse and C2C12 cell I/RI models. Mice overexpressing FGF21 displayed alleviation of serum index, histological lesions and apoptosis levels. Moreover, FGF21 markedly decreased cyclin-dependent kinase 1 (CDK1) and Drp1 phosphorylation at Ser616, accompanied by reduced accumulation in mitochondria. In parallel in vitro studies, cells with FGF21 knockdown displayed enhanced Drp1 activation, and the reverse effect was found when FGF21 was added. More importantly, FGF21 attenuated mitochondrial fission with linear mitochondria rather than fragmented mitochondria. Furthermore, a CDK1 inhibitor reduced Drp1 activation and mitochondrial fission due to FGF21 knockdown. This study shows that FGF21 inhibits Drp1 activation to protect mitochondria from fission, thereby rescuing cells from I/RI-induced apoptosis. Our findings may provide a new therapeutic approach to ameliorate skeletal muscle I/RI.

DOI: https://doi.org/10.1038/s41374-022-00787-7
Am J Physiol Endocrinol Metab. 2023 Feb 15.

Branched chain amino acids alter cellular redox to induce lipid oxidation and reduce de novo lipogenesis in the liver.

Chaitra Surugihalli, Vaishna Muralidaran, Caitlin E Ryan, Kruti Patel, David Zhao, Nishanth E Sunny.

  Metabolic and molecular interactions between branched chain amino acid (BCAA) and lipid metabolism are evident in insulin resistant tissues. However, it remains unclear whether insulin resistance is a prerequisite for these relationships and whether BCAAs or their metabolic intermediates can modulate hepatic lipid oxidation and synthesis. We hypothesized that BCAAs can alter hepatic oxidative function and de novo lipogenesis, independent of them being anaplerotic substrates for the mitochondria. Mice (C57BL/6NJ) were reared on a low-fat (LF), LF diet plus 1.5X BCAAs (LB), high-fat (HF) or HF diet plus 1.5X BCAAs (HB) for 12-wks. Hepatic metabolism was profiled utilizing stable isotopes coupled to mass-spectrometry and nuclear magnetic resonance, together with fed-to-fasted changes in gene and protein expression. A greater induction of lipid oxidation and ketogenesis upon fasting was evident in the BCAA supplemented, insulin sensitive livers from LB mice, while their rates of hepatic de novo lipogenesis remained lower than their LF counterparts. Onset of insulin resistance in HF and HB mice livers blunted these responses. Whole-body turnover of BCAAs and their ketoacids, their serum concentrations, and the ketogenic flux from BCAA catabolism, all remained similar between fasted LF and LB mice. This suggested that the impact of BCAAs on lipid metabolism can occur independent of them or their degradation products fueling anaplerosis through the liver mitochondria. Further, the greater induction of lipid oxidation in the LB livers accompanied higher mitochondrial NADH/NAD+ ratio and higher fed-to-fasting phosphorylation of AMPKα and ACC. Taken together, our results provide evidence that BCAA supplementation, under conditions of insulin sensitivity, improved the feeding-to-fasting induction of hepatic lipid oxidation through changes in cellular redox, thus providing a favorable biochemical environment for flux through β-oxidation and lower de novo lipogenesis.

Keywords:  branched chain amino acids; fatty acid oxidation; lipogenesis; liver metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpendo.00307.2022
Scand J Med Sci Sports. 2023 Feb 15.

Indirect regulation of HIPPO pathway by miRNA mediates high-intensity intermittent exercise to ameliorate aging skeletal muscle function.

Pin-Shi Ni, Song Ma, Zhuang-Zhi Wang, He Jia-Han, Chen-Kai Zhang, Bo-Ming Li, Xiao-Ming Yu, Fang-Hui Li.

  Exercise-induced microRNA (miRNA) and HIPPO pathways participate in the regulation of skeletal muscle plasticity but their underlying mechanisms remain unclear. We aimed to investigate the effect of high-intensity interval training (HIIT) on miRNA expression and the HIPPO pathway in the skeletal muscle of aging rats to determine its role in the amelioration of muscle aging. Thirty-six 18-month-old female rats were randomly divided into sedentary control (SED, n=12), moderate-intensity continuous training (MICT, n=12), and HIIT (n=12) groups, with continuous exercise for eight months. Quantitative reverse transcription-polymerase chain reaction, immunoblotting, KEGG enrichment, and dual-luciferase assays were performed on the target skeletal muscle. Compared with the SED group, the MICT and HIIT groups showed a significant trend of improvement in Lee's index and grip strength and a marked increase in skeletal muscle mitochondrial function, apoptosis, antioxidant, and lipolysis-related protein expression. They also exhibited PI3K/AKT pathway activation and a decrease in expression of HIPPO pathway-related proteins; 20 miRNAs were differentially expressed and enriched in the exercise group compared with the SED group, including the HIPPO pathway and metabolic pathways. Further analysis of L6 cells confirmed that miR-182 may target PTEN, which indirectly regulates HIPPO signaling, but not Mob1. the combined application of HIIT and MICT increased the antioxidant and lipolytic capacities of skeletal muscle and improved atrophy of aging skeletal muscle; HIIT was more effective than MICT. This may be related to HIIT-mediated AKT pathway activation and HIPPO pathway inhibition by miRNAs (miR-486 and miR-182).

Keywords:  Aging; HIPPO pathway; High-Intensive Interval Training; MicroRNA; Quadriceps; Sarcopenia

DOI:  https://doi.org/10.1111/sms.14338
Int Immunopharmacol. 2023 Feb 10. pii: S1567-5769(23)00151-0. [Epub ahead of print]116 109828

Sustained activation of NLRP3 inflammasome contributes to delayed wound healing in aged mice.

Haiyun Li, Zhanqi Wang, Feng Zhou, Guorui Zhang, Xuan Feng, Yi Xiong, Yingying Wu.

  The cutaneous wounds in the elderly heal poorly, resulting in medical and economic burdens posed by defect repairing. Age-related delayed wound healing is associated with persistent inflammation and insufficient ECM deposition. The NLRP3 inflammasome has been proven to be a critical regulator of age-related inflammatory diseases, as well as impaired wound healing. Here, we create a 6 mm full-thickness cutaneous wound on the back of young and aged mice. Compared with young mice, aged counterparts display a retardation in wound healing, accompanied by increased activation of NLRP3 inflammasome. The application of the NLRP3 inhibitor (MCC950) ameliorates wound healing in aged mice. MCC950 inhibits sustained inflammation and reduces pyroptotic cell death in fibroblasts by blocking the abnormal activation of the NLRP3 inflammasome. Our findings illuminate that the NLRP3 inflammasome is a previously unrecognized regulator of aged wound healing and may be a potential target for the therapeutic strategy of delayed wound healing with aging.

Keywords:  Aging; Fibroblast; NLRP3 inflammasome; Wound healing

DOI:  https://doi.org/10.1016/j.intimp.2023.109828
Med Sci Sports Exerc. 2023 Feb 10.

Contribution of High-Intensity Interval Exercise in the Fasted State to Fat Browning: Potential Roles of Lactate and β-hydroxybutyrate.

Sujin Kim, Dong-Ho Park, Sang-Hyun Lee, Hyo-Bum Kwak, Ju-Hee Kang.

PURPOSE: Fat browning contributes to energy consumption and may have metabolic benefits against obesity; however the potential roles of lactate and β-hydroxybutyrate (β-HB) in fat browning remain unclear. We investigated the roles of a single bout of aerobic exercise that increases lactate and β-HB levels in the fasted state on the regulation of fat browning in rats and humans.
METHODS: Male Sprague Dawley rats were exposed to 24-hr fasting and/or a single bout moderate-intensity aerobic exercise (40 min); Sedentary (CON), Exercise (ND-EX), Fasting (FAST), and Exercise+Fasting (F-EX). Adult men (n = 13) were randomly assigned into control with food intake (CON), exercise with intensity at onset of blood lactate accumulation in the fasted state (F-OBLA), and high-intensity interval exercise in the fasted state (F-HIIE) until each participants expended 350 kcal of energy. For evaluating the effects of exercise intensity in rats, we conducted another set of animal experiment including groups of sedentary fed control, fasting control and exercise with moderate-intensity or high-intensity interval exercise for 40 min following 24-hr fasting.
RESULTS: Regardless of fasting, single bout of exercise increases the concentration of lactate and β-HB in rats, but the exercise in the fasted state increases the β-HB level more significantly in rats and humans. F-EX activated fat browning (AMPK/SirT1/PGC1α pathway and PRDM16) and thermogenic factor (UCP1) in white fat of rats. In rats and humans, exercise in the fasted state increased the blood levels of fat browning-related adipomyokines. In particular, compared to F-OBLA, F-HIIE more efficiently increases free fatty acid (FFA) as well as blood levels of fat browning adipomyokines in humans, which was correlated with blood levels of lactate and β-HB. In rats performed exercise with different intensity, the higher plasma lactate and β-HB levels, and higher expression of p-AMPK, UCP1 and PRDM16 in white adipose tissue of high-intensity interval exercise group than those of moderate intensity group were observed.
CONCLUSIONS: A single bout of aerobic exercise in the fasted state significantly induced fat browning-related pathways, FFA and adipomyokines, particularly F-HIIE in human. Although further evidences for supporting our results are required in humans, aerobic exercise in the fasted state with high intensity that increase lactate and β-HB may be a modality of fat browning.

DOI: https://doi.org/10.1249/MSS.0000000000003136
Biophys J. 2023 Feb 10. pii: S0006-3495(22)03005-3. [Epub ahead of print]122(3S1): 380a-381a

Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.

Michael W Rudokas, Marine Cacheux, Xiaohong Wu, Madelyn E Hummel, Lawrence H Young, Fadi G Akar.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2089
Phytomedicine. 2023 Feb 09. pii: S0944-7113(23)00053-3. [Epub ahead of print]112 154705

Diallyl trisulfide inhibits monosodium urate-induced NLRP3 inflammasome activation via NOX3/4-dependent mitochondrial oxidative stress in RAW 264.7 and bone marrow-derived macrophages.

Min Yeong Kim, EunJin Bang, Hyun Hwangbo, Seon Yeong Ji, Da Hye Kim, Hyesook Lee, Cheol Park, Su Hyun Hong, Gi-Young Kim, Yung Hyun Choi.

   BACKGROUND: Monosodium urate (MSU) crystals are associated with gouty inflammatory diseases. MSU-associated inflammation is majorly triggered by NOD-like receptor protein 3 (NLRP3) inflammasome that promotes interleukin (IL)-1β secretion. Although diallyl trisulfide (DATS) is well-known polysulfide garlic compounds with anti-inflammatory effects, its action in MSU-induced inflammasome activation has not been known yet.
PURPOSE: The objective of the current study was to investigate anti-inflammasome effects and mechanisms of DATS in RAW 264.7 and bone marrow-derived macrophages (BMDM).
METHODS: The concentrations of IL-1β were analyzed with enzyme-linked immunosorbent assay. The MSU-induced mitochondrial damage and reactive oxygen species (ROS) production were detected by fluorescence microscope and flow cytometry. The protein expressions of NLRP3 signaling molecules, NADPH oxidase (NOX) 3/4 were assessed with Western blotting.
RESULTS: DATS suppressed MSU-induced IL-1β and caspase-1 accompanied by decreased inflammasome complex formation in RAW 264.7 and BMDM. In addition, DATS restored mitochondrial damage. DATS downregulated NOX 3/4 that were upregulated by MSU as predicted by gene microarray and confirmed by Western blotting.
CONCLUSION: This study first reports mechanistic finding that DATS alleviates MSU-induced NLRP3 inflammasome by mediating NOX3/4-dependent mitochondrial ROS production in macrophages in vitro and ex vivo, suggesting DATS could be effective therapeutic candidate for gouty inflammatory condition.

Keywords:  Diallyl trisulfide (DATS); Mitochondria; Monosodium urate (MSU); NLRP3; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.phymed.2023.154705
Biophys J. 2023 Feb 10. pii: S0006-3495(22)03260-X. [Epub ahead of print]122(3S1): 433a-434a

Bioengineering approaches to promote maturity in human skeletal muscle constructs.

Benjamin R Tollitt, Samantha W Jones, Kai F Hoettges, James R Henstock, Gianluca Neri, Malcolm J Jackson, Anne McArdle.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2344
Cardiol J. 2023 Feb 15.

Sodium-glucose cotransporter 2 inhibitors in obese patients with heart failure.

Shingo Kato, Nobuyuki Horita, Daisuke Utsunomiya.

DOI: https://doi.org/10.5603/CJ.a2023.0004
Appl Physiol Nutr Metab. 2023 Feb 14.

The role of the mechanistic target of rapamycin complex 1 in the regulation of mitochondrial adaptation during skeletal muscle atrophy under denervation or calorie restriction in mice.

Kazuki Uemichi, Takanaga Shirai, Ryunosuke Matsuno, Tomohiro Iwata, Riku Tanimura, Tohru Takemasa.

  Mechanistic target of rapamycin complex 1 (mTORC1) is a protein complex that regulates skeletal muscle protein synthesis and hypertrophy. mTORC1-mediated signaling activities are activated during denervation-induced skeletal muscle atrophy and suppressed during calorie restriction-induced atrophy. Mitochondria control the qualitative plasticity of skeletal muscles primarily through biogenesis, fusion, and fission. We recently showed that mTORC1 activation contributes toward mitochondrial homeostasis. In this study, we examined the role of mTORC1 in mitochondrial adaptation during denervation- or calorie restriction-induced skeletal muscle atrophy. Seven-week-old Institute of Cancer Research mice were subjected to 14 days of denervation or calorie restriction combined with the administration of the mTORC1 inhibitor-"rapamycin". Our results showed that although mTORC1 inhibition did not alter mitochondrial biogenesis, content and enzyme activity, it suppressed the activation of dynamin-related protein 1 (DRP1), a mitochondrial fission-related protein in denervated muscle, and reduced DRP1 expression in calorie-restricted muscle. Furthermore, calorie restriction-induced mitochondrial fragmentation was partially suppressed by mTORC1 inhibition. Taken together, our results indicate that mTORC1 activation upon denervation and inhibition upon calorie restriction contributes to qualitative changes in muscle plasticity by at least partially regulating the mitochondrial fission response.

Keywords:  mTORC1; mitochondrial dynamics; skeletal muscle atrophy

DOI:  https://doi.org/10.1139/apnm-2022-0336
FASEB J. 2023 03;37(3): e22811

Acute hypoxia attenuates resistance exercise-induced ribosome signaling but does not impact satellite cell pool expansion in human skeletal muscle.

Oscar Horwath, Fabian Nordström, Ferdinand von Walden, William Apró, Marcus Moberg.

  Cumulative evidence supports the hypothesis that hypoxia acts as a regulator of muscle mass. However, the underlying molecular mechanisms remain incompletely understood, particularly in human muscle. Here we examined the effect of hypoxia on signaling pathways related to ribosome biogenesis and myogenic activity following an acute bout of resistance exercise. We also investigated whether hypoxia influenced the satellite cell response to resistance exercise. Employing a randomized, crossover design, eight men performed resistance exercise in normoxia (FiO2 21%) or normobaric hypoxia (FiO2 12%). Muscle biopsies were collected in a time-course manner (before, 0, 90, 180 min and 24 h after exercise) and were analyzed with respect to cell signaling, gene expression and satellite cell content using immunoblotting, RT-qPCR and immunofluorescence, respectively. In normoxia, resistance exercise increased the phosphorylation of RPS6, TIF-1A and UBF above resting levels. Hypoxia reduced the phosphorylation of these targets by ~37%, ~43% and ~ 67% throughout the recovery period, respectively (p < .05 vs. normoxia). Resistance exercise also increased 45 S pre-rRNA expression and mRNA expression of c-Myc, Pol I and TAF-1A above resting levels, but no differences were observed between conditions. Similarly, resistance exercise increased mRNA expression of myogenic regulatory factors throughout the recovery period and Pax7+ cells were elevated 24 h following exercise in mixed and type II muscle fibers, with no differences observed between normoxia and hypoxia. In conclusion, acute hypoxia attenuates ribosome signaling, but does not impact satellite cell pool expansion and myogenic gene expression following a bout of resistance exercise in human skeletal muscle.

Keywords:  Pax7; muscle fiber; myogenesis; resistance exercise; ribosome biogenesis

DOI:  https://doi.org/10.1096/fj.202202065RR
Sci Rep. 2023 Feb 15. 13(1): 2715

Butyrate limits human natural killer cell effector function.

Vanessa Zaiatz-Bittencourt, Fiona Jones, Miriam Tosetto, Caitriona Scaife, Gerard Cagney, Evan Jones, Glen A Doherty, Elizabeth J Ryan.

The gut microbiota regulates chronic inflammation and has been implicated in the pathogenesis of a broad spectrum of disease including autoimmunity and cancer. Microbial short-chain fatty acids (SCFAs) e.g., butyrate have demonstrated immunomodulatory effects and are thought to be key mediators of the host-microbiome interaction. Here, we investigated the effect of butyrate on effector functions of blood derived human NK cells stimulated for 18 h with a combination of IL-12/IL-15, a potent mix of cytokines that drive NK cell activation. We show that butyrate has a strong anti-inflammatory effect on NK cells. NK cells cultured in the presence of butyrate expressed lower levels of activating receptors (TRAIL, NKp30, NKp44) and produced lower levels of cytokines (IFNγ, TNF-α, IL-22, granzyme B, granzyme A, perforin) in response to IL-12/IL-15. Butyrate restricted NK cell function by downregulation of mTORC1 activity, c-Myc mRNA expression and metabolism. Using a shotgun proteomic approach, we confirmed the effect of butyrate on NK cell cytokine signaling and metabolism and identified BRD2, MAT2A and EHD1 as downstream mediators of these effects. This insight into the immunomodulatory activity of butyrate on human NK cell function might help to develop new ways to limit NK cell function during chronic inflammation.

DOI: https://doi.org/10.1038/s41598-023-29731-5
Biophys J. 2023 Feb 10. pii: S0006-3495(22)03497-X. [Epub ahead of print]122(3S1): 482a

Disease-associated mutations in Drp1 have fundamentally different effects on the mitochondrial fission machinery.

Brianna L Bauer, Kristy Rochon, Jasmine Liu, Rajesh Ramachandran, Jason A Mears.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2581
Nutr Res Pract. 2023 Feb;17(1): 164-173

Sodium butyrate inhibits high glucose-induced inflammation by controlling the acetylation of NF-κB p65 in human monocytes.

Ha-Rin Moon, Jung-Mi Yun.

   BACKGROUND/OBJECTIVES: Hyperglycemia is a major cause of diabetes and diabetes-related diseases. Sodium butyrate (NaB) is a short-chain fatty acid derivative that produces dietary fiber by anaerobic bacterial fermentation in the large intestine and occurs in foods, such as Parmesan cheese and butter. Butyrate has been shown to prevent obesity, improve insulin sensitivity, and ameliorate dyslipidemia in diet-induced obese mice. Therefore, this study examined the effects and mechanism of NaB on the secretion of inflammatory cytokines induced by high glucose (HG) in THP-1 cells.
MATERIALS/METHODS: THP-1 cells were used as an in vitro model for HG-induced inflammation. The cells were cultured under normal glycemic or hyperglycemic conditions with or without NaB (0-25 μM). Western blotting and quantitative polymerase chain reaction were used to evaluate the protein and mRNA levels of nuclear factor-κB (NF-κB), interleukin-6, tumor necrosis factor-α, acetylated p65, acetyl CREB-binding protein/p300 (CBP/p300), and p300 using THP-1 cells. Histone acetyltransferase (HAT), histone deacetylase (HDAC), and pro-inflammatory cytokine secretion activity were analyzed using an enzyme-linked immunosorbent assay.
RESULTS: HG significantly upregulated histone acetylation, acetylation levels of p300, NF-κB activation, and inflammatory cytokine release in THP-1 cells. Conversely, the NaB treatment reduced cytokine release and NF-κB activation in HG-treated cells. It also significantly reduced p65 acetylation, CBP/p300 HAT activity, and CBP/p300 gene expression. In addition, NaB decreased the interaction of p300 in acetylated NF-κB and TNF-α.
CONCLUSIONS: These results suggest that NaB suppresses HG-induced inflammatory cytokine production through HAT/HDAC regulation in monocytes. NaB has the potential for preventing and treating diabetes and its related complications.

Keywords:  Sodium butyrate; cytokines; high glucose; histone deacetylase; inflammation

DOI:  https://doi.org/10.4162/nrp.2023.17.1.164