bims-kimdis 2023-10-08 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–10–08
34 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.
Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet.
Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial.
The effect of a short-term ketogenic diet on exercise efficiency during graded exercise in healthy adults.
Resistance towards endurance training-mediated skeletal muscle mitochondrial adaptations: implications for individuals with type 1 diabetes mellitus.
Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.
Ketone supplementation dampens subjective and objective responses to alcohol in rats and humans.
Persistent hypercalcemia mimicking hypophosphatasia after discontinuation of a ketogenic diet: a case report.
Editorial: The use of ketogenic diet therapy in the era of individualized therapy.
Urinary ketone bodies and stroke recurrence in patient with acute ischemic stroke or TIA.
Exploiting Enhanced Lipid Metabolism in Glioblastoma through Diet Modification.
Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice.
Metabolic changes following intermittent fasting: A rapid review of systematic reviews.
Effects of a low carbohydrate diet on heart failure symptoms and quality of life in patients with diabetic cardiomyopathy: A randomised controlled trial pilot study.
Mitochondrial dysfunction: A fatal blow in depression.
Mitophagy for cardioprotection.
Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types.
Metformin Improves the Prerequisites for FGF21 Signaling in Patients with Type 2 Diabetes.
Effect of acetate supplementation on traumatic stress-induced behavioral impairments in male rats.
Inflammasomes in human reproductive diseases.
Links between Exercise Capacity, Exercise Training, and Metabolism.
Butyrate alleviates renal inflammation and fibrosis in a rat model of polycystic ovarian syndrome by suppression of SDF-1.
Purification of functional mouse skeletal muscle mitochondria using percoll density gradient centrifugation.
Synthesis of thiophene-substituted ketones via Manganese-Catalyzed Dehydrogenative Coupling Reaction.
Impact of Bmal1 rescue and time-restricted feeding on liver and muscle proteomes during the active phase in mice.
[Protein in the athlete's diet: rationale for intake levels at different training intensities to maintain lean body mass (a brief review)].
Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease.
Inflammasome Signaling, Thromboinflammation, and Venous Thromboembolism.
Mechanisms and regulation of human mitochondrial transcription.
Study: Waist-to-Hip Ratio Might Predict Mortality Better Than BMI.
Fat and inflammation: adipocyte-myeloid cell crosstalk in atherosclerosis.
Diabetic Ketoacidosis.
Obesity: Central Role in Heart Failure With Preserved Ejection Fraction?
Beyond inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, results from the InCHIANTI study.

JACC Basic Transl Sci. 2023 Sep;8(9): 1123-1137

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.

Jessica Gambardella, Stanislovas S Jankauskas, Urna Kansakar, Fahimeh Varzideh, Roberta Avvisato, Nella Prevete, Simone Sidoli, Pasquale Mone, Xujun Wang, Angela Lombardi, Gaetano Santulli.

  Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.

Keywords:  BHB; heart failure; histone methylation; ischemia; mitochondria; myocardial infarction; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.jacbts.2023.03.014
Sci Rep. 2023 09 30. 13(1): 16465

Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet.

Ilya Smolensky, Kilian Zajac-Bakri, Timothy Sasha Odermatt, Catherine Brégère, John F Cryan, Raphael Guzman, Katharina Timper, Dragos Inta.

Low-carbohydrates diets are increasingly used to treat obesity and metabolic disorders. A very low-carbohydrate, ketogenic diet is hard to follow and, due to the very high fat content, linked to severe side effects, like hyperlipidemia and atherogenesis. Therefore, a less restrictive, unsaturated fat-based low-carbohydrate diet appears as a promising alternative. Since neither sex differences, nor their effect on specific metabolic hormones and adipose tissue compartments have been investigated thoroughly in these diets, we aimed to analyze their dynamics and metabolic factors in mice. We found a significant sexual dimorphism with decreased body weight and subcutaneous fat only in males on ketogenic diet, while diminished insulin, elevated ghrelin and FGF-21 were present with a differential time course in both sexes. The non-ketogenic moderate low-carbohydrate diet increased body weight and perigonadal fat in females, but induced leptin elevation in males. Both diets enhanced transiently TNFɑ only in males and had no impact on behavior. Altogether, these results reveal complex sex-dependent effect of dietary interventions, indicating unexpectedly females as more prone to unfavorable metabolic effects of low-carbohydrate diets.

DOI: https://doi.org/10.1038/s41598-023-43587-9
J Transl Med. 2023 10 04. 21(1): 692

Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial.

Massimiliano Caprio, Eleonora Moriconi, Elisabetta Camajani, Alessandra Feraco, Vincenzo Marzolla, Laura Vitiello, Stefania Proietti, Andrea Armani, Stefania Gorini, Caterina Mammi, Gabriella Egeo, Cinzia Aurilia, Giulia Fiorentini, Carlo Tomino, Piero Barbanti.

   BACKGROUND: Migraine is the second world's cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches.
METHODS: This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m2. Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9-12), and a HBD (weeks 13-24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5-8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment.
RESULTS: Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups.
CONCLUSIONS: VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148.

Keywords:  Aldosterone; Diet; Inflammatory state; Ketone bodies; Migraine treatment; Pain; Prevention; Rehabilitation; VLCKD; Weight loss

DOI:  https://doi.org/10.1186/s12967-023-04561-1
J Int Soc Sports Nutr. 2023 Dec;20(1): 2264278

The effect of a short-term ketogenic diet on exercise efficiency during graded exercise in healthy adults.

Wonhee Cho, Hwaebong Jung, Sunghyun Hong, Hyuk In Yang, Dong-Hyuk Park, Sang-Hoon Suh, Dong Hoon Lee, Yong-Sahm Choe, Joon Young Kim, Wooyoung Lee, Justin Y Jeon.

   OBJECTIVE: We examined the effects of short-term KD on exercise efficiency and hormonal response during and after the graded exercise testing.
METHODS: Fourteen untrained healthy adults (8 males, 6 females, age 26.4 ± 3.1 [SD] years; BMI 24.8 ± 4.6 kg/m2; peak VO2max 54.0 ± 5.8 ml/kg FFM/min) completed 3-days of a mixed diet (MD) followed by another 3-days of KD after 3-days of washout period. Upon completion of each diet arm, participants underwent graded exercise testing with low- (LIE; 40% of VO2max), moderate- (MIE; 55%), and high-intensity exercise (HIE; 70%). Exercise efficiency was calculated as work done (kcal/min)/energy expenditure (kcal/min).
RESULTS: Fat oxidation during the recovery period was higher in KD vs. MD. Despite identical workload during HIE, participants after having KD vs. MD showed higher energy expenditure and lower exercise efficiency (10.1 ± 0.7 vs. 12.5 ± 0.3%, p < .01). After KD, free fatty acid (FFA) concentrations were higher during MIE and recovery vs. resting, and beta-hydroxybutylate (BOHB) was lower at HIE vs. resting. Cortisol concentrations after KD was higher during recovery vs. resting, with no significant changes during graded exercise testing after MD.
CONCLUSIONS: Our data suggest that short-term KD is favorable to fat metabolism leading increased circulating FFA and BOHB during LIE to MIE. However, it is notable that KD may cause 1) exercise inefficiency manifested by increased energy expenditure and 2) elevated exercise stress during HIE and recovery. Trial registration: KCT0005172, International Clinical Trials Registry Platform.

Keywords:  Ketogenic diet; exercise efficiency; exercise stress

DOI:  https://doi.org/10.1080/15502783.2023.2264278
J Physiol. 2023 Oct 07.

Resistance towards endurance training-mediated skeletal muscle mitochondrial adaptations: implications for individuals with type 1 diabetes mellitus.

Mitchell J Sammut, Andrew W D'Souza.



Keywords:  combined exercise; mitochondria; skeletal muscle; type 1 diabetes mellitus

DOI:  https://doi.org/10.1113/JP285685
Cell Metab. 2023 Oct 03. pii: S1550-4131(23)00332-7. [Epub ahead of print]35(10): 1767-1781.e6

Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.

Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme.

  Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.

Keywords:  OXPHOS; Pseudomonas aeruginosa; bioenergetics; disease tolerance; infection; inflammation; itaconate; ketogenesis; ketogenic diet; pneumonia

DOI:  https://doi.org/10.1016/j.cmet.2023.09.001
bioRxiv. 2023 Sep 23. pii: 2023.09.23.558269. [Epub ahead of print]

Ketone supplementation dampens subjective and objective responses to alcohol in rats and humans.

Xinyi Li, Zhenhao Shi, Dustin Todaro, Timothy Pond, Juliana Byanyima, Sianneh Vesslee, Rishika Reddy, Ravi Prakash Reddy Nanga, Gabriel Kass, Vijay Ramchandani, Henry R Kranzler, Janaina C M Vendruscolo, Leandro F Vendruscolo, Corinde E Wiers.

Previous preclinical and human studies have shown that high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-β-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 min prior to an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration (BrAC) and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 min after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 min later by an oral alcohol dose (0.8 g/kg). BAL were monitored for 240 min after alcohol exposure. In humans, the intake of KS prior to alcohol significantly blunted BrAC and BAL, reduced ratings of alcohol liking and wanting, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. In conclusion, KS altered physiological and subjective responses to alcohol in both humans and rats and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating and rewarding effects of alcohol and thus be a novel intervention for treating alcohol use disorder.

DOI: https://doi.org/10.1101/2023.09.23.558269
J Pediatr Endocrinol Metab. 2023 Oct 05.

Persistent hypercalcemia mimicking hypophosphatasia after discontinuation of a ketogenic diet: a case report.

Sabitha Sasidharan Pillai, Renee Robilliard, Meghan E Fredette, Monica Serrano-Gonzalez, Kevin J Scully.

   OBJECTIVES: Hypercalcemia has been reported as an uncommon complication of the ketogenic diet (KD). Here we present a toddler whose hypercalcemia persisted for 2 months after stopping the KD.
CASE PRESENTATION: A 2 year 11-month-old child with global developmental delay, infantile spasms, neuromuscular weakness with limited mobility, tracheostomy and ventilator dependence, and oropharyngeal dysphagia with G-tube dependence presented with hypercalcemia in the setting of recurrent vomiting. At presentation, the patient was adherent to a KD and taking topiramate since infancy for intractable seizures. His laboratory parameters at presentation showed hypercalcemia (11.9 mg/dL), hypercalciuria, acute renal failure, low alkaline phosphatase (76 IU/L [110-302 IU/L]), parathyroid hormone (PTH) <6 pg/mL (18-80 pg/mL), normal thyroid function, cortisol and vitamin D level. The patient's hypercalcemia persisted post-discontinuation of the KD and topiramate. PTH-related protein was mildly elevated at 15.3 pmol/L. Follow-up laboratory and imaging studies ruled out malignancy. He was managed with calcitonin 4 u/kg/dose Q12H × 1 day and 8 u/kg/dose Q8H × 1 day, hydration and low-calcium formula. Post-discontinuation of the KD, normalization of alkaline phosphatase levels preceded the normalization of calcium on day 55 and PTH on day 85.
CONCLUSIONS: Hypercalcemia may persist for an extended period after weaning from a KD; lab parameters may mimic that of hypophosphatasia as previously described in the literature. Normalization of alkaline phosphatase, a marker of bone turnover, indicates recovery from the adynamic state induced by the KD and typically precedes the normalization of calcium and PTH.

Keywords:  children; hypercalcemia; ketogenic diet; low alkaline phosphatase

DOI:  https://doi.org/10.1515/jpem-2023-0304
Front Nutr. 2023 ;10 1272170

Editorial: The use of ketogenic diet therapy in the era of individualized therapy.

Aycan Ünalp, Bülent Ünay, Ebru Arhan.



Keywords:  individualized; ketogenic diet; personalized; precision; therapy

DOI:  https://doi.org/10.3389/fnut.2023.1272170
J Clin Neurosci. 2023 Sep 29. pii: S0967-5868(23)00281-3. [Epub ahead of print]117 79-83

Urinary ketone bodies and stroke recurrence in patient with acute ischemic stroke or TIA.

Liye Dai, Anxin Wang, Hongqiu Gu, Yijun Zhang, Yingting Zuo, Xia Meng, Pan Chen, Xue Tian, Hao Li, Yongjun Wang.

   BACKGROUND: Urine ketone bodies may appear in different states in the acute stage of stroke. We aimed to examine the association between urine ketone bodies and recurrent stroke in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) in this study.
METHODS: In Third China National Stroke Registry (CNSR-III), 14,015 patients with AIS or TIA were screened for urine ketone bodies. The outcomes were any stroke, ischemic stroke and combined vascular events within 1 year. The association of urine ketone bodies with recurrent stroke were analyzed by Cox proportional hazards.
RESULTS: During 1 year of follow-up, 1,335 (9.53%) participants experienced recurrent stroke. After adjustment for conventional confounding factors, patients with urine ketone bodies test positive had a higher risk of recurrent stroke (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.13-1.82), compared to those were negative. The correlation between positive urine ketone bodies and recurrent stroke were consistent in patient with (HR, 1.45; 95% CI, 1.00-2.12) and without (HR, 1.40; 95% CI, 1.02-1.94) diabetes. No significant interaction between urine ketone bodies and diabetes were observed.
CONCLUSIONS: Positive ketone bodies in urine was independently associated with recurrent stroke in patients with AIS or TIA.

Keywords:  Diabetes; Stroke; TIA; Urine ketone bodies

DOI:  https://doi.org/10.1016/j.jocn.2023.09.019
Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)05329-4. [Epub ahead of print]117(2S): e113-e114

Exploiting Enhanced Lipid Metabolism in Glioblastoma through Diet Modification.

S Kant, Y Zhao, P Kesarwani, P Chinnaiyan.

PURPOSE/OBJECTIVE(S): Enhanced lipid metabolism has emerged as a central metabolic node in glioblastoma, serving as a 'gain of function' that allows these cells to efficiently adapt to their dynamic tumor microenvironment. Seemingly contradictory to this, pre-clinical studies have demonstrated anti-tumor activity in mice fed a high-fat/low-carbohydrate ketogenic diet (KD), both alone and in combination with radiation therapy (RT). In this study, we sought to identify mechanisms underlying the antitumor activity of a KD in glioblastoma from a metabolic perspective to better understand factors contributing to this apparent disconnect.
MATERIALS/METHODS: Immunocompromised and immunocompetent mice were injected orthotopically with human and mouse-derived glioblastoma cell lines and randomized to four treatment arms. Mice were fed ad libitum a standard diet (SD), KD (Bio-Serve), or a modified unsaturated fatty acid (uFA) rich diet (MD; 60/30/10: fat/protein/carb) alone or in combination with hypofractionated RT (6 Gy x 3). Global metabolomic profiling of tumors and serum were carried out using LC/GC-MS. Lipid droplets were analyzed by flow cytometer and confocal microscopy using BODIPY staining and free fatty acids were measured using a commercially available kit.
RESULTS: A KD demonstrated independent anti-tumor activity and potent synergy with RT in two aggressive glioblastoma models. Metabolomic profiling of tumors revealed significant changes in tumor metabolism in KD-fed mice when compared to SD, with an accumulation of uFAs being a key finding. We therefore sought to determine if this accumulation of fatty acids in KD mice contributed towards the observed anti-tumor activity. Consistent with in vivo results, in vitro studies using the uFA linoleic acid demonstrated anti-proliferative activity, reduced clonogenic capacity, and potent synergy when combined with RT in glioblastoma cells. Through a series of investigations, we went on to determine that this anti-tumor activity was attributed to the ability of uFA to override lipid storage homeostasis in glioblastoma cells, resulting in lipotoxicity. Based on these findings, we hypothesized high fat concentrations, rather than carbohydrate restriction, contributed to the anti-tumor activity of a KD. To test this, we generated a MD rich in uFA that did not require carbohydrate restriction. Similar to a KD, mice fed a MD demonstrated both independent anti-tumor activity and potent synergy when combined with RT.
CONCLUSION: High concentrations of uFA represents a key factor underlying the anti-tumor activity of a KD in glioblastoma by targeting lipid homeostasis. A MD consisting of high concentrations of uFA without carbohydrate restriction demonstrates promising anti-tumor activity in glioblastoma models. As a major limitation of a KD is tolerability, particularly in glioblastoma patients, a MD represents a promising form of dietary modification that may be translated clinically.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.895
Physiol Res. 2023 Aug 31. 72(4): 465-473

Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice.

Y Ohno, M Nakatani, T Ito, Y Matsui, K Ando, Y Suda, K Ohashi, S Yokoyama, K Goto.

G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.
J Hum Nutr Diet. 2023 Oct 02.

Metabolic changes following intermittent fasting: A rapid review of systematic reviews.

Maria G Lange, Alice A Coffey, Paul C Coleman, Thomas M Barber, Thijs Van Rens, Oyinlola Oyebode, Sally Abbott, Petra Hanson.

   BACKGROUND: The prevalence of obesity is rising globally and effective strategies to treat obesity are needed. Intermittent fasting, a dietary intervention for weight management, has received growing interest from the general public, as well as healthcare professionals, as a form of lifestyle intervention.
METHODS: We executed a rapid review using PUBMED database to identify systematic reviews which examined the impact of intermittent fasting on metabolic indices, published between 2011 and 2022.
RESULTS: Intermittent fasting leads to weight loss of a similar magnitude to continuous energy restriction. Most of the evidence shows that intermittent fasting leads to greater fat loss as measured by fat mass (kg) or body fat percentage when compared with ad libitum diet, but fat loss attained during intermittent fasting is not significantly different to continuous energy restriction although recent evidence shows intermittent fasting to be superior. There is mixed evidence for the impact of intermittent fasting on insulin resistance, fasting glucose and lipid profile. Some studies focused on populations of Muslim people, which showed that Ramadan fasting may lead to weight loss and improvement of metabolic parameters during fasting, but the effects are reversed when fasting is finished.
SUMMARY: Intermittent fasting is more effective than an ad libitum dietary intake, and equally or more effective as continuous energy restriction, for weight management. However, there is inconclusive evidence on whether intermittent fasting has a clinically beneficial effect on glucose and lipid metabolism. This article is protected by copyright. All rights reserved.

Keywords:  Alternate day fasting; Intermittent fasting; Obesity; Weight loss

DOI:  https://doi.org/10.1111/jhn.13253
Nutr Metab Cardiovasc Dis. 2023 Aug 26. pii: S0939-4753(23)00338-1. [Epub ahead of print]

Effects of a low carbohydrate diet on heart failure symptoms and quality of life in patients with diabetic cardiomyopathy: A randomised controlled trial pilot study.

Sabine Kleissl-Muir, Alice Owen, Bodil Rasmussen, Caryn Zinn, Andrea Driscoll.

   BACKGROUND AND AIMS: Heart failure, insulin resistance and/or type 2 diabetes mellitus coexist in the syndrome that is diabetic cardiomyopathy. Patients with diabetic cardiomyopathy experience high symptom burden and poor quality of life. We tested the hypothesis that a low carbohydrate diet improves heart failure symptoms and quality of life in patients with diabetic cardiomyopathy.
METHODS AND RESULTS: We conducted a 16-week randomised controlled pilot trial comparing the effects of a low carbohydrate diet (LC) to usual care (UC) in 17 adult patients with diabetic cardiomyopathy. New York Heart Association classification, weight, thirst distress and quality of life scores as well as blood pressure and biochemical data were assessed at baseline and at 16 weeks. Thirteen (n = 8 LC; n = 5 UC) patients completed the trial. The low carbohydrate diet induced significant weight loss in completers (p = 0.004). There was a large between-group difference in systolic blood pressure at the end of the study (Hedges's g 0.99[-014,2.08]). There were no significant differences in thirst or quality of life between groups.
CONCLUSION: This is the first clinical trial utilising the low carbohydrate dietary approach in patients with diabetic cardiomyopathy in an outpatient setting. A low carbohydrate diet can lead to significant weight loss in patients with diabetic cardiomyopathy. Future clinical trials with larger samples and that focus on fluid and sodium requirements of patients with diabetic cardiomyopathy who engage in a low carbohydrate diet are warranted.
CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trial Registry (ANZCTR): ACTRN12620001278921.
DATE OF REGISTRATION: 26th November 2020.

Keywords:  Diabetes mellitus; Heart failure; Low carbohydrate diet; Quality of life; Thirst distress

DOI:  https://doi.org/10.1016/j.numecd.2023.08.015
Biomed Pharmacother. 2023 Oct 04. pii: S0753-3322(23)01450-6. [Epub ahead of print]167 115652

Mitochondrial dysfunction: A fatal blow in depression.

Yu Song, Huan Cao, Chengchao Zuo, Zhongya Gu, Yaqi Huang, Jinfeng Miao, Yufeng Fu, Yu Guo, Yongsheng Jiang, Furong Wang.

  Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining the metabolic balance through intracellular Ca2+ homeostasis, oxidative stress, and axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to the hippocampal neurons is a key component of the plasticity regulation of synapses and plays a critical role in the mechanism of depression. There is evidence suggesting that mitochondrial dysfunction is associated with synaptic impairment. The maintenance of mitochondrial homeostasis includes quantitative maintenance and quality control of mitochondria. Mitochondrial biogenesis produces new and healthy mitochondria, and mitochondrial dynamics cooperates with mitophagy to remove damaged mitochondria. These processes maintain mitochondrial population stability and exert neuroprotective effects against early depression. In contrast, mitochondrial dysfunction is observed in various brain regions of patients with major depressive disorders. The accumulation of defective mitochondria accelerates cellular nerve dysfunction. In addition, impaired mitochondria aggravate alterations in the brain microenvironment, promoting neuroinflammation and energy depletion, thereby exacerbating the development of depression. This review summarizes the influence of mitochondrial dysfunction and the underlying molecular pathways on the pathogenesis of depression. Additionally, we discuss the maintenance of mitochondrial homeostasis as a potential therapeutic strategy for depression.

Keywords:  Major depressive disorder; Mitochondrial dysfunction; Mitochondrial quality control; Neuroinflammation

DOI:  https://doi.org/10.1016/j.biopha.2023.115652
Basic Res Cardiol. 2023 Oct 05. 118(1): 42

Mitophagy for cardioprotection.

Allen Sam Titus, Eun-Ah Sung, Daniela Zablocki, Junichi Sadoshima.

  Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.

Keywords:  Alternative mitophagy; Drp1; Mitochondrial quality control; Mitophagy

DOI:  https://doi.org/10.1007/s00395-023-01009-x
Sci Rep. 2023 Oct 05. 13(1): 16742

Pan-tissue mitochondrial phenotyping reveals lower OXPHOS expression and function across cancer types.

Ilya N Boykov, McLane M Montgomery, James T Hagen, Raphael T Aruleba, Kelsey L McLaughlin, Hannah S Coalson, Margaret A Nelson, Andrea S Pereyra, Jessica M Ellis, Tonya N Zeczycki, Nasreen A Vohra, Su-Fern Tan, Myles C Cabot, Kelsey H Fisher-Wellman.

Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type.

DOI: https://doi.org/10.1038/s41598-023-43963-5
J Clin Endocrinol Metab. 2023 Sep 30. pii: dgad583. [Epub ahead of print]

Metformin Improves the Prerequisites for FGF21 Signaling in Patients with Type 2 Diabetes.

Anne Kathrine Nissen Pedersen, Lars Christian Gormsen, Søren Nielsen, Niels Jessen, Mette Bjerre.

   BACKGROUND: Fibroblast growth factor (FGF)21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21-signalling requires binding to surface receptors, FGFR1c and β-klotho. FGF21 resistance is observed in metabolic diseases and FGF21-signalling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown.
AIM: To investigate how 12-weeks treatment with metformin affects the FGF21-signalling pathway in T2D patients.
DESIGN: Randomized, placebo-controlled study with T2D patients (n=24) receiving either metformin (1000 mg twice daily) or placebo. A control group of BMI and age-matched healthy individuals (n=12) received a similar dose of metformin. Blood samples, muscle- and fat biopsies were collected at study entry and after 12 weeks.
METHODS: Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21-signaling pathway.
RESULTS: Circulating FAP activity decreased after metformin treatment as compared with placebo (p=0.006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of β-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue.
CONCLUSION: Our findings suggest that metformin suppresses the circulating FAP activity and upregulate the expression of FGFR1c and β-klotho for increased FGF21-signalling in adipose tissue thus improving peripheral FGF21-sensitivity.

Keywords:  Fibroblast Activation Protein (FAP); Fibroblast Activation Protein (FGF21); Metformin; Type 2 Diabetes (T2D)

DOI:  https://doi.org/10.1210/clinem/dgad583
Neurobiol Stress. 2023 Nov;27 100572

Effect of acetate supplementation on traumatic stress-induced behavioral impairments in male rats.

Arax Tanelian, Bistra Nankova, Furong Hu, Jordan D Sahawneh, Esther L Sabban.

  Gut microbiota and their metabolites have emerged as key players in the pathogenesis of neuropsychiatric disorders. Recently, we demonstrated that animals susceptible to Single Prolonged Stress (SPS) have an overall pro-inflammatory gut microbiota and significantly lower cecal acetate levels than SPS-resilient rats, which correlated inversely with the anxiety index. Here, we investigated whether the microbial metabolite, acetate, could ameliorate SPS-triggered impairments. Male rats were randomly divided into unstressed controls or groups exposed to SPS. The groups received continued oral supplementation of either 150 mM of sodium acetate or 150 mM of sodium chloride-matched water. Two weeks after SPS, a battery of behavioral tests was performed, and the animals were euthanized the following day. While not affecting the unstressed controls, acetate supplementation reduced the impact of SPS on body weight gain and ameliorated SPS-induced anxiety-like behavior and the impairments in social interaction, but not depressive-like behavior. These changes were accompanied by several beneficial effects of acetate supplementation. Acetate alleviated the stress response by reducing urinary epinephrine levels, induced epigenetic modification by decreasing histone deacetylase (HDAC2) gene expression, inhibited neuroinflammation by reducing the density of Iba1+ cells and the gene expression of IL-1ß in the hippocampus, and increased serum β-hydroxybutyrate levels. The findings reveal a causal relationship between oral acetate treatment and mitigation of several SPS-induced behavioral impairments. Mechanistically, it impacted neuronal and metabolic pathways including changes in stress response, epigenetic modifications, neuroinflammation and showed novel link to ketone body production. The study demonstrates the preventive-therapeutic potential of acetate supplementation to alleviate adverse responses to traumatic stress.

Keywords:  Acetate; Anxiety; Neuroinflammation; SPS; ß-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.ynstr.2023.100572
Mol Hum Reprod. 2023 Oct 03. pii: gaad035. [Epub ahead of print]

Inflammasomes in human reproductive diseases.

Yun Chen, Chenyun Miao, Ying Zhao, Liuqing Yang, Ruye Wang, Dan Shen, Ning Ren, Qin Zhang.

  Inflammasomes are multi-protein complexes localized within immune and non-immune cells that induce caspase activation, proinflammatory cytokine secretion, and ultimately pyroptosis-a type of cell death. Inflammasomes are involved in a variety of human diseases, especially acute or chronic inflammatory diseases. In this review, we focused on the strong correlation between the NLRP3 inflammasome and various reproductive diseases, including ovarian aging or premature ovarian insufficiency, PCOS, endometriosis, recurrent spontaneous abortion, preterm labor, pre-eclampsia, and male subfertility, as well as the multifaceted role of NLRP3 in the pathogenesis and treatment of these diseases. In addition, we provide an overview of the structure and amplification of inflammasomes. This comprehensive review demonstrates the vital role of NLRP3 inflammasome activation in human reproductive diseases together with the underlying mechanisms, offers new insight for mechanistic studies of reproduction, and provides promising possibilities for the development of drugs targeting the NLRP3 inflammasome for the treatment of reproductive disorders in the future.

Keywords:  NLRP3; PCOS; endometriosis; inflammasome; male subfertility; ovarian aging; pre-eclampsia; preterm labor; spontaneous abortion

DOI:  https://doi.org/10.1093/molehr/gaad035
Compr Physiol. 2023 Sep 28. 13(4): 5115-5155

Links between Exercise Capacity, Exercise Training, and Metabolism.

Alena Spagnolo, Sebastian Klug, Christina Schenkl, Michael Schwarzer.

Exercise capacity of an individual describes the ability to perform physical activity. This exercise capacity is influenced by intrinsic factors such as genetic constitution and extrinsic factors such as exercise training. On the metabolic level exercise and metabolism are linked. As an important site of metabolism and the main source for ATP needed for muscle contraction, mitochondrial function can determine exercise capacity, and exercise inversely influences mitochondrial function. It has been suggested that exercise mediates many of its effects due to such metabolic changes. Although extrinsic factors affect exercise capacity, a major part of an individual's exercise capacity is genetically determined, and extrinsic factors can only improve on this baseline. Looking at the effect of exercise capacity on and with disease, the two go hand in hand. On one hand, disease is negatively affecting an individual's exercise capacity; on the other hand, exercise offers an effective treatment option. Combining these factors, exercise capacity is an often-ignored prognostic variable for life expectancy as well as morbidity and mortality. In this review, we aim to provide the current knowledge on the links between inherited and acquired exercise capacity, as well as the mechanisms in which metabolism interacts with exercise capacity. © 2023 American Physiological Society. Compr Physiol 13:5115-5155, 2023.

DOI: https://doi.org/10.1002/cphy.c230004
BMC Pharmacol Toxicol. 2023 10 03. 24(1): 48

Butyrate alleviates renal inflammation and fibrosis in a rat model of polycystic ovarian syndrome by suppression of SDF-1.

Al-Amin M Bashir, Kehinde S Olaniyi.

   BACKGROUND: Polycystic ovarian syndrome (PCOS) is a multifactorial condition with metabolic-related complications, such as diabetic nephropathy and chronic renal disorder, which are the leading cause of renal transplant globally. Protective effects of histone deacetylase (HDAC) inhibitors (HDACi) have been documented in metabolic-linked pathologies. Nonetheless, the current study investigated the restorative role of HDACi, butyrate in experimental PCOS-induced renal disorder.
MATERIALS AND METHODS: Female Wistar rats (8-week-old) were divided into groups; control, butyrate-treated, letrozole and letrozole + butyrate-treated groups. To induce PCOS, 1 mg/kg of letrozole was given (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks.
RESULTS: Rats with PCOS revealed disruption in glucose homeostasis (hyperinsulinemia and impaired glucose tolerance and insulin resistance) and presented with the phenotypes of PCOS (hyperandrogenism, multiple ovarian cysts and elevated LH/FSH ratio). Increased plasma and renal triglycerides and inflammatory (TNF-α/SDF-1/NF-κB) markers were observed with elevated levels of TGFβ-1, renal lipid peroxidation and redox imbalance (GGT, GSH, HIF-1α). Interestingly, animals with PCOS reported increased body weight as well as renal mass. Whereas, heightened levels of plasma urea, creatinine and creatine kinase indicating renal dysfunction, characterized by renal apoptosis (Caspase-6) and increased HDAC2 levels. Notwithstanding, administration of butyrate averted the alterations.
CONCLUSION: The present investigation demonstrates that PCOS declines renal function, which is accompanied by renal inflammation, apoptosis and fibrosis. The study further suggests that butyrate, an HDAC2i restores renal function by suppressing renal SDF-1 with subsequent attenuation of renal inflammation, apoptosis and fibrosis.

Keywords:  Butyrate; Inflammation; Kidney; PCOS; SDF-1

DOI:  https://doi.org/10.1186/s40360-023-00692-9
BMC Res Notes. 2023 Sep 30. 16(1): 243

Purification of functional mouse skeletal muscle mitochondria using percoll density gradient centrifugation.

Rea Victoria P Anunciado-Koza, Anyonya R Guntur, Calvin P Vary, Carlos A Gartner, Madeleine Nowak, Robert A Koza.

   OBJECTIVE: Our goal was to isolate purified mitochondria from mouse skeletal muscle using a Percoll density gradient and to assess bioenergetic function and purity via Seahorse Extracellular Flux (XF) Analyses and mass spectrometry.
RESULTS: Mitochondria isolated from murine quadriceps femoris skeletal muscle using a Percoll density gradient method allowed for minimally contaminated preparations with time from tissue harvest to mitochondrial isolation and quantification in about 3-4 h. Percoll purification from 100 to 200 mg fresh tissue yielded ~ 200-400 ug protein. Mitochondrial bioenergetics evaluated using the Seahorse XFe96 analyzer, a high-throughput respirometry platform, showed optimum mitochondrial input at 500 ng with respiratory control ratio ranging from 3.9 to 7.1 using various substrates demonstrating a high degree of functionality. Furthermore, proteomic analysis of Percoll-enriched mitochondria isolated from skeletal muscle using this method showed significant enrichment of mitochondrial proteins indicating high sample purity. This study established a methodology that ensures sufficient high quality mitochondria for downstream analyses such as mitochondrial bioenergetics and proteomics.

Keywords:  Bioenergetics; Density gradient; Mitochondria; Percoll purification; Skeletal muscle

DOI:  https://doi.org/10.1186/s13104-023-06519-4
Chem Asian J. 2023 Oct 03. e202300725

Synthesis of thiophene-substituted ketones via Manganese-Catalyzed Dehydrogenative Coupling Reaction.

Xiaoyu Zhang, Yujie Zhang, Jiaqiao Ding, Liusheng Wang, Weihua Chen, Xinyan Li, Bing Cui, Mingqin Zhao, Zhihui Shao.

  This study reports an efficient and green one-step method for synthesizing thiophene-substituted ketones from 2-thiophenemethanol and ketones via dehydrogenative coupling using manganese complexes as catalysts. The manganese complex demonstrated a broad applicability under mild conditions and extended the range of usable substrates. Utilizing this strategy, we carried out an efficient and diverse reaction of ketones with 2-thiophenemethanol, and successfully synthesized a series of thiophene-substituted saturated ketones and α, β-unsaturated ketones in good isolated yields.

Keywords:  dehydrogenation; flavor; ketone; manganese catalysis; thiophene

DOI:  https://doi.org/10.1002/asia.202300725
Mol Cell Proteomics. 2023 Oct 02. pii: S1535-9476(23)00166-4. [Epub ahead of print] 100655

Impact of Bmal1 rescue and time-restricted feeding on liver and muscle proteomes during the active phase in mice.

Jacob G Smith, Jeffrey Molendijk, Ronnie Blazev, Wan Hsi Chen, Qing Zhang, Christopher Litwin, Valentina M Zinna, Patrick-Simon Welz, Salvador Aznar Benitah, Carolina M Greco, Paolo Sassone-Corsi, Pura Muñoz-Cánoves, Benjamin L Parker, Kevin B Koronowski.

   OBJECTIVE: Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice.
METHODS: LC-MS/MS was performed on liver and gastrocnemius muscle harvested four hours into the dark phase from wild-type (WT), Bmal1 knockout (KO), and dual liver- and muscle- Bmal1-rescued (LMRE) mice housed under 12-h light/12-h dark cycles with either ad libitum feeding or time-restricted feeding (TRF) in the dark phase. Additional molecular and metabolic analyses were performed on liver and cultured hepatocytes.
RESULTS: Feeding-fasting cycles had only minimal effects on liver and few, if any, on muscle. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver, and 80 in muscle. Rescue of liver and muscle Bmal1 restored ∼50% of proteins in liver and ∼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of FGF1, a liver secreted protein, requires BMAL1, and that autocrine FGF1 signaling modulates mitochondrial respiration in hepatocytes.
CONCLUSIONS: In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.

Keywords:  Bmal1; Circadian clock; FGF1; circadian rhythm; fibroblast growth factor; liver; muscle; time-restricted feeding

DOI:  https://doi.org/10.1016/j.mcpro.2023.100655
Vopr Pitan. 2023 ;92(4): 114-124

[Protein in the athlete's diet: rationale for intake levels at different training intensities to maintain lean body mass (a brief review)].

I S Zilova, E N Trushina.

  Nutrition in sports, as a branch of nutritional science, is a constantly developing field with a growing number of scientific researches and recommendations concerning the justification of the diet composition to ensure the requirements for macro- and micronutrients of the athlete's body at different stages of sports activity and energy value, as well as the use of special dietary supplements of various nature, including protein in forms of specialized dry mixes, drinks, etc. The aim of the research was to present the results of studies conducted abroad, presented in review publications and original articles, on the role of protein and the impact of its various levels of consumption on the maintenance of muscle mass as a criterion for the effectiveness of diets used, including in conditions of their reduced calorie content; on the safety of consuming significantly higher than recommended amounts of protein (>2.0 g/kg of body weight per day); about the relationship between protein dose and the possible increase in lean body mass. Material and methods. For the main source search, the PubMed Internet resource was used, and the websites of the Springer and Elsevier publishers were used to access the full text of the articles. Search depth 10 years. Results. This review presents the official position of the International Society of Sports Nutrition (ISSN) on the role of protein in training optimization, body composition change and improving the performance of athletes. Generalized data on the body's energy costs for the assimilation of nutrients, food thermogenesis and the importance of protein for maintaining resting energy expenditure are presented. Published results based on meta-analyses support the efficacy of higher protein intake in reducing body weight and fat mass while maintaining lean mass in an energy-deficient setting. The anabolic properties of protein under conditions of increased physical exertion will manifest themselves only with sufficient energy and protein supply. The proposed values and boundaries within which increased protein intake effectively affect body composition in the process of adaptation to strength training are given. It has been shown that an increase in protein intake above the average maximum values practically does not lead to an increase in lean body mass without the simultaneous introduction of additional resistance exercises that restores its growth. In accordance with the official position of the ISSN, the recommended protein intake corresponds to values from 1.4 to 2.0 g/kg of body weight per day for individuals performing various special sets of physical exercises. The use of high-protein diets (protein >2.0 g/kg/day) in highly qualified athletes who do not have kidney and liver diseases showed no changes in the biochemical parameters of blood and bone mineral density confirming its safety. Conclusion. Based on the analysis of scientific data, it can be stated that proteins make the main contribution to the thermogenesis of the body compared to other dietary macronutrients. The effect of protein intake on body composition, recovery and muscle building of an athlete has been proven. Athletes require higher amounts of protein to optimal increase of lean body mass under increased training loads and to maintain lean mass under an energy-deficient diet. If necessary, high-protein diets can be used in highly qualified athletes without kidney or liver diseases, but comprehensive researches in this direction should be continued.

Keywords:  athlete; body mass; fat free mass; high protein ration; protein; resistance exercises; sports nutrition; thermogenesis

DOI:  https://doi.org/10.33029/0042-8833-2023-92-4-114-124
Int J Biol Sci. 2023 ;19(14): 4427-4441

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease.

Yong Liu, Yingjin Qiao, Shaokang Pan, Jingfang Chen, Zihui Mao, Kaidi Ren, Yang Yang, Qi Feng, Dongwei Liu, Zhangsuo Liu.

  Diabetic kidney disease (DKD) is a global health issue that presents a complex pathogenesis and limited treatment options. To provide guidance for precise therapies, it is crucial to accurately identify the pathogenesis of DKD. Several studies have recognized that mitochondrial and endoplasmic reticulum (ER) dysfunction are key drivers of the pathogenesis of DKD. The mitochondria-associated ER membrane (MAM) is a dynamic membrane contact site (MSC) that connects the ER and mitochondria and is essential in maintaining the normal function of the two organelles. MAM is involved in various cellular processes, including lipid synthesis and transport, calcium homeostasis, mitochondrial fusion and fission, and ER stress. Meanwhile, recent studies confirm that MAM plays a significant role in the pathogenesis of DKD by regulating glucose metabolism, lipid metabolism, inflammation, ER stress, mitochondrial fission and fusion, and autophagy. Herein, this review aims to provide a comprehensive summary of the physiological function of MAMs and their impact on the progression of DKD. Subsequently, we discuss the trend of pharmaceutical studies that target MAM resident proteins for treating DKD. Furthermore, we also explore the future development prospects of MAM in DKD research, thereby providing a new perspective for basic studies and clinical treatment of DKD.

Keywords:  Mitochondria-associated endoplasmic reticulum membrane (MAM); calcium homeostasis; diabetic kidney disease (DKD); lipid metabolism; mitochondrial physiology

DOI:  https://doi.org/10.7150/ijbs.86608
JACC Basic Transl Sci. 2023 Sep;8(9): 1245-1261

Inflammasome Signaling, Thromboinflammation, and Venous Thromboembolism.

Nicola Potere, Antonio Abbate, Yogendra Kanthi, Marc Carrier, Stefano Toldo, Ettore Porreca, Marcello Di Nisio.

  Venous thromboembolism (VTE) remains a major health burden despite anticoagulation advances, suggesting incomplete management of pathogenic mechanisms. The NLRP3 (NACHT-, LRR- and pyrin domain-containing protein 3) inflammasome, interleukin (IL)-1, and pyroptosis are emerging contributors to the inflammatory pathogenesis of VTE. Inflammasome pathway activation occurs in patients with VTE. In preclinical models, inflammasome signaling blockade reduces venous thrombogenesis and vascular injury, suggesting that this therapeutic approach may potentially maximize anticoagulation benefits, protecting from VTE occurrence, recurrence, and ensuing post-thrombotic syndrome. The nonselective NLRP3 inhibitor colchicine and the anti-IL-1β agent canakinumab reduce atherothrombosis without increasing bleeding. Rosuvastatin reduces primary venous thrombotic events at least in part through lipid-lowering independent mechanisms, paving the way to targeted anti-inflammatory strategies in VTE. This review outlines recent preclinical and clinical evidence supporting a role for inflammasome pathway activation in venous thrombosis, and discusses the, yet unexplored, therapeutic potential of modulating inflammasome signaling to prevent and manage VTE.

Keywords:  anti-inflammatory agents; blood coagulation; embolism and thrombosis; inflammation; interleukin-1; post-thrombotic syndrome

DOI:  https://doi.org/10.1016/j.jacbts.2023.03.017
Nat Rev Mol Cell Biol. 2023 Oct 02.

Mechanisms and regulation of human mitochondrial transcription.

Benedict G Tan, Claes M Gustafsson, Maria Falkenberg.

The expression of mitochondrial genes is regulated in response to the metabolic needs of different cell types, but the basic mechanisms underlying this process are still poorly understood. In this Review, we describe how different layers of regulation cooperate to fine tune initiation of both mitochondrial DNA (mtDNA) transcription and replication in human cells. We discuss our current understanding of the molecular mechanisms that drive and regulate transcription initiation from mtDNA promoters, and how the packaging of mtDNA into nucleoids can control the number of mtDNA molecules available for both transcription and replication. Indeed, a unique aspect of the mitochondrial transcription machinery is that it is coupled to mtDNA replication, such that mitochondrial RNA polymerase is additionally required for primer synthesis at mtDNA origins of replication. We discuss how the choice between replication-primer formation and genome-length RNA synthesis is controlled at the main origin of replication (OriH) and how the recent discovery of an additional mitochondrial promoter (LSP2) in humans may change this long-standing model.

DOI: https://doi.org/10.1038/s41580-023-00661-4
JAMA. 2023 Oct 04.

Study: Waist-to-Hip Ratio Might Predict Mortality Better Than BMI.

Emily Harris.

DOI: https://doi.org/10.1001/jama.2023.19205
Front Immunol. 2023 ;14 1238664

Fat and inflammation: adipocyte-myeloid cell crosstalk in atherosclerosis.

Aleksandra M Mazitova, Ana Cristina Márquez-Sánchez, Ekaterina K Koltsova.

  Adipose tissue inflammation has been implicated in various chronic inflammatory diseases and cancer. Perivascular adipose tissue (PVAT) surrounds the aorta as an extra layer and was suggested to contribute to atherosclerosis development. PVAT regulates the function of endothelial and vascular smooth muscle cells in the aorta and represent a reservoir for various immune cells which may participate in aortic inflammation. Recent studies demonstrate that adipocytes also express various cytokine receptors and, therefore, may directly respond to inflammatory stimuli. Here we will summarize current knowledge on immune mechanisms regulating adipocyte activation and the crosstalk between myeloid cells and adipocytes in pathogenesis of atherosclerosis.

Keywords:  adipocytes; atherosclerosis; cytokines; inflammation; perivascular adipose tissue

DOI:  https://doi.org/10.3389/fimmu.2023.1238664
Emerg Med Clin North Am. 2023 Nov;pii: S0733-8627(23)00051-2. [Epub ahead of print]41(4): 677-686

Diabetic Ketoacidosis.

Bobbi-Jo Lowie, Michael C Bond.

  This article reviews the most current literature on diabetic ketoacidosis, including how to make the diagnosis and management. It discusses euglycemic diabetic ketoacidosis and the risk factors for this rare but dangerous disease process. Pertinent pearls and pitfalls encountered by the emergency physician when managing these patients are included. Because these patients often stay in the emergency department for prolonged periods, recommendations on transitioning to subcutaneous insulin are included, along with dosing recommendations. Finally, the article reviews how to disposition patients with diabetic ketoacidosis and examines important factors that lead to a successful discharge home.

Keywords:  Diabetic ketoacidosis; Euglycemic diabetic ketoacidosis; Hyperglycemia

DOI:  https://doi.org/10.1016/j.emc.2023.06.002
Mayo Clin Proc. 2023 Oct;pii: S0025-6196(23)00411-1. [Epub ahead of print]98(10): 1439-1441

Obesity: Central Role in Heart Failure With Preserved Ejection Fraction?

Megan Pelter, Tamara Horwich.

DOI: https://doi.org/10.1016/j.mayocp.2023.08.018
J Gerontol A Biol Sci Med Sci. 2023 Oct 05. pii: glad238. [Epub ahead of print]

Beyond inflammaging: The Impact of Immune System Aging on Age-Related Muscle Decline, results from the InCHIANTI study.

Raffaello Pellegrino, Roberto Paganelli, Angelo Di Iorio, Stefania Bandinelli, Antimo Moretti, Giovanni Iolascon, Eleonora Sparvieri, Domiziano Tarantino, Toshiko Tanaka, Luigi Ferrucci.

  Aging is characterized by chronic low-level inflammation, and is associated with geriatric syndromes such as sarcopenia and frailty. Our aim was to evaluate the longitudinal variation of muscle area, muscle quality, and muscle strength, relative to the variation of leukocyte-derived markers, and to assess the presence of a pathway of associations among derived leukocytes ratios, and the components of muscle health. The InCHIANTI is a longitudinal cohort study of aging that began in 1998 with follow up visits every three years. Out of the 1453 participants enrolled at baseline, this study includes 1179 participants with complete data. Muscle strength was assessed by hand grip strength test, whereas muscle density and fat area were considered as indirect markers of muscle quality, derived from peripheral quantitative computed tomography of the calf. Muscle area was associated with neutrophil-to-lymphocyte ratio (NL-ratio), age, gender, comorbidities, and BMI. Muscle density variation over time was inversely associated with age, comorbidities, and BMI, while being positively associated with monocytes-to-lymphocyte ratio (ML-ratio) and male gender. Fat area was inversely associated with age, IL-6, male gender, and NL-ratio, while being positively associated with ML-ratio, comorbidities, and BMI. Handgrip strength decreased with age, IL-6 levels, comorbidities, and NL-ratio, but increased with ML-ratio, being male, and having a higher BMI. In a path-analysis model, ML-ratio positively correlates with muscle mass, density, and strength, while NL-ratio only correlates inversely with muscle mass and density. NL-ratio and ML-ratio are associated with aging, and may be implicated in age-related mechanisms that affect body composition and muscle strength. These ratios may represent a link between aging of the immune system and decline of muscle health with aging. However, further studies are needed to identify their usefulness for early detection of sarcopenia, myosteatosis, and frailty in the older adult.

Keywords:  Inflammaging; Lymphocytes; Monocytes; Muscle; Neutrophils

DOI:  https://doi.org/10.1093/gerona/glad238