bims-kimdis 2022-12-25 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–12–25
thirty papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic Diet for Neonatal Hypoxic-Ischemic Encephalopathy.
POSITIVE EFFECTS OF KETOGENIC DIET ON WEIGHT CONTROL IN CHILDREN WITH OBESITY DUE TO PRADER-WILLI SYNDROME.
Comparison of the ketogenic ratio of macronutrients with the low-carbohydrate diet score and their association with risk of type 2 diabetes in postmenopausal women: A secondary analysis of the women's health initiative.
The NLRP3 Inflammasome in Depression: Potential Mechanisms and Therapies.
Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy.
Impact of 4 weeks of western diet and aerobic exercise training on whole-body phenotype and skeletal muscle mitochondrial respiration in male and female mice.
Nutritional Quality of Gluten-Free Bakery Products Labeled Ketogenic and/or Low-Carb Sold in the Global Market.
Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model.
Effect of D-β-hydroxybutyrate-(R)-1,3 Butanediol on Appetite Regulation in People with Prediabetes.
Revised Protein Sparing Diet in Obesity and Type 2 Diabetes Mellitus.
Effects of Carbohydrate Restriction on Body Weight and Glycemic Control in Individuals with Type 2 Diabetes: A Randomized Controlled Trial of Efficacy in Real-Life Settings.
The role of mTORC1 in the regulation of skeletal muscle mass.
Time to run: Late rather than early exercise training in mice remodels the gut microbiome and reduces atherosclerosis development.
The Role of Sodium-Glucose Cotransporter-2 Inhibition in Heart Failure with Preserved Ejection Fraction.
Metabolic effects of alternate-day fasting in males with obesity with or without type 2 diabetes.
Moms' mitochondria may refresh cells in sick kids.
Acute responsiveness to single leg cycling in adults with obesity.
A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.
Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction.
Sodium Butyrate Attenuates AGEs-Induced Oxidative Stress and Inflammation by Inhibiting Autophagy and Affecting Cellular Metabolism in THP-1 Cells.
The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells.
Beyond antioxidants: Selenium and skeletal muscle mitochondria.
Effect of AMPK activation and glucose availability on myotube LAT1 expression and BCAA utilization.
Eight-hour time-restricted eating does not lower daily myofibrillar protein synthesis rates: A randomized control trial.
Inflammation and kidney stones: cause and effect?
β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb.
Butyrate Lowers Cellular Cholesterol through HDAC Inhibition and Impaired SREBP-2 Signalling.
Exercise and mitochondrial mechanisms in patients with sarcopenia.
Skeletal muscle morphology, satellite cells and oxidative profile in relation to physical function and lifelong endurance training in very old men.
Is Aging a Disease? The Theoretical Definition of Aging in the Light of the Philosophy of Medicine.

ACS Chem Neurosci. 2022 Dec 21.

Ketogenic Diet for Neonatal Hypoxic-Ischemic Encephalopathy.

Yue Zhou, Luqiang Sun, Haichuan Wang.

  The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.

Keywords:  Hypoxic−ischemic; cerebral metabolism; encephalopathy; ketogenic diet; neuroprotective strategy

DOI:  https://doi.org/10.1021/acschemneuro.2c00609
Clin Endocrinol (Oxf). 2022 Dec 19.

POSITIVE EFFECTS OF KETOGENIC DIET ON WEIGHT CONTROL IN CHILDREN WITH OBESITY DUE TO PRADER-WILLI SYNDROME.

Pelin Teke Kısa, Orkide Güzel, Nur Arslan, Korcan Demir.

   OBJECTIVE: Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Prevention and management of obesity, which represents the main cause of morbidity and mortality in these patients, is essential. Ketogenic diet (KD) is used in the treatment of various disorders, however knowledge on its effect in PWS is lacking. The present study assesses the characteristics of patients with PWS who were on ketogenic diet.
PATIENTS: This is a retrospective, cross-sectional descriptive study investigating the subjects with PWS, who had received KD for at least 6 months.
RESULTS: Ten patients with PWS [median age 52.5 (47-77) months] complied with KD. The median treatment period was 16.5 [11-52] months. Of the daily calorie, 75-85% were from fat, and 15-25% from protein+carbohydrate. The baseline body weight SD score prior to diet therapy was 2.10 [-1.11-4.11], whereas it was 0.05 [-0.92-1.2] at final evaluation (p=0.007). The baseline median BMI SD score prior to diet therapy was 3.05 [-0.21-3.72], whereas it was 0.41 [-0.87-1.57] at final evaluation (p=0.002). The height SD score remained unchanged. Mild hypercholesterolemia was the most common biochemical abnormality during treatment with KD.
CONCLUSION: Our results indicate that KD might have a favorable effect on weight management in PWS. This article is protected by copyright. All rights reserved.

Keywords:  appetite; dietary intake; hyperphagia; ketones; obesity; weight loss

DOI:  https://doi.org/10.1111/cen.14864
J Acad Nutr Diet. 2022 Dec 19. pii: S2212-2672(22)01253-9. [Epub ahead of print]

Comparison of the ketogenic ratio of macronutrients with the low-carbohydrate diet score and their association with risk of type 2 diabetes in postmenopausal women: A secondary analysis of the women's health initiative.

Tyler J Titcomb, Buyun Liu, Terry L Wahls, Linda G Snetselaar, Aladdin H Shadyab, Fred K Tabung, Nazmus Saquib, Chrisa Arcan, Lesley F Tinker, Robert B Wallace, Wei Bao.

   BACKGROUND: Previous attempts to identify low-carbohydrate diets (LCDs) in epidemiological studies relied on the LCD score, which is unable to identify ketogenic dieters. Ketogenic ratios of macronutrients are clinical equations proposed to predict ketogenic diets; however, their utility in epidemiological studies is unknown.
OBJECTIVE: To determine the number of participants consuming a ketogenic diet, compare ketogenic ratios to the LCD score, and evaluate their association with type 2 diabetes mellitus (T2DM).
DESIGN: Secondary analysis of the Women's Health Initiative (WHI) with 17.9 ± 6.03 years of follow-up. Baseline food frequency questionnaires were used to calculate the ketogenic ratio as follows: (0.9*grams fat + 0.46*grams protein) divided by (0.1*grams fat + 0.58*grams protein + grams net carbohydrate), a value ≥1.5 is the minimum threshold for a ketogenic diet.
PARTICIPANTS/SETTING: 125,982 postmenopausal women without diabetes (age 50-79 years) enrolled in the multicenter WHI observational study and clinical trials were included.
MAIN OUTCOME MEASURES: Risk of self-reported incident T2DM.
STATISTICAL ANALYSIS PERFORMED: Cox proportional hazards models, adjusted for age, race, ethnicity, education, income, health insurance, relationship status, geographic region, WHI study component, female hormone use, smoking status, alcohol use, recreational physical activity, total energy intake, diet quality, body mass index, hyperlipidemia, and hypertension, were used to compare hazard ratios (HRs) and 95% confidence intervals (CIs) for T2DM between quintiles of the ketogenic ratio.
RESULTS: 18,775 incident cases of T2DM occurred. The median ketogenic ratio was 0.35 (interquartile range 0.28-0.42) and 15 individuals (0.01%) exceeded the threshold for a ketogenic diet. Higher ketogenic ratio quintiles were associated with increased risk of T2DM in a dose-dependent manner. Comparing extreme quintiles of the ketogenic ratio, the HR and 95% CI for diabetes was 1.24 (1.18-1.31; Ptrend < 0.001) in fully adjusted models. Similarly, comparing extreme quintiles, the HR (95% CI) for diabetes was 1.36 (1.29-1.43; Ptrend < 0.001) for the LCD score and 1.13 (1.07-1.19; Ptrend < 0.001) for the simplified ketogenic ratio in fully adjusted models.
CONCLUSION: Increasing ketogenic ratio values are associated with increased risk of T2DM and align well with LCD scores; however, too few participants consumed a ketogenic diet to determine its association with T2DM.

Keywords:  diabetes; ketogenic diet; ketogenic ratio; low-carbohydrate diet score; nutritional epidemiology; postmenopausal women

DOI:  https://doi.org/10.1016/j.jand.2022.12.004
Pharmacol Res. 2022 Dec 20. pii: S1043-6618(22)00571-0. [Epub ahead of print] 106625

The NLRP3 Inflammasome in Depression: Potential Mechanisms and Therapies.

Cong-Yuan Xia, Yu-Xuan Guo, Wen-Wen Lian, Yu Yan, Bing-Zhi Ma, Yung-Chi Cheng, Jie-Kun Xu, Jun He, Wei-Ku Zhang.

  Increasing evidence suggest that the failure of clinical antidepressants may be related with neuroinflammation. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex, and has been considered as a key contributor to the development of neuroinflammation. Inhibition of NLRP3 inflammasome is an effective method for depression treatment. In this review, summarized current researches highlighting the role of NLRP3 inflammasome in the pathology of depression. Firstly, we discussed NLRP3 inflammasome activation in patients with depression and animal models. Secondly, we outlined the possible mechanisms driving the activation of NLRP3 inflammasome. Thirdly, we discussed the pathogenetic role of NLRP3 inflammasome in depression. Finally, we overviewed the current and potential antidepressants targeting the NLRP3 inflammasome. Overall, the inhibition of NLRP3 inflammasome activation may be a potential therapeutic strategy for inflammation-related depression.

Keywords:  NLRP3 inflammasome; antidepressant; depression; neuroinflammation; pyroptosis

DOI:  https://doi.org/10.1016/j.phrs.2022.106625
Exp Physiol. 2022 Dec 19.

Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy.

Kaja Falkenhain, Hashim Islam, Jonathan P Little.

   NEW FINDINGS: What is the topic of this review? The integrative physiological response to exogenous ketone supplementation. What advances does it highlight? The physiological effects and therapeutic potential of exogenous ketones on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. Also highlighted are current challenges and future directions of the field.
ABSTRACT: Exogenous oral ketone supplements, primarily in form of ketone salts or esters, have emerged as a useful research tool for manipulating metabolism with potential therapeutic application targeting various aspects of several common chronic diseases. Recent literature has investigated the effects of exogenously induced ketosis on metabolic health, cardiovascular function, cognitive processing, and modulation of inflammatory pathways and immune function. This narrative review provides an overview of the integrative physiological effects of exogenous ketone supplementation and highlights current challenges and future research directions. Much of the existing research on therapeutic applications - particularly mechanistic studies - has involved pre-clinical rodent and/or cellular models, requiring further validation in human clinical studies. Existing human studies report that exogenous ketones can lower blood glucose and improve some aspects of cognitive function, highlighting the potential therapeutic application of exogenous ketones for type 2 diabetes and neurological diseases. There is also support for the ability of exogenous ketosis to improve cardiac metabolism in rodent models of heart failure with supporting human studies emerging; long-terms effects of exogenous ketone supplementation on the human cardiovascular system and lipid profiles are needed. An important avenue for future work is provided by research accelerating technologies that enable continuous ketone monitoring and/or the development of more palatable ketone mixtures that optimize plasma ketone kinetics to enable sustained ketosis. Lastly, research exploring the physiological interactions between exogenous ketones and varying metabolic states (e.g., exercise, fasting, metabolic disease) should yield important insights that can be used to maximize the health benefits of exogenous ketosis.

Keywords:  cardiovascular disease; cognitive function; inflammation; integrative physiology; ketone monoester; ketosis; metabolic health; metabolism; nutrition; type 2 diabetes

DOI:  https://doi.org/10.1113/EP090430
Physiol Rep. 2022 Dec;10(24): e15543

Impact of 4 weeks of western diet and aerobic exercise training on whole-body phenotype and skeletal muscle mitochondrial respiration in male and female mice.

Erin M McGowan, Sarah E Ehrlicher, Harrison D Stierwalt, Matthew M Robinson, Sean A Newsom.

  High dietary fat intake induces significant whole-body and skeletal muscle adaptations in mice, including increased capacity for fat oxidation and mitochondrial biogenesis. The impact of a diet that is high in fat and simple sugars (i.e., western diet [WD]), particularly on regulation of skeletal muscle mitochondrial function, is less understood. The purpose of the current study was to determine physiologic adaptations in mitochondrial respiratory capacity in skeletal muscle during short-term consumption of WD, including if adaptive responses to WD-feeding are modified by concurrent exercise training or may be sex-specific. Male and female C57BL/6J mice were randomized to consume low-fat diet (LFD) or WD for 4 weeks, with some WD-fed mice also performing concurrent treadmill training (WD + Ex). Group sizes were n = 4-7. Whole-body metabolism was measured using in-cage assessment of food intake and energy expenditure, DXA body composition analysis and insulin tolerance testing. High-resolution respirometry of mitochondria isolated from quadriceps muscle was used to determine skeletal muscle mitochondrial respiratory function. Male mice fed WD gained mass (p < 0.001), due to increased fat mass (p < 0.001), and displayed greater respiratory capacity for both lipid and non-lipid substrates compared with LFD mice (p < 0.05). There was no effect of concurrent treadmill training on maximal respiration (WD + Ex vs. WD). Female mice had non-significant changes in body mass and composition as a function of the interventions, and no differences in skeletal muscle mitochondrial oxidative capacity. These findings indicate 4 weeks of WD feeding can increase skeletal muscle mitochondrial oxidative capacity among male mice; whereas WD, with or without exercise, had minimal impact on mass gain and skeletal muscle respiratory capacity among female mice. The translational relevance is that mitochondrial adaptation to increases in dietary fat intake that model WD may be related to differences in weight gain among male and female mice.

Keywords:  lipid metabolism; obesity; respirometry; substrate oxidation

DOI:  https://doi.org/10.14814/phy2.15543
Foods. 2022 Dec 18. pii: 4095. [Epub ahead of print]11(24):

Nutritional Quality of Gluten-Free Bakery Products Labeled Ketogenic and/or Low-Carb Sold in the Global Market.

Nicola Gasparre, Antonella Pasqualone, Marina Mefleh, Fatma Boukid.

  Gluten-free and ketogenic bakery products are gaining momentum. This study aims to develop a better understanding of the nutritional quality of gluten-free bakery products labeled ketogenic and/or low-carb. For this reason, the products available on the global market that were labeled ketogenic and/or low-carb (n = 757) were retrieved and compared to standard gluten-free products (n = 509). Overall, nutritionally, no significant differences were found among ketogenic and/or low-carb products due the high intra-variability of each type, but they differed from standard products. Compared to standard products, all ketogenic and/or low carb, irrespective of categories, showed lower carbohydrates that derived chiefly from fibers and, to a lesser extent, from sugars. They also had higher protein contents (p < 0.05) compared to standard products. Fats was higher (p < 0.05) in ketogenic and/or low-carb baking mixes, savory biscuits, and sweet biscuits than in their standard counterparts. Saturated fats were higher (p < 0.05) in low-carb savory biscuits and breads, as well as in ketogenic sweet biscuits than in the same standard products. Overall, median values of the nutrients align with the definition of the ketogenic diet. Nevertheless, several products did not align with any of the ketogenic definitions. Therefore, consumers need to carefully read the nutritional facts and not rely on mentions such as low-cab and ketogenic to make their decision of purchase/consumption.

Keywords:  biscuits; bread; cake; flour mixes; high fiber; high protein; low carb

DOI:  https://doi.org/10.3390/foods11244095
Front Aging Neurosci. 2022 ;14 1075161

Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model.

Wei Sun, Min Wen, Min Liu, Qingpeng Wang, Quiqin Liu, Lanjie Li, Hans-Christian Siebert, Gabriele Loers, Ruiyan Zhang, Ning Zhang.

  Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of central nervous system (CNS). Aging is the most significant risk factor for the progression of MS. Dietary modulation (such as ketogenic diet) and caloric restriction, can increase ketone bodies, especially β-hydroxybutyrate (BHB). Increased BHB has been reported to prevent or improve age-related disease. The present studies were performed to understand the therapeutic effect and potential mechanisms of exogenous BHB in cuprizone (CPZ)-induced demyelinating model. In this study, a continuous 35 days CPZ mouse model with or without BHB was established. The changes of behavior function, pathological hallmarks of CPZ, and intracellular signal pathways in mice were detected by Open feld test, Morris water maze, RT-PCR, immuno-histochemistry, and western blot. The results showed that BHB treatment improved behavioral performance, prevented myelin loss, decreased the activation of astrocyte as well as microglia, and up-regulated the neurotrophin brain-derived neurotrophic factor in both the corpus callosum and hippocampus. Meanwhile, BHB treatment increased the number of MCT1+ cells and APC+ oligodendrocytes. Furthermore, the treatment decreased the expression of HDAC3, PARP1, AIF and TRPA1 which is related to oligodendrocyte (OL) apoptosis in the corpus callosum, accompanied by increased expression of TrkB. This leads to an increased density of doublecortin (DCX)+ neuronal precursor cells and mature NeuN+ neuronal cells in the hippocampus. As a result, BHB treatment effectively promotes the generation of PDGF-Ra+ (oligodendrocyte precursor cells, OPCs), Sox2+ cells and GFAP+ (astrocytes), and decreased the production of GFAP+ TRAP1+ cells, and Oligo2+ TRAP1+ cells in the corpus callosum of mouse brain. Thus, our results demonstrate that BHB treatment efficiently supports OPC differentiation and decreases the OLs apoptosis in CPZ-intoxicated mice, partly by down-regulating the expression of TRPA1 and PARP, which is associated with the inhibition of the p38-MAPK/JNK/JUN pathway and the activation of ERK1/2, PI3K/AKT/mTOR signaling, supporting BHB treatment adjunctive nutritional therapy for the treatment of chronic demyelinating diseases, such as multiple sclerosis (MS).

Keywords:  PARP; TRPA1; demyelination; multiple sclerosis; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fnagi.2022.1075161
Mol Nutr Food Res. 2022 Dec 24. e2200615

Effect of D-β-hydroxybutyrate-(R)-1,3 Butanediol on Appetite Regulation in People with Prediabetes.

Yutong Liu, Sakina H Bharmal, Wandia Kimita, Maxim S Petrov.

   SCOPE: The primary aim of the present study was to study the effect of acute ketosis on parameters of appetite regulation in prediabetes. The secondary aim was to investigate whether the effect is influenced by eating behaviours.
METHODS AND RESULTS: This was a randomised controlled trial. After an overnight fast, 18 adults with prediabetes (defined in line with the American Diabetes Association criteria) were assigned to consume either a ketone monoester (D-β-hydroxybutyrate-(R)-1,3 butanediol) drink (energy content 123 kcal) or a placebo drink (containing virtually no calories) in cross-over fashion. Blood samples were collected every 30 mins, from baseline to 150 minutes. Paired t-test was used to compare the total area under the curve (AUC) for the changes in parameters of appetite regulation (acylated ghrelin, peptide YY (PYY), and hunger) following both drinks. Eating behaviours were determined with the use of the three-factor eating questionnaire. Significant elevation in blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 minutes. Acute ketosis did not result in statistically significant differences in the AUCs for ghrelin, PYY, and hunger. No statistically significant difference in the AUCs was also observed when participants were stratified by their eating behaviours.
CONCLUSION: Acute ketosis consistently did not affect both objective and subjective parameters of appetite regulation in prediabetes. No subset of people with prediabetes according to eating behaviours had a significant effect of acute ketosis on appetite regulation. This article is protected by copyright. All rights reserved.

Keywords:  appetite; eating behaviour; ketosis; prediabetes

DOI:  https://doi.org/10.1002/mnfr.202200615
Nutrients. 2022 Dec 15. pii: 5325. [Epub ahead of print]14(24):

Revised Protein Sparing Diet in Obesity and Type 2 Diabetes Mellitus.

Raffaele Ivan Cincione, Francesca Losavio, Giuseppe Cibelli, Giovanni Messina, Rita Polito, Elias Casula, Pamela Pia Cincione, Marco Amatruda, Pierpaolo Limone.

  Effective nutrition therapy is a pressing issue in obesity and type 2 diabetes mellitus (T2DM) management. As such, this research aimed to determine the performance of a revised dietary strategy built on the protein-sparing diet in obesity and type 2 diabetes mellitus with regard to obtaining a rapid and stable improvement in glucometabolic control, body weight, body composition, and energy metabolism when applying the strategy in just twenty-one days. The revised protein-sparing diet differs from the traditional protein-sparing modified fast (PSMF) because it does not include foods. The daily calorie intake of this diet is exclusively derived from Isolate whey protein in addition to a formulation of Isolate whey protein enriched with essential amino acids in free form, with the addition of lipids such as extra virgin olive oil and coconut oil as a source of medium chain fatty acids, where the latter is taken for only the first four days of the diet, together with the use, for the same duration, of extended-release metformin, as the only antihyperglycemic allowed. Anthropometric measurements, bioimpedance analysis, indirect calorimetry, and blood chemistry assessments were conducted at the beginning of the study, time 0 (T0), and at the end, time 1 (T1), i.e., on the 21st day. The main outcomes of the revised protein-sparing diet after only twenty-one days were a reduction in body weight with the predominant loss of visceral atherogenic abdominal fat and, therefore, a possible contextual reduction in ectopic fat deposits together with a simultaneous reduction in insulin resistance and normalization of insulin levels, maintenance of free fat mass and basal metabolism, restoration of metabolic flexibility, and improvement of the glucometabolic and lipidic parameters. These results demonstrate the promising potential of the revised protein-sparing diet as an "etiologic tool" in the integrated nutritional treatment of metabolic diseases such as obesity and type 2 diabetes mellitus.

Keywords:  body composition; diabetes reversal; ectopic fat; fat mass; free fat mass; indirect calorimetry; metabolic inflexibility; obesity; revised protein sparing diet; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/nu14245325
Nutrients. 2022 Dec 09. pii: 5244. [Epub ahead of print]14(24):

Effects of Carbohydrate Restriction on Body Weight and Glycemic Control in Individuals with Type 2 Diabetes: A Randomized Controlled Trial of Efficacy in Real-Life Settings.

Philip Weber, Mads N Thomsen, Mads Juul Skytte, Amirsalar Samkani, Martin Hansen Carl, Arne Astrup, Jan Frystyk, Jens J Holst, Bolette Hartmann, Sten Madsbad, Faidon Magkos, Thure Krarup, Steen B Haugaard.

  A fully provided, hypocaloric, carbohydrate-reduced high-protein (CRHP) diet compared to a hypocaloric conventional diabetes (CD) diet for 6 weeks improved glycemic control to a greater extent in face of an intended 6% weight loss in individuals with type 2 diabetes mellitus (T2DM). The present 24-week extension of that study reports on the efficacy of CRHP and CD diets in a real-life setting. Sixty-five individuals with T2DM who completed the initial 6-week fully provided diet period (% energy from carbohydrate, protein, and fat was 30/30/40 in CRHP, and 50/17/33 in CD) continued a free-living, dietician guided 24-week period of which 59 individuals completed. The CRHP compared to CD group reported a 4% lower carbohydrate intake and had higher urea excretion by 22% (both p ≤ 0.05) at week 30, suggesting less difference in carbohydrate and protein intake between groups during the 24-week extension compared to week 6. The loss of body weight during the initial 6 weeks was maintained in both groups during the 24-week extension (-5.5 ± 4.5 and -4.6 ± 4.8 kg) as well as HbA1c (-8.4 ± 6.2 and -8.4 ± 6.9 mmol/mol) with no significant differences between groups. The additional benefits on glucoregulation harnessed by carbohydrate restriction under full diet provision for 6 weeks combined with titrated weight loss could not be maintained in a real-life setting of self-prepared diet aiming on similar diets for 6 months.

Keywords:  carbohydrate restriction; glucose metabolism; lipid metabolism; macronutrients; type 2 diabetes

DOI:  https://doi.org/10.3390/nu14245244
Fac Rev. 2022 ;11 32

The role of mTORC1 in the regulation of skeletal muscle mass.

Sue C Bodine.

  Skeletal muscle mass is a very plastic characteristic of skeletal muscle and is regulated by signaling pathways that control the balance between anabolic and catabolic processes. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR) has been shown to be critically important in the regulation of skeletal muscle mass through its regulation of protein synthesis and degradation pathways. In this commentary, recent advances in the understanding of the role of mTORC1 in the regulation of muscle mass under conditions that induce hypertrophy and atrophy will be highlighted.

Keywords:  aging; atrophy; hypertrophy; protein synthesis

DOI:  https://doi.org/10.12703/r/11-32
FASEB J. 2023 Jan;37(1): e22719

Time to run: Late rather than early exercise training in mice remodels the gut microbiome and reduces atherosclerosis development.

Milena Schönke, Zhixiong Ying, Artemiy Kovynev, Wietse In Het Panhuis, Anne Binnendijk, Sabine van der Poel, Amanda C M Pronk, Trea C M Streefland, Menno Hoekstra, Sander Kooijman, Patrick C N Rensen.

  The metabolic and inflammatory processes that are implicated in the development of cardiovascular diseases are under control of the biological clock. While skeletal muscle function exhibits circadian rhythms, it is unclear to what extent the beneficial health effects of exercise are restricted to unique time windows. We aimed to study whether the timing of exercise training differentially modulates the development of atherosclerosis and elucidate underlying mechanisms. We endurance-trained atherosclerosis-prone female APOE*3-Leiden.CETP mice fed a Western-type diet, a well-established human-like model for cardiometabolic diseases, for 1 h five times a week for 4 weeks either in their early or in their late active phase on a treadmill. We monitored metabolic parameters, the development of atherosclerotic lesions in the aortic root and assessed the composition of the gut microbiota. Late, but not early, exercise training reduced fat mass by 19% and the size of early-stage atherosclerotic lesions by as much as 29% compared to sedentary animals. No correlation between cholesterol exposure and lesion size was evident, as no differences in plasma lipid levels were observed, but circulating levels of the pro-inflammatory markers ICAM-1 and VCAM-1 were reduced with late exercise. Strikingly, we observed a time-of-day-dependent effect of exercise training on the composition of the gut microbiota as only late training increased the abundance of gut bacteria producing short-chain fatty acids with proposed anti-inflammatory properties. Together, these findings indicate that timing is a critical factor to the beneficial anti-atherosclerotic effects of exercise with a great potential to further optimize training recommendations for patients.

Keywords:  atherosclerosis; circadian rhythms; exercise; gut microbiota; lipid metabolism

DOI:  https://doi.org/10.1096/fj.202201304R
Pharmacy (Basel). 2022 Nov 30. pii: 166. [Epub ahead of print]10(6):

The Role of Sodium-Glucose Cotransporter-2 Inhibition in Heart Failure with Preserved Ejection Fraction.

Lindsay Brust-Sisti, Nicole Rudawsky, Jimmy Gonzalez, Luigi Brunetti.

  Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic mediations found to also reduce cardiovascular morbidity and mortality and hospitalization for heart failure. Positive results from the EMPEROR-Preserved (empagliflozin) and PRESERVED-HF (dapagliflozin) studies led to recommendations for SGLT2 inhibitors in HFpEF within major international heart failure guidelines. However, studies of ipragliflozin and luseogliflozin, agents approved outside the United States (U.S.), reported different outcomes relative to pivotal trials and failed to realize benefits in the HFpEF population. Varying definitions of HFpEF and outcomes studied complicate the interpretation of study results. SGLT2 inhibitors may cause common adverse events (genital mycotic infections, volume depletion) in addition to rare but severe sequela, including euglycemic diabetic ketoacidosis, Fournier's gangrene, and lower limb amputation. While evidence of CV benefits grows, SGLT2 inhibitor prescribing has lagged, particularly among patients without diabetes. In the U.S., high cost and administrative hurdles may contribute to decreased patient and clinician uptake of this drug class. Future trial results and clinical experience with SGLT2 inhibitors may lead to expanded use and greater uptake among patients with heart failure.

Keywords:  canagliflozin; dapagliflozin; empagliflozin; ertugliflozin; heart failure; sodium-glucose transporter 2

DOI:  https://doi.org/10.3390/pharmacy10060166
Front Physiol. 2022 ;13 1061063

Metabolic effects of alternate-day fasting in males with obesity with or without type 2 diabetes.

Arthur Ingersen, Hildegunn Rømma Helset, Monika Calov, Elizaveta Chabanova, Eva Gjerlevsen Harreskov, Christina Jensen, Christina Neigaard Hansen, Clara Prats, Jørn Wulff Helge, Steen Larsen, Flemming Dela.

  Alternate-day fasting induces oscillations in energy stores. We hypothesized that repeated oscillations increases insulin secretion and sensitivity, and improve metabolic health in patients with obesity with or without type 2 diabetes (T2DM). Twenty-three male patients fasted every other day for 30 h for 6 weeks. Experiments included resting energy expenditure, continuous glucose monitoring, intravenous glucose tolerance test, euglycemic hyperinsulinemic clamp, body composition, hepatic triglyceride content, muscle biopsies which were performed at baseline, during 3 weeks without allowed weight loss, and after additional 3 weeks with weight loss. Bodyweight decreased ∼1% and further ∼3% during weeks one to three and four to six, respectively (p < 0.05). Only minor changes in fat mass occurred in weeks 1-3. With weight loss, visceral fat content decreased by 13 ± 3% and 12 ± 2% from baseline in patients with and without T2DM, respectively (p < 0.05). Hepatic triglyceride content decreased by 17 ± 9% and 36 ± 9% (with diabetes) and 27 ± 8% and 40 ± 8% (without diabetes) from baseline to week 3 and week 6, respectively (all p < 0.05). Muscle lipid and glycogen content oscillated with the intervention. Glucose homeostasis, insulin secretion and sensitivity was impaired in patients with T2DM and did not change without weight loss, but improved (p < 0.05) when alternate day fasting was combined with weight loss. In conclusion, alternate-day fasting is feasible in patients with obesity and T2DM, and decreases visceral fat and liver fat deposits. Energy store oscillations by alternate-day fasting do not improve insulin secretion or sensitivity per se. Clinical Trial registration: (ClinicalTrials.gov), (ID NCT02420054).

Keywords:  fasting; glucose homeostasis; insulin sensitivity; visceral fat; weight loss; β-cell

DOI:  https://doi.org/10.3389/fphys.2022.1061063
Science. 2022 Dec 23. 378(6626): 1267

Moms' mitochondria may refresh cells in sick kids.

Mitch Leslie.

Technique is designed to treat mitochondrial disease.

DOI: https://doi.org/10.1126/science.adg3936
Physiol Rep. 2022 Dec;10(24): e15539

Acute responsiveness to single leg cycling in adults with obesity.

Kevin J Gries, Corey R Hart, Hawley E Kunz, Zachary Ryan, Xiaoyan Zhang, Mojtaba Parvizi, Yuanhang Liu, Surendra Dasari, Ian R Lanza.

  Obesity is associated with several skeletal muscle impairments which can be improved through an aerobic exercise prescription. The possibility that exercise responsiveness is diminished in people with obesity has been suggested but not well-studied. The purpose of this study was to investigate how obesity influences acute exercise responsiveness in skeletal muscle and circulating amino metabolites. Non-obese (NO; n = 19; 10F/9M; BMI = 25.1 ± 2.8 kg/m2 ) and Obese (O; n = 21; 14F/7M; BMI = 37.3 ± 4.6 kg/m2 ) adults performed 30 min of single-leg cycling at 70% of VO2 peak. 13 C6 -Phenylalanine was administered intravenously for muscle protein synthesis measurements. Serial muscle biopsies (vastus lateralis) were collected before exercise and 3.5- and 6.5-h post-exercise to measure protein synthesis and gene expression. Targeted plasma metabolomics was used to quantitate amino metabolites before and 30 and 90 min after exercise. The exercise-induced fold change in mixed muscle protein synthesis trended (p = 0.058) higher in NO (1.28 ± 0.54-fold) compared to O (0.95 ± 0.42-fold) and was inversely related to BMI (R2 = 0.140, p = 0.027). RNA sequencing revealed 331 and 280 genes that were differentially expressed after exercise in NO and O, respectively. Gene set enrichment analysis showed O had six blunted pathways related to metabolism, cell to cell communication, and protein turnover after exercise. The circulating amine response further highlighted dysregulations related to protein synthesis and metabolism in adults with obesity at the basal state and in response to the exercise bout. Collectively, these data highlight several unique pathways in individuals with obesity that resulted in a modestly blunted exercise response.

Keywords:  amino acid metabolism; exercise; protein synthesis; transcriptome

DOI:  https://doi.org/10.14814/phy2.15539
J Physiol. 2022 Dec 19.

A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.

Ronald G Jones, Andrea Dimet-Wiley, Amin Haghani, Francielly Morena da Silva, Camille R Brightwell, Seongkyun Lim, Sabin Khadgi, Yuan Wen, Cory M Dungan, Robert T Brooke, Nicholas P Greene, Charlotte A Peterson, John J McCarthy, Steve Horvath, Stanley J Watowich, Christopher S Fry, Kevin A Murach.

   KEY POINTS: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodeling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2, and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle Myc is the Yamanaka factor most induced by exercise in skeletal muscle, so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation gene landscapes in mice and humans A single pulse of MYC is sufficient to remodel the muscle methylome We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses ABSTRACT: Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from 1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2, and Myc (OKSM) reprogramming-factor expression murine model, 2) an in vivo inducible muscle-specific Myc induction murine model, 3) a translatable high-volume hypertrophic exercise training approach in aged mice, and 4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM, and exercise training in mice as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Abstract figure legend Diverse forms of exercise training improve muscle function and whole-body health, even if initiated late in life. Information on conserved exercise-controlled molecular cues that underpin a younger muscle phenotype in aged muscle has potential utility in the development of anti-ageing therapies. Induction of the Yamanaka factors Oct3/4, Klf4, Sox2, and Myc are known to ameliorate ageing hallmarks. Comparison of transcriptomic data from aged exercise-trained mice and humans to muscle fibre-specific genetically driven models of epigenetic reprogramming (e.g. Yamanaka factor or Myc expression) unearthed conserved biomarkers associated with molecular age mitigation. Considering reduced biological age according to DNA methylome analysis, high-volume exercise training can be classified as an epigenetic reprogramming stimulus. Chronic exercise should be considered alongside and/or as a method to inform healthspan-extending longevity approaches such as pharmacologic and dietary interventions. This article is protected by copyright. All rights reserved.

Keywords:  DNA methylation; MYC; Yamanaka factors; ageing

DOI:  https://doi.org/10.1113/JP283836
Front Cardiovasc Med. 2022 ;9 1016452

Skeletal muscle phenotypic switching in heart failure with preserved ejection fraction.

Eng Leng Saw, Louis Dominic Werner, Payman Zamani, Julio A Chirinos, María Valero-Muñoz, Flora Sam.

   Background: Skeletal muscle (SkM) phenotypic switching is associated with exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Patients with HFpEF have decreased type-1 oxidative fibers and mitochondrial dysfunction, indicative of impaired oxidative capacity. The SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) mice are commonly used in HFpEF pre-clinical studies and demonstrate cardiac, lung, kidney, and white adipose tissue impairments. However, the SkM (specifically the oxidative-predominant, soleus muscle) has not been described in this preclinical HFpEF model. We sought to characterize the soleus skeletal muscle in the HFpEF SAUNA mice and investigate its translational potential.
Methods: HFpEF was induced in mice by uninephrectomy, d-aldosterone or saline (Sham) infusion by osmotic pump implantation, and 1% NaCl drinking water was given for 4 weeks. Mice were euthanized, and the oxidative-predominant soleus muscle was collected. We examined fiber composition, fiber cross-sectional area, capillary density, and fibrosis. Molecular analyses were also performed. To investigate the clinical relevance of this model, the oxidative-predominant, vastus lateralis muscle from patients with HFpEF was biopsied and examined for molecular changes in mitochondrial oxidative phosphorylation, vasculature, fibrosis, and inflammation.
Results: Histological analyses demonstrated a reduction in the abundance of oxidative fibers, type-2A fiber atrophy, decreased capillary density, and increased fibrotic area in the soleus muscle of HFpEF mice compared to Sham. Expression of targets of interest such as a reduction in mitochondrial oxidative-phosphorylation genes, increased VEGF-α and an elevated inflammatory response was also seen. The histological and molecular changes in HFpEF mice are consistent and comparable with changes seen in the oxidative-predominant SkM of patients with HFpEF.
Conclusion: The HFpEF SAUNA model recapitulates the SkM phenotypic switching seen in HFpEF patients. This model is suitable and relevant to study SkM phenotypic switching in HFpEF.

Keywords:  atrophy; exercise intolerance; heart failure with preserved ejection fraction; oxidative metabolism fibers; skeletal muscle

DOI:  https://doi.org/10.3389/fcvm.2022.1016452
Molecules. 2022 Dec 09. pii: 8715. [Epub ahead of print]27(24):

Sodium Butyrate Attenuates AGEs-Induced Oxidative Stress and Inflammation by Inhibiting Autophagy and Affecting Cellular Metabolism in THP-1 Cells.

Man Yan, Xiang Li, Chang Sun, Jiajun Tan, Yuanyuan Liu, Mengqi Li, Zishang Qi, Jiayuan He, Dongxu Wang, Liang Wu.

  In recent years, sodium butyrate has gained increased attention for its numerous beneficial properties. However, whether sodium butyrate could alleviate inflammatory damage by macrophage activation and its underlying mechanism remains unclear. The present study used an advanced glycosylation products- (AGEs-) induced inflammatory damage model to study whether sodium butyrate could alleviate oxidative stress, inflammation, and metabolic dysfunction of human monocyte-macrophage originated THP-1 cells in a PI3K-dependent autophagy pathway. The results indicated that sodium butyrate alleviated the AGEs-induced oxidative stress, decreased the level of reactive oxygen species (ROS), increased malondialdehyde (MDA) and mRNA expression of pro-inflammatory cytokines of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and increased the content of superoxide dismutase (SOD). Sodium butyrate reduced the protein expression of the NLR family, pyrin domain-containing protein 3 (NLRP3) and Caspase-1, and decreased the nucleus expression of nuclear factor-kappaB (NF-κB). Sodium butyrate decreased the expression of light-chain-associated protein B (LC3B) and Beclin-1, and inhibited autophagy. Moreover, sodium butyrate inhibited the activation of the PI3K/Akt pathway in AGEs-induced THP-1 cells. In addition, the metabolomics analysis showed that sodium butyrate could affect the production of phosphatidylcholine, L-glutamic acid, UDP-N-acetylmuraminate, biotinyl-5'-AMP, and other metabolites. In summary, these results revealed that sodium butyrate inhibited autophagy and NLRP3 inflammasome activation by blocking the PI3K/Akt/NF-κB pathway, thereby alleviating oxidative stress, inflammation, and metabolic disorder induced by AGEs.

Keywords:  advanced glycation end products; cellular metabolism; diabetic nephropathy; inflammatory damage; sodium butyrate

DOI:  https://doi.org/10.3390/molecules27248715
FASEB J. 2023 Jan;37(1): e22708

The novel sustained 3-hydroxybutyrate donor poly-D-3-hydroxybutyric acid prevents inflammatory bowel disease through upregulation of regulatory T-cells.

Rimina Suzuki, Mayuko Mishima, Masaki Nagane, Hinano Mizugaki, Takehito Suzuki, Mariko Komuro, Takuto Shimizu, Tomoki Fukuyama, Shiro Takeda, Masaya Ogata, Takayoshi Miyamoto, Naoyuki Aihara, Junichi Kamiie, Shinji Kamisuki, Hiroto Yokaryo, Tadashi Yamashita, Takumi Satoh.

  Inflammatory bowel disease (IBD) is a chronic persistent intestinal disorder, with ulcerative colitis and Crohn's disease being the most common. However, the physio-pathological development of IBD is still unknown. Therefore, research on the etiology and treatment of IBD has been conducted using a variety of approaches. Short-chain fatty acids such as 3-hydroxybutyrate (3-HB) are known to have various physiological activities. In particular, the production of 3-HB by the intestinal microflora is associated with the suppression of various inflammatory diseases. In this study, we investigated whether poly-D-3-hydroxybutyric acid (PHB), a polyester of 3-HB, is degraded by intestinal microbiota and works as a slow-release agent of 3-HB. Further, we examined whether PHB suppresses the pathogenesis of IBD models. As long as a PHB diet increased 3-HB concentrations in the feces and blood, PHB suppressed weight loss and histological inflammation in a dextran sulfate sodium-induced IBD model. Furthermore, PHB increased the accumulation of regulatory T cells in the rectum without affecting T cells in the spleen. These results indicate that PHB has potential applications in treating diseases related to the intestinal microbiota as a sustained 3-HB donor. We show for the first time that biodegradable polyester exhibits intestinal bacteria-mediated bioactivity toward IBD. The use of bioplastics, which are essential materials for sustainable social development, represents a novel approach to diseases related to dysbiosis, including IBD.

Keywords:  3-hydroxybutyrate; Tregs; biodegraded plastic; inflammatory bowel disease; poly-D-3-hydroxybutyric acid; short-chain fatty acids

DOI:  https://doi.org/10.1096/fj.202200919R
Front Vet Sci. 2022 ;9 1011159

Beyond antioxidants: Selenium and skeletal muscle mitochondria.

Lauren T Wesolowski, Pier L Semanchik, Sarah H White-Springer.

  The element, Selenium (Se), has an essential nutritive and biological role as a trace mineral known primarily for its vital antioxidant functions as a constituent of the selenoenzyme, glutathione peroxidase. However, Se also has a much more global biological impact beyond antioxidant function. The objective of this review is to present an overview of prior research on the extra-antioxidant effects of Se with a key focus on skeletal muscle mitochondrial energetics. Cognizance of these additional functions of Se is requisite when formulating and recommending dietary supplementation of Se in humans or animals. Chief amongst its myriad of biological contributions, Se influences mitochondrial capacity and function and, subsequently, muscular health. Dietary Se supplementation has been shown to increase skeletal muscle mitochondrial volume density and within some cell lines, Se treatment increases mitochondrial biogenesis and respiratory capacity. In addition, the selenoproteins H, N, W, and O and deiodinases exhibit varying effects on mitochondrial and/or skeletal muscle function. Selenoprotein H enhances mitochondrial biogenesis whereas selenoproteins N and W appear to influence muscle calcium homeostasis which impacts mitochondrial function. Moreover, selenoprotein O's intramitochondrial residence facilitates Se's redox function. Deiodinases regulate thyroid hormone activation which impacts muscle cell regeneration, metabolism, and reactive oxygen species production. Although the precise relationships between dietary Se and skeletal muscle mitochondria remain unclear, previous research constitutes a firm foundation that portends promising new discoveries by future investigations.

Keywords:  mitochondria; mitochondrial biogenesis; selenium; selenoprotein; skeletal muscle

DOI:  https://doi.org/10.3389/fvets.2022.1011159
Amino Acids. 2022 Dec 22.

Effect of AMPK activation and glucose availability on myotube LAT1 expression and BCAA utilization.

Caroline N Rivera, Rachel M Watne, Zoe A Brown, Samantha A Mitchell, Andrew J Wommack, Roger A Vaughan.

  Those with insulin resistance often display increased circulating branched-chain amino acids (BCAA), which has been largely attributable to reduced BCAA catabolic capacity. Metabolic stimuli such as exercise activates AMP-activated kinase (AMPK), which promotes the metabolism of BCAA and induction/activation of BCAA catabolic enzymes. Though much attention has been paid to BCAA catabolic machinery, few studies have assessed the effect of AMPK activation on the predominant BCAA transporter, L-type amino acid transporter 1 (LAT1). This study assessed the effect of AMPK activation on LAT1 expression via common chemical AMPK activators in a cell model of skeletal muscle. C2C12 myotubes were treated with either 1 mM AICAR, 1 mM Metformin, or filter-sterilized water (control) for 24 h with either low- (5 mM) or high-glucose (25 mM) media. LAT1 and pAMPK protein content were measured via western blot. BCAA media content was measured using liquid chromatography-mass spectrometry. AICAR treatment significantly increased pAMPK and reduced LAT1 expression. Collectively, pAMPK and LAT1 displayed a significant inverse relationship independent of glucose levels. During low-glucose experiments, AICAR-treated cells had higher BCAA media content compared to other groups, and an inverse relationship between LAT1 and BCAA media content was observed, however, these effects were not consistently observed during high-glucose conditions. Further investigation with AICAR with and without concurrent LAT1 inhibition (via JPH203) also revealed reduced BCAA utilization in AICAR-treated cells regardless of LAT1 inhibition (which also independently reduced BCAA utilization). pAMPK activation via AICAR (but not Metformin) may reduce LAT1 expression and BCAA uptake in a glucose-dependent manner.

Keywords:  Insulin resistance; Isoleucine; Leucine; Skeletal muscle; Valine; pAMPK:AMPK

DOI:  https://doi.org/10.1007/s00726-022-03224-7
Obesity (Silver Spring). 2022 Dec 22.

Eight-hour time-restricted eating does not lower daily myofibrillar protein synthesis rates: A randomized control trial.

Evelyn B Parr, Imre W K Kouw, Michael J Wheeler, Bridget E Radford, Rebecca C Hall, Joan M Senden, Joy P B Goessens, Luc J C van Loon, John A Hawley.

OBJECTIVE: This study aimed to assess the impact of time-restricted eating (TRE) on integrated skeletal muscle myofibrillar protein synthesis (MyoPS) rates in males with overweight/obesity.
METHODS: A total of 18 healthy males (age 46 ± 5 years; BMI: 30 ± 2 kg/m2 ) completed this exploratory, parallel, randomized dietary intervention after a 3-day lead-in diet. Participants then consumed an isoenergetic diet (protein: ~1.0 g/kg body mass per day) following either TRE (10:00 a.m. to 6:00 p.m.) or an extended eating control (CON; 8:00 a.m. to 8:00 p.m.) protocol for 10 days. Integrated MyoPS rates were measured using deuterated water administration with repeated saliva, blood, and muscle sampling. Secondary measures included continuous glucose monitoring and body composition (dual-energy x-ray absorptiometry).
RESULTS: There were no differences in daily integrated MyoPS rates (TRE: 1.28% ± 0.18% per day, CON: 1.26% ± 0.22% per day; p = 0.82) between groups. From continuous glucose monitoring, 24-hour total area under the curve was reduced following TRE (-578 ± 271 vs. CON: 12 ± 272 mmol/L × 24 hours; p = 0.001). Total body mass declined (TRE: -1.6 ± 0.9 and CON: -1.1 ± 0.7 kg; p < 0.001) with no differences between groups (p = 0.22). Lean mass loss was greater following TRE compared with CON (-1.0 ± 0.7 vs. -0.2 ± 0.5 kg, respectively; p = 0.01).
CONCLUSION: Consuming food within an 8-hour time-restricted period does not lower daily MyoPS rates when compared with an isoenergetic diet consumed over 12 hours. Future research should investigate whether these results translate to free-living TRE.

DOI: https://doi.org/10.1002/oby.23637
Curr Opin Urol. 2022 Dec 26.

Inflammation and kidney stones: cause and effect?

Giovanna Capolongo, Manuel Ferraro, Robert Unwin.

PURPOSE OF REVIEW: This short review is intended to highlight the potential role of inflammation as a key pathological driver, rather than a mere consequence, of nephrolithiasis. Although there is clearly a strong likelihood that the relationship is bidirectional, and that kidney stone-triggered inflammation can establish a vicious cycle of tissue injury and stone formation.
RECENT FINDINGS: These consist of data from both recent preclinical and clinical studies demonstrating the importance of inflammation in models of stone disease and in kidney tissue from patients with nephrolithiasis, and as a potential driver of disease recurrence and a suitable treatment target. In particular, the role of immune cells and their relationship to the NLRP3 inflammasome is becoming clearer, as well as the potential contribution to tissue injury and stone formation of the pro-inflammatory cytokines interleukin-1β and interleukin-18.
SUMMARY: This concept is not new and raises the possibility that targeting inflammation directly may prove to be a novel and suitable means of treatment for at least some types of kidney stone, and in certain clinical settings, both acutely and as prevention, especially in those patients experiencing recurrent stone episodes and/or who have a well defined metabolic cause such as uric acid or calcium oxalate stones.

DOI: https://doi.org/10.1097/MOU.0000000000001066
Cell Rep. 2022 Dec 20. pii: S2211-1247(22)01739-9. [Epub ahead of print]41(12): 111847

β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb.

Yufan Zheng, Wenrui Sun, Cong Shan, Borui Li, Jiaying Liu, Hao Xing, Qingling Xu, Baiping Cui, Wenjia Zhu, Jia Chen, Liyan Liu, Tian Yang, Ning Sun, Xiaobo Li.

  Acute pancreatitis and hyperamylasemia are often seen in patients with acute liver failure (ALF). However, the underlying mechanisms remain elusive. This study describes pancreatic tissue damage and exocrine dysfunction in a mouse model of major-liver-resection-induced ALF. The analysis of 1,264 clinical cases of liver failure (LF) showed that the incidence of hyperamylasemia and hyperlipasemia in patients with LF is 5.5% and 20%, respectively. Metabolomic studies indicate that glutathione (GSH)-deficiency-caused ferroptosis contributes to pancreatic damage in mouse ALF. β-hydroxybutyrate (β-HB) is the only metabolite downregulated in the liver, serum, and pancreas. Our data suggest that β-HB protects pancreatic cells and tissues from GSH-deficiency-caused ferroptosis. β-HB administration in ALF mice restores the expression of ferroptosis-suppressor genes through histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb)-mediated chromatin opening. Our findings highlight β-HB as an endogenous metabolite regulating ferroptosis in the pancreas and extend our understanding of the pathophysiology of ALF-induced pancreatitis.

Keywords:  CP: Metabolism; CP: Molecular biology; H3K9bhb; acute liver failure; chromatin opening; epigenetic regulation; ferroptosis; pancreatitic damage; β-hydroxybutyrate; β-hydroxybutyrylation

DOI:  https://doi.org/10.1016/j.celrep.2022.111847
Int J Mol Sci. 2022 Dec 07. pii: 15506. [Epub ahead of print]23(24):

Butyrate Lowers Cellular Cholesterol through HDAC Inhibition and Impaired SREBP-2 Signalling.

Stephanie Bridgeman, Hon Chiu Woo, Philip Newsholme, Cyril Mamotte.

  In animal studies, HDAC inhibitors such as butyrate have been reported to reduce plasma cholesterol, while conferring protection from diabetes, but studies on the underlying mechanisms are lacking. This study compares the influence of butyrate and other HDAC inhibitors to that of statins on cholesterol metabolism in multiple cell lines, but primarily in HepG2 hepatic cells due to the importance of the liver in cholesterol metabolism. Sodium butyrate reduced HepG2 cholesterol content, as did sodium valproate and the potent HDAC inhibitor trichostatin A, suggesting HDAC inhibition as the exacting mechanism. In contrast to statins, which increase SREBP-2 regulated processes, HDAC inhibition downregulated SREBP-2 targets such as HMGCR and the LDL receptor. Moreover, in contrast to statin treatment, butyrate did not increase cholesterol uptake by HepG2 cells, consistent with its failure to increase LDL receptor expression. Sodium butyrate also reduced ABCA1 and SRB1 protein expression in HepG2 cells, but these effects were not consistent across all cell types. Overall, the underlying mechanism of cell cholesterol lowering by sodium butyrate and HDAC inhibition is consistent with impaired SREBP-2 signalling, and calls into question the possible use of butyrate for lowering of serum LDL cholesterol in humans.

Keywords:  HDAC inhibitors; LDL; SREBP-2; butyrate; cholesterol; statins

DOI:  https://doi.org/10.3390/ijms232415506
Front Physiol. 2022 ;13 1040381

Exercise and mitochondrial mechanisms in patients with sarcopenia.

Hamed Alizadeh Pahlavani, Ismail Laher, Beat Knechtle, Hassane Zouhal.

  Sarcopenia is a severe loss of muscle mass and functional decline during aging that can lead to reduced quality of life, limited patient independence, and increased risk of falls. The causes of sarcopenia include inactivity, oxidant production, reduction of antioxidant defense, disruption of mitochondrial activity, disruption of mitophagy, and change in mitochondrial biogenesis. There is evidence that mitochondrial dysfunction is an important cause of sarcopenia. Oxidative stress and reduction of antioxidant defenses in mitochondria form a vicious cycle that leads to the intensification of mitochondrial separation, suppression of mitochondrial fusion/fission, inhibition of electron transport chain, reduction of ATP production, an increase of mitochondrial DNA damage, and mitochondrial biogenesis disorder. On the other hand, exercise adds to the healthy mitochondrial network by increasing markers of mitochondrial fusion and fission, and transforms defective mitochondria into efficient mitochondria. Sarcopenia also leads to a decrease in mitochondrial dynamics, mitophagy markers, and mitochondrial network efficiency by increasing the level of ROS and apoptosis. In contrast, exercise increases mitochondrial biogenesis by activating genes affected by PGC1-ɑ (such as CaMK, AMPK, MAPKs) and altering cellular calcium, ATP-AMP ratio, and cellular stress. Activation of PGC1-ɑ also regulates transcription factors (such as TFAM, MEFs, and NRFs) and leads to the formation of new mitochondrial networks. Hence, moderate-intensity exercise can be used as a non-invasive treatment for sarcopenia by activating pathways that regulate the mitochondrial network in skeletal muscle.

Keywords:  aging; exercise; mechanism; mitochondria; sarcopenia

DOI:  https://doi.org/10.3389/fphys.2022.1040381
J Appl Physiol (1985). 2022 Dec 22.

Skeletal muscle morphology, satellite cells and oxidative profile in relation to physical function and lifelong endurance training in very old men.

Elisabeth Skoglund, Per Stål, Tommy R Lundberg, Thomas Gustafsson, Per A Tesch, Lars-Eric Thornell.

  In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, including a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EA) aged 82-92 years, and nineteen subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 years were analyzed. ULSAM subjects were divided into high (n=9, HF) and low (n=10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome C oxidase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differences between LF and HF (P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong endurance training, but not higher physical function, was associated with the preservation of muscle oxidative capacity, even beyond the age of 80.

Keywords:  endurance exercise; healthy aging; skeletal muscle; skeletal muscle morphology

DOI:  https://doi.org/10.1152/japplphysiol.00343.2022
J Med Philos. 2022 Dec 23. 47(6): 770-783

Is Aging a Disease? The Theoretical Definition of Aging in the Light of the Philosophy of Medicine.

Cristian Saborido, Pablo García-Barranquero.

  In the philosophical debate on aging, it is common to raise the question of the theoretical definition of aging in terms of its possible characterization as a disease. Understanding aging as a disease seems to imply its medicalization, which has important practical consequences. In this paper, we analyze the question of whether aging is a disease by appealing to the concept of disease in the philosophy of medicine. As a result of this analysis, we argue that a pragmatist approach to the conception of disease is the best alternative to highlight the relevance of the medicalization of aging. From this pragmatist perspective, it can be seen that the notion of aging is going through a conceptual change, and aging can today be understood as a not radically different process from any other condition that is usually considered a disease.

Keywords:   aging ; disease ; philosophy of medicine ; pragmatism

DOI:  https://doi.org/10.1093/jmp/jhac030