bims-kimdis 2024-09-22 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–09–22
23 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.
Rationale and protocol for a safety, tolerability and feasibility randomized, parallel arm, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms.
Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.
Acute Changes in Liver Function Tests During Initiation of Ketogenic Diet.
Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".
Molecular Mechanisms of Healthy Aging: The Role of Caloric Restriction, Intermittent Fasting, Mediterranean Diet, and Ketogenic Diet-A Scoping Review.
Therapeutic ketogenic diet as treatment for anorexia nervosa.
The effect of ketogenic diet on adipokines levels: a systematic review and meta-analysis of randomized-controlled trials.
Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.
Nutrient analysis of three low-carbohydrate diets differing in carbohydrate content.
Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway.
Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age.
Health Effects and Mechanisms of Inulin Action in Human Metabolism.
Exercise as a modality to improve heart transplantation-related functional impairments: An article review.
Effect of ketone monoester supplementation on elite operators' mountaineering training.
Plasma levels of EPA and DHA after ingestion of a single dose of EPA and DHA ethyl esters.
Evaluating the efficacy of intermittent fasting and exercise combinations for weight loss: A network meta-analysis.
Optimal fasting duration for mice as assessed by metabolic status.
Understanding the role of the human gut microbiome in overweight and obesity.
Insulin Resistance, Obesity, and Lipotoxicity.
Anabolic deficits and divergent unfolded protein response underlie skeletal and cardiac muscle growth impairments in the Yoshida hepatoma tumor model of cancer cachexia.
Inflammasome activity regulation by PUFA metabolites.
Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis.

bioRxiv. 2024 Sep 02. pii: 2024.08.30.610511. [Epub ahead of print]

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.

Zachary Foulks, Carla J Weinheimer, Attila Kovacs, Jessica Michael, Kelly D Pyles, Thiago N Menezes, Kevin Cho, Gary J Patti, Kyle S McCommis.

Failing hearts increasingly metabolize ketone bodies, and enhancing ketosis improves heart failure (HF) remodeling. Circulating ketones are elevated by fasting/starvation, which is mimicked with a high-fat, low-carbohydrate "ketogenic diet" (KD). While speculated that KD improves HF through increased ketone oxidation, some evidence suggests KD paradoxically downregulates cardiac ketone oxidation despite increased ketone delivery. We sought to clarify the significance of cardiac ketone metabolism during KD in HF. Mice were subjected to transverse aortic constriction with apical myocardial infarction (TAC-MI) and fed either low-fat (LF) control or KD. Cardiac-specific mitochondrial pyruvate carrier 2 (csMPC2-/-) mice were used as a second model of heart failure. In both mice, feeding a KD improved HF, determined by echocardiography, heart weights, and gene expression analyses. Although KD increases plasma ketone bodies, gene expression for ketone metabolic genes is decreased in the hearts of KD-fed mice. Cardiac-specific β-hydroxybutyrate dehydrogenase 1 (csBDH1-/-), the first enzyme in ketone catabolism, mice were also studied and crossed with the csMPC2-/- mice to create double knockout (DKO) mice. These mice were aged to 16 weeks and switched to LF or KD, and KD was able to completely normalize the hearts of both csMPC2-/- and DKO mice, suggesting that ketone metabolism is unnecessary for improving heart failure with ketogenic diet. These studies were then repeated, and mice injected with U-13C-β-hydroxybutyrate to evaluate ketone metabolism. KD feeding significantly decreased the enrichment of the TCA cycle from ketone body carbons, as did the BDH1-deletion in DKO mice. Gene expression and respirometry suggests that KD instead increases cardiac fat oxidation. In conclusion, these results suggest that ketogenic diet decreases cardiac ketone metabolism and does not require ketone metabolism to improve heart failure.

DOI: https://doi.org/10.1101/2024.08.30.610511
PLoS One. 2024 ;19(9): e0307951

Rationale and protocol for a safety, tolerability and feasibility randomized, parallel arm, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms.

Brianna J Stubbs, Gabriela Alvarez Azañedo, Sawyer Peralta, Stephanie Roa Diaz, Wyatt Gray, Laura Alexander, Wendie Silverman-Martin, Thelma Y Garcia, Traci M Blonquist, Vaibhav Upadhyay, Peter J Turnbaugh, James B Johnson, John C Newman.

BACKGROUND: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that interventions which target common underlying mechanism of aging could ameliorate frailty. Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on inflammatory and metabolic aging pathways in laboratory animal models. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults.
OBJECTIVES: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a broad population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures.
METHODS: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n = 30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12.
CONCLUSION: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of aging-related endpoints. This data will inform design of larger trials to rigorously test KE effects on aging mechanisms and clinical outcomes relevant to frailty.

DOI: https://doi.org/10.1371/journal.pone.0307951
Nutrients. 2024 Sep 05. pii: 3007. [Epub ahead of print]16(17):

Effects of Different Exercises Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis.

Yongchao Xie, Yu Gu, Zhen Li, Bingchen He, Lei Zhang.

   BACKGROUND: Exercise and dietary interventions are essential for maintaining weight and reducing fat accumulation. With the growing popularity of various dietary strategies, evidence suggests that combining exercise with dietary interventions offers greater benefits than either approach alone. Consequently, this combined strategy has become a preferred method for many individuals aiming to maintain health. Calorie restriction, 5/2 intermittent fasting, time-restricted feeding, and the ketogenic diet are among the most popular dietary interventions today. Aerobic exercise, resistance training, and mixed exercise are the most widely practiced forms of physical activity. Exploring the best combinations of these approaches to determine which yields the most effective results is both meaningful and valuable. Despite this trend, a comparative analysis of the effects of different exercise and diet combinations is lacking. This study uses network meta-analysis to evaluate the impact of various combined interventions on body composition and to compare their efficacy.
METHODS: We systematically reviewed literature from database inception through May 2024, searching PubMed, Web of Science, Embase, and the Cochrane Library. The study was registered in PROSPERO under the title: "Effects of Exercise Combined with Different Dietary Interventions on Body Composition: A Systematic Review and Network Meta-Analysis" (identifier: CRD42024542184). Studies were meticulously selected based on specific inclusion and exclusion criteria (The included studies must be randomized controlled trials involving healthy adults aged 18 to 65 years. Articles were rigorously screened according to the specified inclusion and exclusion criteria.), and their risk of bias was assessed using the Cochrane risk of bias tool. Data were aggregated and analyzed using network meta-analysis, with intervention efficacy ranked by Surface Under the Cumulative Ranking (SUCRA) curves.
RESULTS: The network meta-analysis included 78 randomized controlled trials with 5219 participants, comparing the effects of four combined interventions: exercise with calorie restriction (CR+EX), exercise with time-restricted eating (TRF+EX), exercise with 5/2 intermittent fasting (5/2F+EX), and exercise with a ketogenic diet (KD+EX) on body composition. Intervention efficacy ranking was as follows: (1) Weight Reduction: CR+EX > KD+EX > TRF+EX > 5/2F+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.94 (-3.64, 9.52); 2.37 (-0.40, 5.15); 1.80 (-1.75, 5.34)). (2) BMI: CR+EX > KD+EX > 5/2F+EX > TRF+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 1.95 (-0.49, 4.39); 2.20 (1.08, 3.32); 1.23 (-0.26, 2.71)). (3) Body Fat Percentage: CR+EX > 5/2F+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of 5/2F+EX, TRF+EX and KD+EX are 2.66 (-1.56, 6.89); 2.84 (0.56, 5.13); 3.14 (0.52, 5.75).). (4) Lean Body Mass in Male: CR+EX > TRF+EX > KD+EX (Relative to CR+EX, the effect sizes of TRF+EX and KD+EX are -1.60 (-6.98, 3.78); -2.76 (-7.93, 2.40)). (5) Lean Body Mass in Female: TRF+EX > CR+EX > 5/2F+EX > KD+EX (Relative to TRF+EX, the effect sizes of CR+EX, 5/2F+EX and KD+EX are -0.52 (-2.58, 1.55); -1.83 (-4.71, 1.04); -2.46 (-5.69,0.76).).
CONCLUSION: Calorie restriction combined with exercise emerged as the most effective strategy for reducing weight and fat percentage while maintaining lean body mass. For women, combining exercise with time-restricted eating proved optimal for preserving muscle mass. While combining exercise with a ketogenic diet effectively reduces weight, it is comparatively less effective at decreasing fat percentage and preserving lean body mass. Hence, the ketogenic diet combined with exercise is considered suboptimal.

Keywords:  BMI; aerobic exercise; body fat percentage; caloric restriction; intermittent fasting; ketogenic diet; lean body mass; resistance exercise; weight

DOI:  https://doi.org/10.3390/nu16173007
J Child Neurol. 2024 Sep 16. 8830738241272063

Acute Changes in Liver Function Tests During Initiation of Ketogenic Diet.

Akshat Katyayan, Anuranjita Nayak, Gloria Diaz-Medina, Maureen Handoko, James John Riviello.

   BACKGROUND: Ketogenic diet is an effective therapy for patients with medically refractory epilepsy. It is generally well tolerated, with the most common side effects being gastrointestinal. Hepatic toxicity has been described as an uncommon side effect of ketogenic diet, usually with long-term use. However, there are limited data to implicate ketogenic diet in acute liver toxicity.
METHODS AND RESULTS: We analyzed all patients who underwent elective inpatient ketogenic diet initiation at our institution from June 2019 to June 2022. Of the 25 patients reviewed, we found 6 patients who showed acute, asymptomatic changes in liver function tests during initiation, in both hepatocellular and cholestatic patterns. Two patients stopped the ketogenic diet acutely and 3 patients continued ketogenic diet with changes in medications and/or addition of choline-all patients had improvement and normalization of liver function tests in the short term. One patient had acute normalization of chronically elevated liver function tests on ketogenic diet initiation.
CONCLUSION: Ketogenic diet can cause acute changes in liver function tests during initiation of ketogenic diet, with both hepatocellular and cholestatic patterns, with and without the concurrent use of hepatotoxic medications. In most patients, ketogenic diet can be continued successfully by making changes to medications or addition of choline.

Keywords:  epilepsy; hepatotoxicity; ketogenic diet; liver function tests

DOI:  https://doi.org/10.1177/08830738241272063
Crit Rev Biochem Mol Biol. 2024 Sep 17. 1-23

Exercise training and changes in skeletal muscle mitochondrial proteins: from blots to "omics".

Elizabeth G Reisman, Nikeisha J Caruana, David J Bishop.

  Mitochondria are essential, membrane-enclosed organelles that consist of ∼1100 different proteins, which allow for many diverse functions critical to maintaining metabolism. Highly metabolic tissues, such as skeletal muscle, have a high mitochondrial content that increases with exercise training. The classic western blot technique has revealed training-induced increases in the relatively small number of individual mitochondrial proteins studied (∼5% of the >1100 proteins in MitoCarta), with some of these changes dependent on the training stimulus. Proteomic approaches have identified hundreds of additional mitochondrial proteins that respond to exercise training. There is, however, surprisingly little crossover in the mitochondrial proteins identified in the published human training studies. This suggests that to better understand the link between training-induced changes in mitochondrial proteins and metabolism, future studies need to move beyond maximizing protein detection to adopting methods that will increase the reliability of the changes in protein abundance observed.

Keywords:  Mitochondria; fiber type; proteins; proteomics; skeletal muscle; training

DOI:  https://doi.org/10.1080/10409238.2024.2383408
Nutrients. 2024 Aug 28. pii: 2878. [Epub ahead of print]16(17):

Molecular Mechanisms of Healthy Aging: The Role of Caloric Restriction, Intermittent Fasting, Mediterranean Diet, and Ketogenic Diet-A Scoping Review.

Roxana Surugiu, Mihaela Adela Iancu, Ștefănița Bianca Vintilescu, Mioara Desdemona Stepan, Daiana Burdusel, Amelia Valentina Genunche-Dumitrescu, Carmen-Adriana Dogaru, Gheorghe Gindrovel Dumitra.

  As the population ages, promoting healthy aging through targeted interventions becomes increasingly crucial. Growing evidence suggests that dietary interventions can significantly impact this process by modulating fundamental molecular pathways. This review focuses on the potential of targeted dietary strategies in promoting healthy aging and the mechanisms by which specific nutrients and dietary patterns influence key pathways involved in cellular repair, inflammation, and metabolic regulation. Caloric restriction, intermittent fasting, the Mediterranean diet, as well as the ketogenic diet showed promising effects on promoting healthy aging, possibly by modulating mTORC1 AMPK, an insulin signaling pathway. By understanding the intricate interplay between diet and molecular pathways, we can develop personalized dietary strategies that not only prevent age-related diseases, but also promote overall health and well-being throughout the aging process.

Keywords:  caloric restriction; dietary interventions; healthy aging; intermittent fasting; ketogenic diet; longevity; mediterranean diet

DOI:  https://doi.org/10.3390/nu16172878
Front Nutr. 2024 ;11 1392135

Therapeutic ketogenic diet as treatment for anorexia nervosa.

Guido K W Frank, Barbara Scolnick.

  Anorexia nervosa (AN) is a severe psychiatric disorder. However, we lack neurobiological models and interventions to explain and treat the core characteristics of food restriction, feeling fat, and body size overestimation. Research has made progress in understanding brain function involved in the pathophysiology of AN, but translating those results into biological therapies has been challenging. Studies have suggested that metabolic factors could contribute to developing and maintaining AN pathophysiology. Here, we describe a neurobiological model for why using a therapeutic ketogenic diet could address key alterations in brain function in AN and prevent the desire for weight loss and associated eating disorder-specific symptoms. This translational model is based on animal studies and human data and integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function. Pilot data indicate that the intervention can dramatically reduce eating and body-related fears, although larger studies across illness stages still need to be conducted.

Keywords:  anorexia nervosa; behavior; brain; ketogenic; metabolism; treatment

DOI:  https://doi.org/10.3389/fnut.2024.1392135
Acta Diabetol. 2024 Sep 20.

The effect of ketogenic diet on adipokines levels: a systematic review and meta-analysis of randomized-controlled trials.

Gui Lian Xiao, Tao Wang, Jiong Kuang, Wen Li Mai, Hua Liu, Shi Ping Ma, Mohammad Hassan Sohouli, Somaye Fatahi, Chengwen Li, Shufang Zou.

   BACKGROUND: Considering the impact of adipokines on metabolic syndrome-related disorders and even chronic illnesses, it would appear vital to look for efficient treatments for these variables. The goal of this study was to thoroughly examine how the ketogenic diet (KD) affects adipokines.
METHODS: Using standard keywords, the databases Scopus, PubMed/Medline, Web of Science, Cochrane, and Embase were searched to find all controlled trials looking into how KD affected adipokines (leptin, adiponectin, and ghrelin). By using a random-effects model analysis, pooled weighted mean difference and 95% confidence intervals were obtained.
RESULTS: This article featured twenty-two studies. The combined results demonstrated that, as compared to the control group, leptin levels in all populations are significantly lower when KD is adhered to (WMD: - 0.14 ng/ml, 95% CI: - 8.66, - 3.61, P < 0.001). On the other hand, no discernible impact of this diet on ghrelin and adiponectin concentrations was noted. The subgroup analysis results demonstrated that the drop in leptin levels was considerably higher in persons with BMI > 30 kg/m2 and in trials that followed the KD for ≤ 8 weeks than in the other groups.
CONCLUSIONS: Generally speaking, this diet can be utilized as a potentially helpful supplementary therapy to improve this adipokine, given the significance that leptin plays on numerous metabolic illnesses.

Keywords:  Adipokines; Adiponectin; Ketogenic diet; Leptin; Meta-analysis; Obesity

DOI:  https://doi.org/10.1007/s00592-024-02362-6
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01087-8. [Epub ahead of print]43(9): 114736

Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation.

Wei Wang, Alesja Dernst, Bianca Martin, Lucia Lorenzi, Maria Cadefau-Fabregat, Kshiti Phulphagar, Antonia Wagener, Christina Budden, Neil Stair, Theresa Wagner, Harald Färber, Andreas Jaensch, Rainer Stahl, Fraser Duthie, Susanne V Schmidt, Rebecca C Coll, Felix Meissner, Sergi Cuartero, Eicke Latz, Matthew S J Mangan.

  Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.

Keywords:  CP: Immunology; HDAC; IL-10; NLRP3; SCFA; acetylation; butyrate; cFLIP; caspase-8; inflammasome; propionate

DOI:  https://doi.org/10.1016/j.celrep.2024.114736
Front Nutr. 2024 ;11 1449109

Nutrient analysis of three low-carbohydrate diets differing in carbohydrate content.

Lani Banner, Beth H Rice Bradley, Jonathan Clinthorne.

   Introduction: Low-carbohydrate diets are increasing in popularity. Despite clinical evidence demonstrating their safety and efficacy, concerns regarding the nutrient adequacy of low-carbohydrate diets persist. The aims of this study were to assess the nutrient adequacy of three 7-day meal plans that delivered 20 (VLCD20), 40 (VLCD40), and 100 (LCD100) grams of net carbohydrate per day respectively.
Methods: Nutrient analyses were conducted using USDA Food Data Central.
Results: All three low-carbohydrate meal plans exceeded recommendations for vitamins A, C, D, E, K, thiamin, riboflavin, niacin, B6, folate and B12 in males and females 31-70 years and exceeded calcium recommendations for adults 31-50 years but remained below the Tolerable Upper Intake Level. VLCD40 and LCD100 met or exceeded fiber recommendations for females ages 31-70 years and were adequate for males 51-70 years. None of the meal plans contributed meaningful amounts of added sugar. The plans exceeded the Recommended Dietary Allowance for protein for adults ages 31-70 years of age but were within the Acceptable Macronutrient Distribution Range of 10-35% of energy. The plans slightly exceeded recommendations for saturated fat and sodium but were lower in these nutrients than the average American diet and had more favorable omega-6 to omega-3 and sodium to potassium ratios than is typical. All three meals plans met or exceeded the Estimated Average Requirement for micronutrients in females ages 31-50 years, the population group most likely to consume low-carbohydrate diets.
Discussion: Well-constructed low-carbohydrate meal plans can be nutritionally adequate in adults.

Keywords:  diet; ketogenic diet; low-carbohydrate; low-carbohydrate diet; micronutrients; nutrient adequacy

DOI:  https://doi.org/10.3389/fnut.2024.1449109
Genes Dis. 2024 Nov;11(6): 101100

Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway.

Yongshun Wang, Jie Yuan, Huadong Liu, Jie Chen, Jieru Zou, Xiaoyi Zeng, Lei Du, Xin Sun, Zhengyuan Xia, Qingshan Geng, Yin Cai, Jingjin Liu.

  High-intensity interval training (HIIT) has been found to be more effective in relieving heart failure (HF) symptoms, than moderate-intensity continuous aerobic training (MICT). Additionally, higher meteorin-like protein (Metrnl) levels are seen after HIIT versus MICT. We investigated whether Metrnl contributed to post-HF cardiac functional improvements, and the signaling pathways involved. 50 HF patients underwent MICT, and another 50, HIIT, which was followed by cardiac function and serum Metrnl measurements. Metrnl was also measured in both blood and skeletal muscle samples of mice with transverse aortic constriction-induced HF after undergoing HIIT. Afterward, shRNA-containing adenovectors were injected into mice, yielding five groups: control, HF, HF + HIIT + scrambled shRNA, HF + HIIT + shMetrnl, and HF + Metrnl (HF + exogenous Metrnl). Mass spectrometry identified specific signaling pathways associated with increased Metrnl, which was confirmed with biochemical analyses. Glucose metabolism and mitochondrial functioning were evaluated in cardiomyocytes from the five groups. Both HF patients and mice had higher circulating Metrnl levels post-HIIT. Metrnl activated AMPK in cardiomyocytes, subsequently increasing histone deacetylase 4 (HDAC4) phosphorylation, leading to its cytosolic sequestration and inactivation via binding with chaperone protein 14-3-3. HDAC4 inactivation removed its repression on glucose transporter type 4, which, along with increased mitochondrial complex I-V expression, yielded improved aerobic glucose respiration and alleviation of mitochondrial dysfunction. All these changes ultimately result in improved post-HF cardiac functioning. HIIT increased skeletal muscle Metrnl production, which then operated on HF hearts to alleviate their functional defects, via increasing aerobic glucose metabolism through AMPK-HDAC4 signaling.

Keywords:  AMPK; GLUT4; HDAC4; Heart failure; High intensity interval training; Meteorin-like protein

DOI:  https://doi.org/10.1016/j.gendis.2023.101100
Open Life Sci. 2024 ;19(1): 20220959

Hypomethylation in promoters of PGC-1α involved in exercise-driven skeletal muscular alterations in old age.

Qiaowei Li, Qin Liu, Zhong Lin, Wenwen Lin, Feng Huang, Pengli Zhu.

  Exercise training can significantly improve skeletal muscle mitochondrial function and has been proven to be highly relevant to alterations in skeletal muscle DNA methylation. However, it remains unclear whether late-in-life exercise has an effect on promoter methylation of PGC-1α, a key regulator of mitochondrial biogenesis. Here we employed two distinct exercise modalities, constant medium intensity exercise training (CMIT) and high-intensity interval exercise training (HIIT), to investigate their impacts on PGC-1α expression and methylation regulation in skeletal muscle of aged mice. The results revealed a notable decrease in PGC-1α expression in skeletal muscle of aged mice, accompanied by elevated methylation levels of the PGC-1α promoter, and increased DNA methyltransferase (DNMT) protein expressions. However, both forms of exercise training significantly corrected PGC-1α epigenetic changes, increased PGC-1α expression, and ameliorated skeletal muscle reduction. Furthermore, exercise training led to elevated expression of proteins related to mitochondrial biogenesis and energy metabolism in skeletal muscle, improving mitochondrial structure and function. In conclusion, late-in-life exercise improved skeletal muscle function, morphology, and mitochondria biogenesis, which may be associated with hypomethylation in promoters of PGC-1α and increased content of skeletal muscle PGC-1α. Notably, there was no clear difference between HIIT and CMIT in PGC-1α expression and skeletal muscle function.

Keywords:  DNA methylation; PGC-1α; exercise; sarcopenia

DOI:  https://doi.org/10.1515/biol-2022-0959
Nutrients. 2024 Sep 02. pii: 2935. [Epub ahead of print]16(17):

Health Effects and Mechanisms of Inulin Action in Human Metabolism.

Jaime Alonso-Allende, Fermín I Milagro, Paula Aranaz.

  Inulin is a plant polysaccharide which, due to its chemical structure, is not digestible by human gut enzymes but by some bacteria of the human microbiota, acting as a prebiotic. Consequently, inulin consumption has been associated with changes in the composition of the intestinal microbiota related to an improvement of the metabolic state, counteracting different obesity-related disturbances. However, the specific mechanisms of action, including bacterial changes, are not exactly known. Here, a bibliographic review was carried out to study the main effects of inulin on human metabolic health, with a special focus on the mechanisms of action of this prebiotic. Inulin supplementation contributes to body weight and BMI control, reduces blood glucose levels, improves insulin sensitivity, and reduces inflammation markers, mainly through the selective favoring of short-chain fatty acid (SCFA)-producer species from the genera Bifidobacterium and Anaerostipes. These SCFAs have been shown to ameliorate glucose metabolism and decrease hepatic lipogenesis, reduce inflammation, modulate immune activity, and improve anthropometric parameters such as body weight or BMI. In conclusion, the studies collected suggest that inulin intake produces positive metabolic effects through the improvement of the intestinal microbiota and through the metabolites produced by its fermentation.

Keywords:  SCFA; bifidobacteria; health; insulin; inulin; microbiota; obesity; pathway

DOI:  https://doi.org/10.3390/nu16172935
World J Transplant. 2024 Sep 18. 14(3): 91637

Exercise as a modality to improve heart transplantation-related functional impairments: An article review.

Arnengsih Nazir.

  Heart transplantation (HT), the treatment choice of advanced heart failure patients, is proven effective in increasing the survival and functional status of the recipients. However, compared to normal controls, functional status is lower in HT recipients. Exercise given in cardiac rehabilitation has been shown to improve exercise capacity as measured with peak oxygen uptake (VO2 peak) and muscle strength after completion of the program and cessation of exercise results in loss of exercise benefits. Several factors related to cardiac denervation and the use of immunosuppressive agents in HT recipients result in functional impairments including cardiovascular, pulmonary, exercise capacity, psychological, and quality of life (QoL) problems. High-intensity interval training (HIIT) is the most common type of exercise used in HT recipients and given as a hospital-based program. Improvement of functional impairments was found to have occurred due to primarily musculoskeletal adaptations through improvement of muscle structure and aerobic capacity and cardiovascular adaptations. In general, exercise given after transplantation improved VO2 peak significantly and improvement was better in the HIIT group compared to moderate intensity continuous training or no-exercise groups. Improvement of QoL was ascribed to improvement of exercise capacity, symptoms, pulmonary function, physical capacity improvement, anxiety, and depression.

Keywords:  Cardiac rehabilitation; Exercise tolerance; Functional status; Heart transplantation; High-intensity interval training; Muscle strength; Quality of life

DOI:  https://doi.org/10.5500/wjt.v14.i3.91637
Front Physiol. 2024 ;15 1411421

Effect of ketone monoester supplementation on elite operators' mountaineering training.

Toshiya Miyatsu, Jeremy McAdam, Kody Coleman, Ed Chappe, Steven C Tuggle, Tyler McClure, Marcas M Bamman.

   Introduction: Special Operations Forces (SOF) often conduct operations in physiologically stressful environments such as severe heat, cold, or hypoxia, which can induce decreases in a variety of cognitive abilities. Given the promising empirical demonstration of the efficacy of exogenous ketone monoester (KME) supplementation in attenuating cognitive performance decrease during hypoxia at rest in a laboratory setting, we conducted a real-world, field experiment examining KME's efficacy during high-altitude mountaineering, an austere environment in which US SOF have conducted increasing numbers of operations over the past two decades.
Methods: Specifically, 34 students and cadre at the US Army 10th Special Forces Group Special Operations Advanced Mountaineering School (SOAMS) participated in a randomized, double-blind, placebo (PLA)-controlled crossover trial (KME vs. PLA) over 2 days of tactical mountain operations training. The participants ascended from 7,500 ft in altitude (basecamp) to 12,460 ft on 1 day and 13,627 ft the other day (in randomized order), while performing various training activities inducing high physical and cognitive loads over 8-12 h, and consumed six doses of KME or PLA 2-3 h apart throughout each training day.
Results and Discussion: While KME increased blood ketone levels and decreased glucose levels, there were no clear indications that the elevated ketone level enhanced physical or cognitive performance. KME also produced a greater incidence of heartburn, nausea, and vomiting. In these elite operators, high-altitude mountaineering had a limited impact on cognitive performance, and KME supplementation did not demonstrate any benefit.

Keywords:  cognitive performance; high altitude; hypobaric hypoxia; military; resilience; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fphys.2024.1411421
Lipids. 2024 Sep 19.

Plasma levels of EPA and DHA after ingestion of a single dose of EPA and DHA ethyl esters.

Henrieke Marie-Luise Schmieta, Theresa Greupner, Inga Schneider, Sonja Wrobel, Vanessa Christa, Laura Kutzner, Andreas Hahn, William S Harris, Nils Helge Schebb, Jan Philipp Schuchardt.

  Omega-3 polyunsaturated fatty acids (n3 PUFA), specifically eicosapentaenoic acid (EPA, 20:5n3), and docosahexaenoic acid (DHA, 22:6n3), are essential for maintaining health. To better understand their biology, it is important to define their bioavailability. The aim of this cross-over study was to investigate and compare the acute effects on plasma EPA and DHA levels after single doses of EPA oil (99% pure) and DHA (97% pure) ethyl esters. Twelve men aged 20-40 years with a body-mass-index of 20-27 kg/m2 and low fish consumption were recruited. Several measures (e.g., 4-week run-in period, standardized diet, and blood collection protocols) were taken to reduce the inter-individual variability of plasma fatty acids levels. Using a cross-over design, the subjects received 2.2 g of EPA in the first test period and 2.3 g of DHA in the second. The test periods were separated by 2 weeks. Blood samples were taken before dosing and after 2, 4, 6, 8, 12, 24, 48, and 72 h. The mean ± SE maximum concentrations for EPA were higher than for DHA (115 ± 11 μg/mL vs. 86 ± 12 μg/mL; p = 0.05). The mean ± SE incremented area under the plasma concentration curve over 72 h for EPA (2461 ± 279 μg/mL) was 2.4 times higher (p < 0.001) than that for DHA (1021 ± 170 μg/mL). The mean ± SE half-life was for EPA and DHA was 45 ± 8 and 66 ± 12 h. Our results indicate that EPA administration in single doses leads to higher circulating plasma levels of EPA compared to an effect of an equivalent dose of DHA on DHA plasma levels.

Keywords:  bioavailability; docosahexaenoic acid; eicosapentaenoic acid; kinetics; oral single dose; polyunsaturated fatty acid metabolism

DOI:  https://doi.org/10.1002/lipd.12417
Obes Rev. 2024 Sep 14. e13834

Evaluating the efficacy of intermittent fasting and exercise combinations for weight loss: A network meta-analysis.

Xiaoyan Cheng, Shunli Sun, Maolin Chen, Xinyou Zhou, Mingxin Rao, Dongjuan Guo, Jinfeng Xie, Qiang Huang, Liqiang Su.

   OBJECTIVE: The purpose of this study is to utilize network meta-analysis (NMA) to synthesize relevant randomized controlled trials (RCTs) and evaluate the most effective intermittent fasting (IF) combined with exercise interventions for weight loss.
METHODS: This study searched five databases up until April 2024, obtaining RCTs that investigated the effects of intermittent fasting (IF) combined with exercise. The quality of the literature was assessed using the Cochrane tool, followed by a random-effects statistical analysis of each intervention. Eventually, a NMA was conducted to compare the effectiveness of each intervention on weight loss, thereby determining their combined effectiveness on reducing weight.
RESULTS: A total of nine trials, comparing 12 interventions involving 570 participants, were included. All interventions significantly reduced body weight (BW) and fat mass (FM) compared to the control (CON) group. In terms of BW reduction, the alternate-day fasting + moderate-intensity continuous training (ADF + MICT) intervention had the highest surface under the cumulative ranking curve average (SUCRA) score 88.1(MD: -4.44,95% CI -5.95, -2.92). Furthermore, for improving FM, the ADF + MICT intervention also had the highest SUCRA score 92.7(MD: -3.65,95% CI -5.05, -2.25), making it the optimal intervention for improving FM.
CONCLUSION: The NMA results indicate that all interventions are effective in reducing weight. Among them, ADF + MICT is the most effective strategy for reducing BW, and it is also the best approach for improving FM.

Keywords:  intermittent fasting combined with exercise; network meta‐analysis; weight loss

DOI:  https://doi.org/10.1111/obr.13834
Sci Rep. 2024 09 14. 14(1): 21509

Optimal fasting duration for mice as assessed by metabolic status.

Jian Fu, Sha Liu, Mengyao Li, Fangrui Guo, Xiaoran Wu, Jiahao Hu, Lixin Wen, Ji Wang, Xiaowen Li.

  In the study of obesity and diabetes, mice are widely used for experimental research, and fasting is a common procedure used to reset metabolism in mouse models. The fasting duration for experimental mice varies greatly in nutritional and metabolic studies, ranging from 2 to 48 h. This study aims to assess the optimal fasting duration for mice fed low- and high-fat diets over a short period of time. C57BL/6J mice were fed a low-fat diet (LFD) or high-fat diet (HFD) and fasted for 4, 6, 8, 10, 12, or 24 h. The effects of different conditions after fasting on the metabolic level of mice were explored, and the data were collected for analysis. Our data indicate that fasting has inconsistent effects on mice fed a low-fat or high-fat diet. To compare the metabolic differences between mice in different dietary levels and thereby secure better scientific data, mice should fast for 6 h in animal experiments. Fasting for 6 h is also recommended when comparing glucose tolerance with insulin tolerance.

Keywords:  Fasting duration; High-fat diet; Metabolic research; Mouse model; Nutritional research

DOI:  https://doi.org/10.1038/s41598-024-72695-3
Ann N Y Acad Sci. 2024 Sep 16.

Understanding the role of the human gut microbiome in overweight and obesity.

Michael I McBurney, Clara E Cho.

  The gut microbiome may be related to the prevalence of overweight and obesity, but high interindividual variability of the human microbiome complicates our understanding. Obesity often occurs concomitantly with micronutrient deficiencies that impair energy metabolism. Microbiota composition is affected by diet. Host-microbiota interactions are bidirectional. We propose three pathways whereby these interactions may modulate the gut microbiome and obesity: (1) ingested compounds or derivatives affecting small intestinal transit, endogenous secretions, digestion, absorption, microbiome balance, and gut barrier function directly affect host metabolism; (2) substrate availability affecting colonic microbial composition and contact with the gut barrier; and (3) microbial end products affecting host metabolism. The quantity/concentration, duration, and/or frequency (circadian rhythm) of changes in these pathways can alter the gut microbiome, disrupt the gut barrier, alter host immunity, and increase the risk of and progression to overweight and obesity. Host-specific characteristics (e.g., genetic variations) may further affect individual sensitivity and/or resilience to diet- and microbiome-associated perturbations in the colonic environment. In this narrative review, the effects of selected interventions, including fecal microbiota transplantation, dietary calorie restriction, dietary fibers and prebiotics, probiotics and synbiotics, vitamins, minerals, and fatty acids, on the gut microbiome, body weight, and/or adiposity are summarized to help identify mechanisms of action and research opportunities.

Keywords:  dietary fiber; dietary restriction; fatty acids; fecal microbiota transplantation; minerals; prebiotics; probiotics; symbiotics; vitamins

DOI:  https://doi.org/10.1111/nyas.15215
Adv Exp Med Biol. 2024 ;1460 391-430

Insulin Resistance, Obesity, and Lipotoxicity.

Dilek Yazıcı, Selin Çakmak Demir, Havva Sezer.

  Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.

Keywords:  Cardiomyopathy; Ceramides; Cytokines; Diabetic nephropathy; Diacylglycerol; Endoplasmic reticulum stress; Fatty acids; Insulin resistance; Lipotoxicity; Nonalcoholic fatty liver disease; Obesity; Polycystic ovary syndrome; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1007/978-3-031-63657-8_14
Physiol Rep. 2024 Sep;12(18): e70044

Anabolic deficits and divergent unfolded protein response underlie skeletal and cardiac muscle growth impairments in the Yoshida hepatoma tumor model of cancer cachexia.

Daniel J Belcher, Nina Kim, Blanca Navarro-Llinas, Maria Möller, Francisco J López-Soriano, Silvia Busquets, Gustavo A Nader.

  Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH-130 ascites hepatoma model of cancer cachexia. AH-130 tumor-bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage-inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon-γ in the heart, while an increase in interleukin-1β mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH-130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro-inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting.

Keywords:  cancer; inflammation; ribosomal RNA; unfolded protein response; wasting

DOI:  https://doi.org/10.14814/phy2.70044
Front Immunol. 2024 ;15 1452749

Inflammasome activity regulation by PUFA metabolites.

Sinemyiz Atalay Ekiner, Agnieszka Gęgotek, Elżbieta Skrzydlewska.

  Oxidative stress and the accompanying chronic inflammation constitute an important metabolic problem that may lead to pathology, especially when the body is exposed to physicochemical and biological factors, including UV radiation, pathogens, drugs, as well as endogenous metabolic disorders. The cellular response is associated, among others, with changes in lipid metabolism, mainly due to the oxidation and the action of lipolytic enzymes. Products of oxidative fragmentation/cyclization of polyunsaturated fatty acids (PUFAs) [4-HNE, MDA, 8-isoprostanes, neuroprostanes] and eicosanoids generated as a result of the enzymatic metabolism of PUFAs significantly modify cellular metabolism, including inflammation and the functioning of the immune system by interfering with intracellular molecular signaling. The key regulators of inflammation, the effectiveness of which can be regulated by interacting with the products of lipid metabolism under oxidative stress, are inflammasome complexes. An example is both negative or positive regulation of NLRP3 inflammasome activity by 4-HNE depending on the severity of oxidative stress. 4-HNE modifies NLRP3 activity by both direct interaction with NLRP3 and alteration of NF-κB signaling. Furthermore, prostaglandin E2 is known to be positively correlated with both NLRP3 and NLRC4 activity, while its potential interference with AIM2 or NLRP1 activity is unproven. Therefore, the influence of PUFA metabolites on the activity of well-characterized inflammasome complexes is reviewed.

Keywords:  PUFA metabolites; eicosanoids; inflammasome complexes; inflammation; lipid mediators; oxidative stress

DOI:  https://doi.org/10.3389/fimmu.2024.1452749
J Am Heart Assoc. 2024 Sep 18. e036555

Exercise Alleviates Cardiovascular Diseases by Improving Mitochondrial Homeostasis.

Huijie Zhang, Yuxuan Zhang, Jiaqiao Zhang, Dandan Jia.

  Engaging in regular exercise and physical activity contributes to delaying the onset of cardiovascular diseases (CVDs). However, the physiological mechanisms underlying the benefits of regular exercise or physical activity in CVDs remain unclear. The disruption of mitochondrial homeostasis is implicated in the pathological process of CVDs. Exercise training effectively delays the onset and progression of CVDs by significantly ameliorating the disruption of mitochondrial homeostasis. This includes improving mitochondrial biogenesis, increasing mitochondrial fusion, decreasing mitochondrial fission, promoting mitophagy, and mitigating mitochondrial morphology and function. This review provides a comprehensive overview of the benefits of physical exercise in the context of CVDs, establishing a connection between the disruption of mitochondrial homeostasis and the onset of these conditions. Through a detailed examination of the underlying molecular mechanisms within mitochondria, the study illuminates how exercise can provide innovative perspectives for future therapies for CVDs.

Keywords:  cardiovascular diseases; exercise; exerkines; mitochondrial homeostasis

DOI:  https://doi.org/10.1161/JAHA.124.036555