bims-kimdis 2024-12-08 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–12–08
twenty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.
Current situation and challenge of exogenous 3-hydroxybutyrate derived from polyhydroxyalkanoates for elderly health: A review.
Exogenous ketone therapy does not protect brain tissue after moderate-sized intracerebral hemorrhage despite signs of early neurological benefit.
The effects of portfolio moderate-carbohydrate and ketogenic diets on anthropometric indices, metabolic status, and hormonal levels in overweight or obese women with polycystic ovary syndrome: a randomized controlled trial.
The impact of a ketogenic diet on weight loss, metabolism, body composition and quality of life.
Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.
Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.
Mendelian randomization study on the association of circulating ketone bodies with lung cancer and respiratory diseases.
Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice.
Clockwork conditioning: Aligning the skeletal muscle clock with time-of-day exercise for cardiometabolic health.
Survey of Latin American ketogenic diet centers: Challenges and success for "La Terapia Cetogénica".
Replacing dietary carbohydrate with protein and fat improves lipoprotein subclass profile and liver fat in type 2 diabetes independent of body weight: evidence from two randomized controlled trials.
Menstrual cycle phase does not influence muscle protein synthesis or whole-body myofibrillar proteolysis in response to resistance exercise.
Butyrate metabolism in rumen epithelium affected by host and diet regime through regulating microbiota in a goat model.
Deciphering the mechanisms and effects of hyperglycemia on skeletal muscle atrophy.
Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.
Attenuation of adipose tissue inflammation by pro-resolving lipid mediators.
Exploring ketogenic diet resistance in glucose transporter type 1 deficiency syndrome: A comprehensive review and critical appraisal.
Effects of time-of-day resistance training on muscle strength, hormonal adaptations, and sleep quality during Ramadan fasting.
Effect of sodium butyrate on kidney and liver mitochondrial dysfunction in a lipopolysaccharide mouse model.
The role of exosomes for sustained specific cardiorespiratory and metabolic improvements in males with type 2 diabetes after detraining.
Rapamycin administration causes a decrease in muscle contractile function and systemic glucose intolerance concomitant with reduced skeletal muscle Rictor, the mTORC2 component, expression independent of energy intake in young rats.
Effects of probiotic supplementation with high-intensity interval training on cardiorespiratory endurance and metabolism in Middle-Aged Obese Women.
What is ageing? Even the field's researchers can't agree.

Cell Chem Biol. 2024 Nov 25. pii: S2451-9456(24)00459-8. [Epub ahead of print]

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

Sidharth S Madhavan, Stephanie Roa Diaz, Sawyer Peralta, Mitsunori Nomura, Christina D King, Kaya E Ceyhan, Anwen Lin, Dipa Bhaumik, Anna C Foulger, Samah Shah, Thanh Blade, Wyatt Gray, Manish Chamoli, Brenda Eap, Oishika Panda, Diego Diaz, Thelma Y Garcia, Brianna J Stubbs, Scott M Ulrich, Gordon J Lithgow, Birgit Schilling, Eric Verdin, Asish R Chaudhuri, John C Newman.

  Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). We identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility. βHB primarily provides ATP substrate during periods of reduced glucose availability, and regulates other cellular processes through protein interactions. We demonstrate βHB-induced protein insolubility is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. This mechanism is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We generate libraries of the βHB-induced protein insolublome using mass spectrometry proteomics, and identify common protein domains and upstream regulators. We show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain. These data indicate a metabolically regulated mechanism of proteostasis relevant to aging and AD.

Keywords:  Alzheimer disease; aging; ketone body; neurodegenerative disease; proteostasis

DOI:  https://doi.org/10.1016/j.chembiol.2024.11.001
Int J Biol Macromol. 2024 Dec 02. pii: S0141-8130(24)09139-6. [Epub ahead of print]285 138328

Current situation and challenge of exogenous 3-hydroxybutyrate derived from polyhydroxyalkanoates for elderly health: A review.

Dai-Xu Wei, Zongcun Chen.

  3-Hydroxybutyrate (3HB), predominantly found in the liver, muscles, and brain, is the most important endogenous ketone body in humans. During prolonged fasting and starvation, 3HB can partially replace glucose to meet some of the body's energy needs. In recent years, the resurgence of the ketogenic diet (KD) and systematic exploration of the favorable biocompatibility of polyhydroxyalkanoates (PHAs), the precursor polymer to 3HB, have led to numerous reports indicating that the benefits of exogenous 3HB supplementation outweigh the drawbacks, particularly for middle-aged and elderly individuals. In this review, the physicochemical properties, physiological functions, and biosafety of 3HB in the elderly population are introduced. The effects of exogenous 3HB supplements, including KD, ketone esters, 1,3-butanediol, and ketone salts, on the elderly are compared. It is proposed that exogenous 3HB derived from PHAs is optimal for this population. Exogenous 3HB supplementation for elderly health maintenance and disease treatment is summarized, with an outline of four challenges related to the mechanistic and clinical research of exogenous 3HB supplementation for elderly health. This aims to explore its novel therapeutic potential as a small molecule in the context of aging.

Keywords:  3-Hydroxybutyrate; Elderly; Polyhydroxyalkanoates

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138328
PLoS One. 2024 ;19(12): e0311778

Exogenous ketone therapy does not protect brain tissue after moderate-sized intracerebral hemorrhage despite signs of early neurological benefit.

Noam H Sander, Shubham Soni, Cassandra M Wilkinson, Elmira Khiabani, Jason R B Dyck, Frederick Colbourne.

Ketone bodies, or ketones, are an alternative energy source and have several nonmetabolic signaling actions, such as inhibiting inflammation. Because of this, exogenous ketone supplementation has been used to help treat various diseases. β-hydroxybutyrate (βHB) is the major ketone body that has reduced neurological injury and brain edema in animal models of ischemic stroke and traumatic brain injury. However, the therapeutic potential of βHB in intracerebral hemorrhage (ICH) has not yet been determined. Here we investigated the effects of exogenous βHB treatment following ICH on inflammation, edema, injury size, and functional outcomes. To do this, we administered 250 mg/kg of βHB (subcutaneously every 12 hours) starting 2 hours after collagenase-induced ICH in rats over 3 experiments. First, we observed that βHB-treated rats had significant reductions in transcript expression of pro-inflammatory markers Il1b (p = 0.0210), Tnfa (p = 0.0108), and Mcp1 (p = 0.0473) 3 days post-ICH. Second, βHB significantly improved neurological deficits measured by the neurological deficit scale on day 3 (p = 0.0416) in another cohort of rats, despite no treatment effect on edema (p = 0.2110). To test whether the effects of acute βHB treatment (for 7 days post-ICH) were chronically sustained, the third experiment used serial behavioural testing which confirmed that βHB significantly improved neurological deficit scores (p = 0.0459) 3 days post-ICH. These effects were not sustained at 7, 14, and 28 days post-ICH (all p≥0.1546). Similarly, βHB treatment did not yield differences in forelimb use asymmetry (all p>0.45) or brain lesion volume (p = 0.3381), the primary endpoint of this study. Thus, our studies show that an acute βHB treatment post-ICH can provide some early signs of functional benefit without evidence of lasting effects or neuroprotection. However, it remains to be tested whether other βHB dosing regimens may favorably affect these and other neurological, behavioral, and biochemical parameters, particularly given the early signals of reduced striatal inflammation.

DOI: https://doi.org/10.1371/journal.pone.0311778
Nutr J. 2024 Dec 02. 23(1): 152

The effects of portfolio moderate-carbohydrate and ketogenic diets on anthropometric indices, metabolic status, and hormonal levels in overweight or obese women with polycystic ovary syndrome: a randomized controlled trial.

Maryam Sharifi, Amir Saber, Jalal Moludi, Yahya Salimi, Alireza Jahan-Mihan.

   BACKGROUND: Polycystic Ovary Syndrome (PCOS) is one of the most common hormonal disorders in reproductive-age women caused by hyperinsulinemia. The portfolio Moderate-carbohydrate diet (PMCD) is a plant-based diet with a carbohydrate content of 40% and incorporates five cholesterol-lowering foods. While, the ketogenic diet is a high-fat diet with 70% fat, promoting a ketosis state. To the best of our knowledge, no study compared the therapeutic effects of these two diets in PCOS patients. Thus, this study aimed to compare the impact of PLCD and KD on anthropometric indices, metabolic status, and hormonal levels in overweight or obese women with PCOS.
METHODS: This open-label, randomized clinical trial was conducted on forty-six PCOS women. 21 women in PMCD and 19 in the KD group completed the study. The anthropometric indices including body mass index (BMI) and fat body mass (FBM), metabolic markers (fasting blood glucose (FBG)) and plasma lipid profiles including low-density lipoprotein (LDL), triglycerides, and high-density lipoproteins (HDL) were measured. Reproductive hormones such as luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEA-s) and free testosterone were assessed at the baseline and after the intervention.
RESULTS: However, after 8 weeks both diets demonstrated enhancement in anthropometric indices (BMI, FBM, lean body mass), metabolic status (FBG, insulin serum levels), and reproductive hormones such as LH, free testosterone, and DHEA-s. The mean difference in the KD improved more than the PMCD in the field of BMI reduction (MD (SD) 2.73 (0.351) vs. MD (SD) 1.71 (0.775)) and LH (MD 4.13 (1.375) vs.MD 2.46 (1.105)). Nevertheless, the lipid profile including LDL-C and triglycerides improved more in the PMCD compared to the KD (MD 33.95 (7.345) vs. MD 23.34 (14.136)) and (MD 38.20 (10.757) vs. MD 57.62 (21.688)) respectively. There were no significant changes in the Ferriman-Gallwey score within or between the two groups.
CONCLUSION: The findings revealed that both diets were effective in improving PCOS manifestations. However, the KD exhibited greater effectiveness in enhancing body measurements, metabolic factors, and reproductive hormone levels compared to the PMCD in obese PCOS women. Furthermore, PMCD could be more beneficial for PCOS women with lipide disorders.
REGISTRATION NUMBER OF CLINICAL TRIAL: IRCT20200912048693N3, Trial registered 2022-12-14. https://www.irct.ir/trial/67548.

Keywords:  Insulin resistance; Ketogenic diet; Polycystic ovary syndrome; Portfolio low-carbohydrate diet

DOI:  https://doi.org/10.1186/s12937-024-01056-7
iScience. 2024 Dec 20. 27(12): 111291

The impact of a ketogenic diet on weight loss, metabolism, body composition and quality of life.

Simon Hirschberger, David Effinger, Polina Yoncheva, Annika Schmid, Mara-Noel Weis, Lesca-Miriam Holdt, Daniel Teupser, Simone Kreth.

  A ketogenic diet (KD) is increasingly debated as a countermeasure against nutrition-related modern diseases. While being immunologically beneficial, KD is still suspected of having severe metabolic side effects and negatively impacting general well-being, which prevents its widespread clinical use. We conducted a prospective pre-post interventional study investigating the effects of an eucaloric KD on metabolism, weight loss, body composition, diet adherence, and quality of life. The study had two stages: first, feasibility was tested in healthy, normal-weight participants over three weeks. After positive results, the KD period was expanded to three months, enrolling adults with overweight. Significant weight loss was observed in both groups, reducing body fat without affecting muscle or bone mass and without adverse metabolic changes. Quality of life improved, and fatigue symptoms in subjects with overweight decreased. These findings may help to overcome reservations about KD, encouraging its use as a medical tool for treating nutrition-related disorders.

Keywords:  Diet; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2024.111291
Aging Cell. 2024 Dec 04. e14386

Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.

Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Brent Appelman, Michèle van Vugt, Anita E Grootemaat, Nicole N van der Wel, Jos J de Koning, Frank W Bloemers, Rob C I Wüst.

  Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals. Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2.s-1.mg-1, p = 0.95) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%, p = 0.25), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U., p < 0.0001), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%, p = 0.002) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%, p = 0.005). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density. Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.

Keywords:  ageing; maximal oxygen uptake; mitochondrial morphology; mitochondrial respiration; skeletal muscle

DOI:  https://doi.org/10.1111/acel.14386
BMC Med. 2024 12 05. 22(1): 578

Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.

Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.

  Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.

Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect

DOI:  https://doi.org/10.1186/s12916-024-03775-4
Cell Death Dis. 2024 Dec 03. 15(12): 874

β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.

Ya-Ping Bai, Yu-Jie Xing, Tao Ma, Kai Li, Teng Zhang, De-Guo Wang, Shu-Jun Wan, Cui-Wei Zhang, Yue Sun, Meng-Yan Wang, Guo-Dong Wang, Wen-Jun Pei, Kun Lv, Yan Zhang, Xiang Kong.

β-Hydroxybutyrate (β-OHB), the primary ketone body, is a bioactive metabolite that acts as both an energy substrate and a signaling molecule. Recent studies found that β-OHB inhibits the production of pro-inflammatory cytokines in macrophages, but its underlying molecular mechanisms have not yet been fully elucidated. Lysine β-hydroxybutyrylation (Kbhb), a post-translational modification mediated by β-OHB, plays a key role in regulating the expression and activity of modified proteins. However, whether macrophages undergo protein Kbhb and whether Kbhb modification regulates macrophage polarization remains largely unknown. In this study, treatment with β-OHB and ketone ester significantly decreased the lipopolysaccharide (LPS)-induced enhancement of the M1 phenotype of mouse bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and peritoneal macrophages (PMs) in vitro and in vivo. Moreover, β-OHB treatment induced global protein Kbhb, which is associated with the regulation of macrophage M1 polarization. Proteome-wide Kbhb analysis in β-OHB-treated BMDMs revealed 3469 Kbhb modification sites within 1549 proteins, among which interleukin-12-responding proteins were significantly upregulated. Our results indicated that β-OHB regulated M1 macrophage polarization by inducing Kbhb modification of the signal transducer and activator of transcription 1 (STAT1) K679 site, which inhibited its LPS-induced phosphorylation and transcription. Altogether, our study demonstrated the presence of a widespread Kbhb landscape in the β-OHB-treated macrophages and provided novel insights into the anti-inflammatory effects of β-OHB.

DOI: https://doi.org/10.1038/s41419-024-07268-3
J Cachexia Sarcopenia Muscle. 2024 Dec 02.

Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Stefano Donega, Nirad Banskota, Esha Gupta, Marta Gonzalez-Freire, Ann Zenobia Moore, Ceereena Ubaida-Mohien, Rachel Munk, Linda Zukley, Yulan Piao, Chris Bergeron, Jan Bergeron, Arsun Bektas, Marta Zampino, Carole Stagg, Fred Indig, Lisa M Hartnell, Mary Kaileh, Kenneth Fishbein, Richard G Spencer, Myriam Gorospe, Supriyo De, Josephine M Egan, Ranjan Sen, Luigi Ferrucci.

   BACKGROUND: Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.
METHODS: Using RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22-89 years), we explored gene and splicing variant expression profiles associated with self-reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit-O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak.
RESULTS: The four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein-coding genes associated with four energetic measures adjusting for age, muscle fiber-ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up-regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism.
CONCLUSIONS: A consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy-splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.

Keywords:  VO2; aging; alternative splicing; energy; exercise; kPCr; mitochondria respirometry; muscle; physical activity

DOI:  https://doi.org/10.1002/jcsm.13603
Sci Rep. 2024 12 04. 14(1): 30205

Mendelian randomization study on the association of circulating ketone bodies with lung cancer and respiratory diseases.

Xisha Tang, Huijia Zhuang, Hai Yu.

  The liver produces various ketone bodies (KBs) including 3-Hydroxybutyrate (3-OHB), acetoacetate (AcAc), and acetone, with 3-OHB being the major component. Previous studies have shown that KBs protect against respiratory diseases; however, there is no evidence of a genetic link. To avoid biases existing in traditional observational studies, a two-sample Mendelian randomization (MR) analysis was carried out to investigate genetic causation and novel therapeutic uses for KBs. This study used databases from genome-wide association studies (GWAS) and single nucleotide polymorphisms as instrumental variables for KBs from a recently published metabonomics study (n = 121,584) and respiratory diseases [lung cancer, n = 85,716; asthma, n = 127,669; chronic bronchitis, n = 450,422; chronic obstructive pulmonary disease (COPD), n = 468,475; FEV1/FVC < 0.7, n = 353,315] from their publicly available GWAS, respectively. Strong sets of instrumental variables (P < 5 × 10- 8) were selected, with inverse-variance weighted as the primary MR method. Sensitivity analyses included Cochran's Q test, MR Egger, MR-PRESSO, leave-one-out test, and funnel plots. The Steiger test and reversed MR were used to exclude reverse causality. Additionally, independent replication MR studies were conducted using databases from another large public GWAS and similar methods as described above. After MR analyses and sensitivity filtering, we discovered a protective effect of 3-OHB on lung cancer (odds ratio [OR] = 0.771; 95% confidence interval [CI] = 0.648-0.916; PFDR=0.006), small cell carcinoma (OR = 0.485, 95% CI = 0.301-0.781, PFDR=0.006), asthma (OR = 0.585, 95% CI = 0.395-0.867, PFDR=0.010), chronic bronchitis (OR = 0.753, 95% CI = 0.570-0.994, PFDR=0.045), COPD (OR = 0.690, 95% CI = 0.535-0.890, PFDR=0.008) and lung function (OR = 0.970, 95%CI = 0.950-0.990, PFDR =0.008). In summary, our findings suggest that 3-OHB acts as a protective factor against lung cancer and respiratory diseases. However, heterogeneity implies that other mechanisms may also be involved in COPD improvement by 3-OHB.

Keywords:  3-Hydroxybutyrate; Asthma; COPD; Lung cancer; Mendelian randomization

DOI:  https://doi.org/10.1038/s41598-024-81591-9
Aging Cell. 2024 Dec 04. e14434

Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice.

Hongchao Wang, Ling Feng, Zhangming Pei, Jianxin Zhao, Shourong Lu, Wenwei Lu.

  The metabolism of branched-chain amino acids by gut microbiota can improve overall health and may reverse aging. In this study, we investigated Parabacteroides merdae, a gut microbe that is known to catabolise branched-chain amino acids (BCAAs). Three metabolites of BCAAs isovalerate, 2-methylbutyrate, and isobutyrate were used to treat D-gal induced aging mice. The results showed that these treatments could delay aging in mice by providing health benefits in reducing oxidative stress and inflammation, improving muscle capacity, reversing brain acetylcholine levels, and regulating blood glucose. The mechanism was preliminarily explored by combining the gut microbiota metagenome and faecal serum metabolome. Parabacteroides merdae altered the species composition and structure of the gut microbiota in mice. Increasing the abundance of beneficial bacteria, such as Bifidobacterium pseudolongum. Three metabolites affects the gut microbiota and the body's pathways of protein and improves the overall health through a variety of signaling pathways. Overall, regulating the gut microbiota involved in branched-chain amino acid metabolism to bring health benefits may be a new way of reversing aging.

Keywords:  aging; branched‐chain amino acids; gut microbiota; metabolism; mice

DOI:  https://doi.org/10.1111/acel.14434
J Mol Cell Cardiol. 2024 Nov 29. pii: S0022-2828(24)00201-3. [Epub ahead of print]198 36-44

Clockwork conditioning: Aligning the skeletal muscle clock with time-of-day exercise for cardiometabolic health.

Spencer B Procopio, Karyn A Esser.

  Circadian rhythms have evolved to synchronize gene expression, physiology, and behavior with time-of-day changes in the external environment. In every mammalian cell exists a core clock mechanism that consists of a transcriptional-translational feedback loop that drives rhythmic gene expression. Circadian disruption, as observed in shift workers and genetic mouse models, contributes to the onset and progression of cardiometabolic disorders. The central clock, located in the hypothalamus, is uniquely sensitive to external light cues, while the peripheral clocks are responsive to non-photic stimuli such as feeding and activity in addition to signals from the central clock. Recent research has illustrated the sensitivity of the skeletal muscle circadian clock to exercise timing, offering a promising avenue for therapeutic intervention in cardiometabolic health. Here we provide an in-depth examination of the molecular mechanisms underlying skeletal muscle clock function and its impact on cardiometabolic pathways, including glucose and lipid metabolism, as well as inflammation. To highlight the role of exercise as a time-cue for the skeletal muscle clock, we discuss evidence of exercise-induced shifts in the skeletal muscle clock and the differential response to exercise performed at different times of the day. Furthermore, we present data in support of time-of-day exercise as a potential therapeutic strategy for mitigating cardiometabolic disease burden. By exploring the relationship between the skeletal muscle clock, exercise timing, and cardiometabolic health, we identify new areas for future research and offer valuable insights into novel therapeutic approaches aimed at improving cardiometabolic disease outcomes.

Keywords:  Cardiometabolic disease; Circadian rhythm; Exercise; Muscle clock; Skeletal muscle

DOI:  https://doi.org/10.1016/j.yjmcc.2024.11.011
Epileptic Disord. 2024 Dec 05.

Survey of Latin American ketogenic diet centers: Challenges and success for "La Terapia Cetogénica".

Marisa Armeno, Eric H Kossoff, Laura Guilhoto, Roberto Caraballo.

   OBJECTIVE: Despite growing recognition of the efficacy of ketogenic diet therapies (KDT) in reducing seizure frequency and improving the quality of life for individuals with epilepsy, several factors hinder their widespread adoption across Latin America. Specific challenges in the region have been discussed but not formally studied. Currently, no data exist on the availability and operation of KDT teams in the region. To address this gap, we conducted a survey of KDT centers across Latin American countries in the framework of the biannual International Ketogenic Diet Conference in September 2023.
METHODS: A seven-question survey was distributed via email to neurologists, dietitians, or through indexed publications.
RESULTS: Of the 16 centers approached, 14 (87.5%) responded, identifying 98 KDT centers. Nearly half (49%) are public institutions, primarily in Brazil, Chile, and Mexico; 44 are private; and 5 are mixed. Core teams in all centers included a neurologist and dietitian, with some teams in Argentina, Chile, and Paraguay also involving a medical nutritionist. None of the centers reported a protocol for transitioning to adult care, and consistent data on Glut1 patients and protocols were lacking.
SIGNIFICANCE: Over the past two decades, the KDT landscape in Latin America has improved, with established centers expanding and new ones emerging. However, continued efforts are needed to promote KDT adoption in countries where it is not yet practiced and in regions with limited resources and expertise.

Keywords:  KDT centers; Latin America; ketogenic dietary therapy; survey

DOI:  https://doi.org/10.1002/epd2.20319
Am J Clin Nutr. 2024 Nov 29. pii: S0002-9165(24)01425-4. [Epub ahead of print]

Replacing dietary carbohydrate with protein and fat improves lipoprotein subclass profile and liver fat in type 2 diabetes independent of body weight: evidence from two randomized controlled trials.

Mads N Thomsen, Mads J Skytte, Amirsalar Samkani, Philip Weber, Mogens Fenger, Jan Frystyk, Elizaveta Hansen, Jens J Holst, Sten Madsbad, Faidon Magkos, Henrik S Thomsen, Rosemary L Walzem, Steen B Haugaard, Thure Krarup.

   BACKGROUND: Dyslipidemia with elevated levels of triacylglycerol-rich lipoproteins (TRL), small-dense LDL (sdLDL) and reduced HDL is linked to hepatic steatosis and promotes atherogenesis in type 2 diabetes (T2D).
OBJECTIVE: We have shown that moderate carbohydrate restriction reduces liver fat in T2D independent of changes in body weight. We tested whether this is accompanied by parallel improvements in plasma lipoprotein subclasses.
METHODS: We determined the density profile of circulating lipoproteins in patients with T2D from two previous randomized controlled trials. In the iso-energetic study ('Iso'), 30 participants were allocated in a cross-over design to 6 + 6 weeks of an isocaloric carbohydrate-reduced high-protein (CRHP, C/P/F=30/30/40 E%) or conventional diabetes (CD, C/P/F=50/17/33 E%) diet aimed at weight maintenance. In the hypo-energetic study ('Hypo'), 72 participants were allocated in a parallel-group design to 6 weeks of a hypocaloric CRHP or CD diet aimed at matched ∼6% weight loss. Both studies provided all meals from a metabolic kitchen to maximize adherence.
RESULTS: In the Iso study, the CRHP diet reduced mean (95% CI) TRL (-33 (-48, -14)%) and LDL5 (-16 (-26, -4)%), and increased HDL2/HDL3 (10 (0, 22)%) compared with the CD diet. In the Hypo study, weight loss induced by CRHP diet tended to reduce TRL (-16 (-30, 1)%), reduced LDL5 (-13 (-22, -3)%), and increased HDL2/HDL3 (11 (1, 22)%) compared with an equivalent weight loss induced by CD diet. The CRHP diet decreased intrahepatic triglyceride (IHTG) more than the CD diet (Iso: -55 (-74, -22)%; Hypo: -26 (-45, 0)%), and changes in IHTG correlated directly with changes in TRL and LDL5 (r=0.36-0.55, p<0.01 for all) in both studies.
CONCLUSIONS: Replacing dietary carbohydrate with protein and fat improves dyslipidemia in T2D independently of changes in body weight, by inducing an atheroprotective shift in the lipoprotein particle profile possibly facilitated by reduced IHTG accumulation.
CLINICALTRIALS:
GOV REGISTRATION: NCT02764021; https://clinicaltrials.gov/study/NCT02764021?term=NCT02764021&rank=1 NCT03814694; https://clinicaltrials.gov/study/NCT03814694?term=NCT03814694&rank=1.

Keywords:  Carbohydrate restriction; Dyslipidemia; Fatty liver; Lipoprotein metabolism; Nutrition therapy; Obesity; Type 2 diabetes; Weight loss

DOI:  https://doi.org/10.1016/j.ajcnut.2024.11.030
J Physiol. 2024 Dec 04.

Menstrual cycle phase does not influence muscle protein synthesis or whole-body myofibrillar proteolysis in response to resistance exercise.

Lauren M Colenso-Semple, James McKendry, Changhyun Lim, Philip J Atherton, Daniel J Wilkinson, K Smith, Stuart M Phillips.

  It has been hypothesised that skeletal muscle protein turnover is affected by menstrual cycle phase with a more anabolic environment during the follicular vs. the luteal phase. We assessed the influence of menstrual cycle phase on muscle protein synthesis and myofibrillar protein breakdown in response to 6 days of controlled resistance exercise in young females during peak oestrogen and peak progesterone, using stable isotopes, unbiased metabolomics and muscle biopsies. We used comprehensive menstrual cycle phase-detection methods, including cycle tracking, blood samples and urinary test kits, to classify menstrual phases. Participants (n = 12) completed two 6 day study phases in a randomised order: late follicular phase and mid-luteal phase. Participants performed unilateral resistance exercise in each menstrual cycle phase, exercising the contralateral leg in each phase in a counterbalanced manner. Follicular phase myofibrillar protein synthesis (MPS) rates were 1.33 ± 0.27% h-1 in the control leg and 1.52 ± 0.27% h-1 in the exercise leg. Luteal phase MPS was 1.28 ± 0.27% h-1 in the control leg and 1.46 ± 0.25% h-1 in the exercise leg. We observed a significant effect of exercise (P < 0.001) but no effect of cycle phase or interaction. There was no significant effect of menstrual cycle phase on whole-body myofibrillar protein breakdown (P = 0.24). Using unbiased metabolomics, we observed no notable phase-specific changes in circulating blood metabolites associated with any particular menstrual cycle phase. Fluctuations in endogenous ovarian hormones influenced neither MPS, nor MPB in response to resistance exercise. Skeletal muscle is not more anabolically responsive to resistance exercise in a particular menstrual cycle phase. KEY POINTS: It has been hypothesised that the follicular (peak oestrogen) vs. the luteal (peak progesterone) phase of the menstrual cycle is more advantageous for skeletal muscle anabolism in response to resistance exercise. Using best practice methods to assess menstrual cycle status, we measured integrated (over 6 days) muscle protein synthesis (MPS) and myofibrillar protein breakdown (MPB) following resistance exercise in females (n = 12) in their follicular and luteal phases. We observed the expected differences in oestrogen and progesterone concentrations that confirmed our participants' menstrual cycle phase; however, there were no notable metabolic pathway differences, as measured using metabolomics, between cycle phases. We observed that resistance exercise stimulated MPS, but there was no effect of menstrual cycle phase on either resting or exercise-stimulated MPS or MPB. Our data show no greater anabolic effect of resistance exercise in the follicular vs. the luteal phase of the menstrual cycle.

Keywords:  exercise; human muscle; menstrual cycle; protein metabolism

DOI:  https://doi.org/10.1113/JP287342
Anim Nutr. 2024 Dec;19 41-55

Butyrate metabolism in rumen epithelium affected by host and diet regime through regulating microbiota in a goat model.

Yimin Zhuang, Mahmoud M Abdelsattar, Yuze Fu, Naifeng Zhang, Jianmin Chai.

  The rumen is an important organ that enables ruminants to digest nutrients. However, the biological mechanism by which the microbiota and its derived fatty acids regulate rumen development is still unclear. In this study, 18 female Haimen goats were selected and slaughtered at d 30, 60, and 90 of age. Multi-omics analyses (rumen microbial sequencing, host transcriptome sequencing, and rumen epithelial metabolomics) were performed to investigate host-microbe interactions from preweaning to postweaning in a goat model. With increasing age, and after the introduction of solid feed, the increased abundances of Prevotella and Roseburia showed positive correlations with volatile fatty acid (VFA) levels and morphological parameters (P < 0.05). Epithelial transcriptomic analysis showed that the expression levels of hub genes, including 3-hydroxy-3-methylglutaryl-CoA synthase isoform 2 (HMGCS2), enoyl-CoA hydratase, short chain 1 (ECHS1), and peroxisome proliferator activated receptor gamma (PPARG), were positively associated with animal phenotype (P < 0.05). These hub genes were mainly correlated to VFA metabolism, oxidative phosphorylation, and the mammalian target of rapamycin (mTOR) and peroxisome proliferator activated receptor (PPAR) signaling pathways (P < 0.05). Moreover, the primary metabolites in the epithelium changed from glucose preweaning to (R)-3-hydroxybutyric acid (BHBA) and acetoacetic acid (ACAC) postweaning (P < 0.05). Diet and butyrate were the major factors shaping epithelial metabolomics in young ruminants (P < 0.05). Multi-omics analysis showed that the rumen microbiota and VFA were mainly associated with the epithelial transcriptome, and that alterations in gene expression influenced host metabolism. The "butanoate metabolism" pathway, which transcriptomic and metabolomic analyses identified as being upregulated with age, produces ketones that regulate the "oxidative phosphorylation" pathway, which could provide energy for the development of rumen papillae. Our findings reveal the changes that occur in the rumen microbiota, host transcriptome, and metabolome with age, and validate the role of microbiota-derived VFA in manipulating host gene expression and subsequent metabolism. This study provides insight into the molecular mechanisms of host-microbe interactions in goats and supplies a theoretical basis and guidance for precise nutritional regulation during the critical time window for rumen development of young ruminants.

Keywords:  Host-microbe interaction; Multi-omics; Rumen epithelial development; Rumen microbiota

DOI:  https://doi.org/10.1016/j.aninu.2024.04.027
Metabol Open. 2024 Dec;24 100332

Deciphering the mechanisms and effects of hyperglycemia on skeletal muscle atrophy.

Khushboo Gaur, Lucy Mohapatra, Pranay Wal, Amana Parveen, Shivam Kumar, Vaishali Gupta.

  Hyperglycemia, a hallmark of diabetes mellitus, significantly contributes to skeletal muscle atrophy, characterized by progressive muscle mass and strength loss. This review summarizes the mechanisms of hyperglycemia-induced muscle atrophy, examines clinical evidence, and discusses preventive and therapeutic strategies. A systematic search of electronic databases, including PubMed, Scopus, and Web of Science, was conducted to identify relevant papers on hyperglycemic skeletal muscle atrophy. Key mechanisms include insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Crucial molecular pathways involved are Phosphoinositide 3-kinase/Protein kinase B signaling, Forkhead box O transcription factors, the ubiquitin-proteasome system, and myostatin-mediated degradation. Hyperglycemia disrupts normal glucose and lipid metabolism, exacerbating muscle protein degradation and impairing synthesis. Clinical studies support the association between hyperglycemia and muscle atrophy, emphasizing the need for early diagnosis and intervention. Biomarkers, imaging techniques, and functional tests are vital for detecting and monitoring muscle atrophy in hyperglycemic patients. Management strategies focus on glycemic control, pharmacological interventions targeting specific molecular pathways, nutritional support, and tailored exercise regimens. Despite these advances, research gaps remain in understanding the long-term impact of hyperglycemia on muscle health and identifying novel therapeutic targets. The review aims to provide a comprehensive understanding of the mechanisms, clinical implications, and potential therapeutic strategies for addressing hyperglycemia-induced skeletal muscle atrophy.

Keywords:  Glucocorticoids; Inflammation; Insulin resistance; Oxidative stress; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.metop.2024.100332
FASEB J. 2024 Dec 15. 38(23): e70223

Purification of mitochondria from skeletal muscle tissue for transcriptomic analyses reveals localization of nuclear-encoded noncoding RNAs.

Jessica Silver, Adam J Trewin, Stella Loke, Larry Croft, Mark Ziemann, Megan Soria, Hayley Dillon, Søren Nielsen, Séverine Lamon, Glenn D Wadley.

Mitochondria are central to cellular function, particularly in metabolically active tissues such as skeletal muscle. Nuclear-encoded RNAs typically localize within the nucleus and cytosol but a small population may also translocate to subcellular compartments such as mitochondria. We aimed to investigate the nuclear-encoded RNAs that localize within the mitochondria of skeletal muscle cells and tissue. Intact mitochondria were isolated via immunoprecipitation (IP) followed by enzymatic treatments (RNase-A and proteinase-K) optimized to remove transcripts located exterior to mitochondria, making it amenable for high-throughput transcriptomic sequencing. Small RNA sequencing libraries were successfully constructed from as little as 1.8 ng mitochondrial RNA input. Small RNA sequencing of mitochondria from rat myoblasts revealed the enrichment of over 200 miRNAs. Whole-transcriptome RNA sequencing of enzymatically purified mitochondria isolated by IP from skeletal muscle tissue showed a striking similarity in the degree of purity compared to mitoplast preparations which lack an outer mitochondrial membrane. In summary, we describe a novel, powerful sequencing approach applicable to animal and human tissues and cells that can facilitate the discovery of nuclear-encoded RNA transcripts localized within skeletal muscle mitochondria.

DOI: https://doi.org/10.1096/fj.202401618R
Curr Opin Endocr Metab Res. 2024 Sep;36 100539

Attenuation of adipose tissue inflammation by pro-resolving lipid mediators.

Madison Clark, Bianca E Suur, Matúš Soták, Emma Börgeson.

Adipose tissue inflammation drives systemic pathophysiology, for instance, obesity-related cardiometabolic disease. Specialized pro-resolving lipid mediators are a superfamily of endogenously produced lipids that promote the resolution of inflammation, an actively regulated process. New evidence suggests that such lipids (e.g. lipoxins) could resolve adipose tissue inflammation and, thus, subvert obesity-related diseases. A key feature of pro-resolving lipids is their ability to promote an M2-like macrophage phenotype and enhance efferocytosis while avoiding adverse side-effects typically associated with anti-inflammatory drugs, such as increased sensitivity to infections. This brief review discusses the therapeutic potential of pro-resolving lipid mediators in mitigating systemic disease fueled by adipose tissue inflammation in both experimental and human disease models.

DOI: https://doi.org/10.1016/j.coemr.2024.100539
Epilepsia Open. 2024 Dec 06.

Exploring ketogenic diet resistance in glucose transporter type 1 deficiency syndrome: A comprehensive review and critical appraisal.

Raffaele Falsaperla, Vincenzo Sortino, Gerhard Josef Kluger, Thomas Herberhold, Andrea Rüegger, Pasquale Striano, Martino Ruggieri, Joerg Klepper, Georgia Ramantani.

  Glucose transporter type 1 deficiency syndrome (GLUT1DS) commonly presents with early-onset epilepsy that often resists conventional pharmacological treatment. Ketogenic diet therapy (KDT) is the preferred approach to address the underlying metabolic anomaly. However, a subset of GLUT1DS patients presents resistance to KDT, with the causes remaining elusive. This comprehensive literature review aims to explore the characteristics of KDT failure in GLUT1DS and identify risk factors within this population. Our goal is to improve counseling and prognostication for these patients. So, we conducted a comprehensive literature review on PubMed, focusing on studies documenting pediatric GLUT1DS patients with drug-resistant epilepsy unresponsive to KDT. We identified five cases of KDT failure in female GLUT1DS patients, aged 10 days to 13 years at diagnosis. Predominant seizure types were absence seizures, with a few cases of clonic, tonic, or myoclonic seizures. EEG consistently revealed 2-3.5 Hz generalized spike-and-wave discharges. Genetic investigations revealed point mutations and deletions in two cases each. Despite an in-depth search, no specific features were found to reliably distinguish KDT non-responders from responders, underscoring the need for further research. In cases of KDT ineffectiveness for seizure control in GLUT1DS patients, exploring alternative therapeutic strategies becomes imperative to managing symptoms while maintaining quality of life. Large-scale multicenter studies, facilitated through international collaborations like the European Network for Therapy in Rare Epilepsies (NETRE), hold promise in elucidating the complexities of this patient population and developing personalized therapeutic approaches. PLAIN LANGUAGE SUMMARY: Glucose transporter type 1 deficiency syndrome often causes difficult-to-treat epilepsy. The ketogenic diet works for many patients, but some do not respond. This review investigated cases of diet failure but could not identify common features among poor responders. Further research is needed to understand these cases and explore alternative treatments.

Keywords:  GLUT1DS; drug‐resistant epilepsy; ketogenic diet therapies; metabolic disease; resistance

DOI:  https://doi.org/10.1002/epi4.13110
Front Nutr. 2024 ;11 1439738

Effects of time-of-day resistance training on muscle strength, hormonal adaptations, and sleep quality during Ramadan fasting.

Raoua Triki, Abderraouf Ben Abderrahman, Iyed Salhi, Fatma Rhibi, Ayoub Saeidi, Abdullah Almaqhawi, Anthony C Hackney, Ismail Laher, Urs Granacher, Hassane Zouhal.

   Objectives: We investigated the timing of resistance training (RT) during Ramadan fasting (RF) on muscle strength, hormonal adaptations, and sleep quality.
Methods: Forty healthy and physically active male Muslims (age = 25.7 ± 5.6 years, body mass = 85.1 ± 17.5 kg, height = 175 ± 9 cm, BMI = 28.3 ± 5.7 kg/m2) were enrolled in this study and 37 completed pre and post-tests. Subjects were randomly allocated into two experimental groups. Group 1 (FAST, n = 20) completed an 8-week whole-body RT in the late afternoon (between 16 h and 18 h) while fasting. Group 2 (FED, n = 20) completed the similar RT protocol compared with FAST at night (between 20 h and 22 h). The following parameters were analyzed at various time-points: 2 weeks before the start of RF (T0), on the 15th day of Ramadan (T1), on the 29th day of Ramadan (T2), and 21 days after the last day of RF (T3) where both groups were in a fed state. One-repetition maximum tests (1-RM) were conducted for the squats (1-RMSQ), the deadlift (1-RMDL) and the bench press (1-RMBP). Sleep quality was assessed using the full Pittsburgh Sleep Quality Index (PSQI). Blood samples were taken to determine cortisol, testosterone and IGF-1 levels. Additionally, acute hormonal responses were evaluated before (BF), immediately after (AF), and 30 min after a RT session (AF-30 min) at T0, T1, T2, and T3.
Results: Significant group-by-time interactions were identified for 1-RMSQ (p = 0.001; effect size [ES] = 0.43) and 1-RMDL (p = 0.001; ES = 0.36). Post-hoc tests indicated significant 1-RMSQ (p = 0.03; ES = 0.12) and 1-RMDL (p = 0.04; ES = 0.21) improvements from T0-T2 for FED. Additionally, significant group-by-time interactions were observed for the chronic effects on cortisol (p = 0.03; ES = 0.27) and testosterone levels (p = 0.01; ES = 0.32). Post-hoc tests indicated significant increases of cortisol levels among FAST at T1 and T2 compared to T0 (p = 0.05; ES = 0.41, p = 0.03; ES = 0.34) and a significant increase in cortisol levels in FED at T1 (p = 0.05; ES = 0.29) and T2 (p = 0.04; ES = 0.25). However, the observed increase was lower compared to FAST. Post-hoc tests also indicated significant increases of testosterone only among FED at T2 (p = 0.04; ES = 0.31). A significant group-by-time interaction was found for the acute effect of exercise on cortisol level (p = 0.04; ES = 0.34). The cortisol level immediately after RT was higher in FAST only at T1 (p = 0.03; ES = 0.39) and T2 (p = 0.05; ES = 0.22) compared with T0. No significant group-by-time interactions were identified for sleep quality (p = 0.07; ES = 0.43).
Conclusion: Muslims can safely practice RT during RF. However, training in a fed state during Ramadan might be more effective than during fasted state for the enhancement of maximal strength with better hormonal responses observed.

Keywords:  fasting; hormonal adaptation; muscle performance; sleep quality; training

DOI:  https://doi.org/10.3389/fnut.2024.1439738
FASEB J. 2024 Dec 15. 38(23): e70228

Effect of sodium butyrate on kidney and liver mitochondrial dysfunction in a lipopolysaccharide mouse model.

Muznah Khan, Sumera Farooqi, Katherine L Mitchell, Subir Kumar Roy Chowdhury, Marian Cabrera-Ayala, Jessica Huang, Douglas C Wallace, Scott L Weiss.

  Sodium butyrate can reduce inflammation, but it is not known if butyrate can improve mitochondrial dysfunction during sepsis. We tested butyrate to prevent or reverse lipopolysaccharide (LPS)-induced mitochondrial dysfunction in murine kidney and liver. C57BL/6 mice were grouped as control (n = 9), intraperitoneal (IP) LPS (n = 8), pretreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 8) followed 2 h later by LPS, posttreatment with IP butyrate 600 (n = 3) or 1200 mg/kg (n = 7) 1 h after LPS, or butyrate 1200 mg/kg only (n = 8). Kidney and liver tissue were collected at 24 h to measure mitochondrial respiration, electron transport system (ETS) complex activity and subunit expression, and content (citrate synthase [CS] activity and mtDNA/nDNA). Kidney mitochondrial respiration was decreased after LPS compared to controls. Pretreatment with butyrate 1200 mg/kg increased kidney OXPHOSCI+II, ETSCI+II, ETSCII, and CIV respiration compared to LPS; posttreatment did not achieve significant increases except for OXPHOSCI. Liver mitochondrial respiration exhibited a similar pattern as in kidney, but differences were not significant. ETS complex and CS activity did not differ between groups, but CI and CII subunit expression trended higher with butyrate in kidney. Changes in mtDNA/nDNA followed a similar pattern as respiration in kidney and liver with a decrease after LPS that was not present with butyrate pretreatment. These data show that butyrate can prevent-but not significantly reverse-the LPS-induced decrease in kidney mitochondrial respiration without a clear effect in liver. Mitochondrial protection was not attributable to changes in ETS complex activity but may reflect maintenance of ETS subunit expression.

Keywords:  endotoxins; metabolism; mice; microbiota; mitochondria; sepsis

DOI:  https://doi.org/10.1096/fj.202401379RR
EBioMedicine. 2024 Dec 02. pii: S2352-3964(24)00507-3. [Epub ahead of print]110 105471

The role of exosomes for sustained specific cardiorespiratory and metabolic improvements in males with type 2 diabetes after detraining.

Lucia Mastrototaro, Maria Apostolopoulou, Sonja Hartwig, Klaus Strassburger, Polina Lipaeva, Nina Trinks, Yanislava Karusheva, Sofiya Gancheva, Sandra Trenkamp, Stefan Lehr, Hadi Al-Hasani, Julia Szendroedi, Michael Roden.

   BACKGROUND: High-intensity interval training (HIIT) has been shown to improve cardiorespiratory fitness (V˙O2 max) but may ameliorate insulin sensitivity only in insulin-resistant humans. It is yet unclear whether these benefits persist after detraining and to which extent duration and effectiveness of metabolic improvements differ between individuals without and with prediabetes or type 2 diabetes (T2D). Understanding these differences is relevant for developing targeted exercise training modes for individuals with different stages of dysglycemia.
METHODS: Men with (20 T2D) and without T2D (12 insulin-sensitive, IS-NDM; 10 insulin-resistant, IR-NDM) underwent hyperinsulinemic-euglycemic clamps, spiroergometry, ectopic lipid quantification and muscle biopsies at baseline, after 12-week HIIT and after 4-week detraining.
FINDINGS: After detraining, the HIIT-stimulated V˙O2 max declined in T2D and IR-NDM, but remained higher compared to baseline in all groups. The HIIT-induced changes in hepatic insulin sensitivity and ectopic lipid content were sustained after detraining in T2D and IR-NDM, whereas improvements of whole-body insulin sensitivity were abolished in T2D. T2D and IR-NDM showed persistent increases in the number of small extracellular vesicles, which carry among others antioxidant proteins. The ratio of reduced-to-oxidized glutathione further decreased after detraining in all groups, whereas changes in proteins involved in mitochondrial turnover were dependent on insulin sensitivity, with some evidence for upregulation of fusion and mitophagy in T2D and IR-NDM and upregulation of fission in IS-NDM. Levels of different lipolytic proteins were reduced in all participants after detraining.
INTERPRETATION: HIIT offers sustained improvement of energy metabolism and hepatic insulin sensitivity in insulin-resistant humans, but long-term adherence is required to maintain these benefits.
FUNDING: Funding bodies that contributed to this study are listed in the Acknowledgements section.

Keywords:  Detraining; Exercise; Insulin sensitivity; Inter-organ crosstalk; Small extracellular vesicles

DOI:  https://doi.org/10.1016/j.ebiom.2024.105471
PLoS One. 2024 ;19(12): e0312859

Rapamycin administration causes a decrease in muscle contractile function and systemic glucose intolerance concomitant with reduced skeletal muscle Rictor, the mTORC2 component, expression independent of energy intake in young rats.

Satoru Ato, Chieri Oya, Riki Ogasawara.

Emerging evidence suggests the potential of rapamycin, an antibiotic from Streptomyces hygroscopicus that functions as a mechanistic target of rapamycin (mTOR) inhibitor, as a mimetic of caloric restriction (CR) for maintaining skeletal muscle health. Several studies showed that rapamycin administration (RAP) reduced appetite and energy intake. However, the physiological and molecular differences between RAP and CR in skeletal muscle are not fully understood. Here we observed the effects of 4 weeks of RAP administration and CR corresponding to the reduction in energy intake produced by RAP administration (PF, paired feeding) on fast glycolytic and slow oxidative muscle in young adult rats. We found that 4 weeks of RAP demonstrated low fast-glycolytic muscle mass with smaller type I and IIb/x myofiber size independent of the energy intake. In addition, PF improved the contractile function of the plantar flexor muscle, whereas RAP did not improve its function. The suppressing response of mTORC1 signaling to RAP is greater in slow-oxidative muscles than in fast-glycolytic muscles. In addition, systemic glucose tolerance was exacerbated by RAP, with reduced expression of Rictor and hexokinase in skeletal muscle. These observations imply that RAP may have a slight but significant negative impact and it obviously different to CR in young adult skeletal muscle.

DOI: https://doi.org/10.1371/journal.pone.0312859
J Int Soc Sports Nutr. 2024 Dec;21(1): 2425609

Effects of probiotic supplementation with high-intensity interval training on cardiorespiratory endurance and metabolism in Middle-Aged Obese Women.

Yi-Chen Chen, Hsuan-Yun Wang, Futoshi Ogita, Chi-Hsiang Hung, Chia-Hua Kuo, Jie-Ping Wang, Chia-Min Wang, Chien-Wen Hou, Ting-Yao Wang.

   INTRODUCTION: High-intensity interval training (HIIT) has been shown to improve chronic diseases. Probiotics have been found to have similar effects. However, the additive effects of HIIT in combination with probiotics supplementation are unclear. The aim of current study was to investigate whether there were additive effects when implementing both HIIT and probiotics simultaneously.
METHODS: Forty-seven obese middle-aged women (Age: 44.5 ± 5.94 years, body fat percentage: 40.0 ± 4.1%) were recruited and assigned into four groups: control group (C, n = 12), probiotics group (P, n = 12), HIIT group (H, n = 11), and HIIT with probiotics group (HP, n = 12). All the participants consumed probiotics (Lactiplantibacillus plantarum TWK10, 6 × 1010 CFU/day) or placebo supplements daily. Exercise intervention groups conducted HIIT training (85-90% vVO2max for 2 min, followed by a 1-min inactive rest interval, repeated for 7 cycles) 3 sessions per week for 8 weeks. Anthropometry, cardiorespiratory endurance, blood glucose, and lipid profile were measured at baseline and after the 8-week intervention.
RESULTS: After the intervention, there were significant changes between groups in the variations and rates of change in waist circumference, hip circumference, and TTE. The waist circumference in group H significantly increased compared to groups C and P, while group HP did not show significant difference compared to group C. On the other hand, the hip circumference decreased significantly in group HP compared to group C, and the decreased rate in group HP was significantly greater than in groups C and P. Furthermore, the increase rates in TTE were higher in group H and HP compared to group C.
CONCLUSION: HIIT improves TTE but negatively affects waist circumference compared to the control group. However, when combined with probiotics, the probiotics not only help enhance TTE but also counteract the negative impact on waist circumference and further reduce hip circumference, resulting in a synergistic effect.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT06285578.

Keywords:  Lactiplantibacillus plantarum TWK10; gut microbiota; maximal oxygen uptake; obese women; running economy; time to exhaustion

DOI:  https://doi.org/10.1080/15502783.2024.2425609
Nature. 2024 Dec 03.

What is ageing? Even the field's researchers can't agree.

Smriti Mallapaty.



Keywords:  Ageing; Diseases

DOI:  https://doi.org/10.1038/d41586-024-03936-8