bims-kimdis 2023-05-07 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–05–07
eleven papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Metabolic Effects of Ketogenic Diets and Their Utilization in Obesity Management: A Systematic Review.
Ketogenic diets, exercise performance, and training adaptations.
Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders.
Effects of very low carbohydrate ketogenic diets on skeletal health.
Daily Intake of D-β-Hydroxybutyric Acid (D-BHB) Reduces Body Fat in Japanese Adult Participants: A Randomized, Double-Blind, Placebo-Controlled Study.
Exogenous ketosis increases circulating dopamine concentration and maintains mental alertness in ultra-endurance exercise.
The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.
The ER-mitochondria interface, where Ca2+ and cell death meet.
Lower mitochondrial respiration does not lead to decreased fat oxidation in young African American women without obesity.
The effect of electrical stimulation of skeletal muscle on cardioprotection and on muscle-derived myokine levels in rats: A pilot study.
Mitochondrial protein import clogging as a mechanism of disease.

Cureus. 2023 Mar;15(3): e36720

Metabolic Effects of Ketogenic Diets and Their Utilization in Obesity Management: A Systematic Review.

Vani Malhotra, Anupama Sawal.

  A ketogenic diet (KD), more commonly called a "keto" diet, is a dietary regime that focuses on reducing carbohydrates and replacing them with healthy fats. It has proven to improve health and has resurfaced as a trendy weight loss method. Keto, in simple terms, works by mimicking starvation and forcing the body to utilize and deplete fat as its core energy source instead of its usual source of glucose (sugar). More technically, it gives ignition to a process called 'ketosis'. Ketosis is the process of generation of ketone bodies when the liver metabolizes fat. There are several versions of this diet, each of which addresses slightly variable issues as well as hones unique requirements. Individuals will require a unique combination of fat, carbohydrates, and protein depending on their genetic and physical makeup. The advantages and hazards of using the KD to manage obesity are examined in this review of the literature.

Keywords:  carbohydrates; fats; ketogenic diet; ketosis; metabolism; obesity

DOI:  https://doi.org/10.7759/cureus.36720
Curr Opin Clin Nutr Metab Care. 2023 Apr 28.

Ketogenic diets, exercise performance, and training adaptations.

Fernando Klitzke Borszcz, Mariana Papini Gabiatti, Ricardo Dantas de Lucas, Fernanda Hansen.

PURPOSE OF REVIEW: The ketogenic diet has been proposed as a nutritional strategy in sports. This review was undertaken to provide an overview of the recent literature concerning the effects of ketogenic diet on exercise performance and training adaptations.
RECENT FINDINGS: Most recent literature on the ketogenic diet and exercise performance showed no beneficial effects, especially for trained individuals. During a period of intensified training, performance was clearly impaired during the ketogenic intervention, while a diet with high carbohydrates maintained physical performance. The main effect of the ketogenic diet resides in metabolic flexibility, inducing the metabolism to oxidize more fat for ATP resynthesis regardless of submaximal exercise intensities.
SUMMARY: The ketogenic diet is not a reasonable nutritional strategy, as it has no advantage over normal/high carbohydrate-based diets on physical performance and training adaptations even when used only in a specific training/nutritional periodization stage.

DOI: https://doi.org/10.1097/MCO.0000000000000940
Front Psychiatry. 2023 ;14 1142682

Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders.

Naomi Elyse Omori, Mantas Kazimieras Malys, Geoffrey Woo, Latt Mansor.

  In recent times, advances in the field of metabolomics have shed greater light on the role of metabolic disturbances in neuropsychiatric conditions. The following review explores the role of ketone bodies and ketosis in both the diagnosis and treatment of three major psychiatric disorders: major depressive disorder, anxiety disorders, and schizophrenia. Distinction is made between the potential therapeutic effects of the ketogenic diet and exogenous ketone preparations, as exogenous ketones in particular offer a standardized, reproducible manner for inducing ketosis. Compelling associations between symptoms of mental distress and dysregulation in central nervous system ketone metabolism have been demonstrated in preclinical studies with putative neuroprotective effects of ketone bodies being elucidated, including effects on inflammasomes and the promotion of neurogenesis in the central nervous system. Despite emerging pre-clinical data, clinical research on ketone body effectiveness as a treatment option for psychiatric disorders remains lacking. This gap in understanding warrants further investigating, especially considering that safe and acceptable ways of inducing ketosis are readily available.

Keywords:  BHB; anxiety; depression; diagnosis; ketone; schizophrenia; treatment; β-hydroxybutyric acid

DOI:  https://doi.org/10.3389/fpsyt.2023.1142682
Curr Opin Endocrinol Diabetes Obes. 2023 May 03.

Effects of very low carbohydrate ketogenic diets on skeletal health.

Cora M Best, Simon Hsu.

PURPOSE OF REVIEW: Very low carbohydrate ketogenic diet (KD) therapy has been associated with skeletal demineralization in children with drug-resistant epilepsy, but the cause of this association is unclear. Recently, interest in the KD has grown owing to its potential benefits for other illnesses including cancer, type 2 diabetes, obesity, and polycystic kidney disease. Summaries of the best available evidence regarding effects of a KD on skeletal health are lacking.
RECENT FINDINGS: Recent rodent studies found that a KD can harm the growing skeleton, which corroborates most but not all studies in pediatric patients. Proposed mechanisms include chronic metabolic acidosis and depressed osteoanabolic hormones. Relative to other weight-reducing diets, a weight-reducing KD for treatment of obesity and/or type 2 diabetes in adults has not been associated with adverse skeletal effects. By contrast, recent evidence suggests that adaptation to a eucaloric KD may impair bone remodeling in elite adult athletes. Discrepancies in the literature may relate to differences between study populations and in diet formulation.
SUMMARY: Attention to skeletal health is warranted when using KD therapy given the uncertainty in the literature and suggestive harms in certain populations. Future research should focus on potential mechanisms of injury.

DOI: https://doi.org/10.1097/MED.0000000000000811
J Nutr Sci Vitaminol (Tokyo). 2023 ;69(2): 121-128

Daily Intake of D-β-Hydroxybutyric Acid (D-BHB) Reduces Body Fat in Japanese Adult Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

Shohei Katsuya, Yoshikazu Kawata, Tsuyoshi Goto, Jun Tsubota.

  Currently, there is considerable interest in ketone metabolism owing to the benefits for human health. Conventionally, strict dietary restrictions on carbohydrates are required to increase plasma ketone levels, while supplementation with D-β-hydroxybutyric acid (D-BHB) can easily increase plasma ketone levels. We hypothesized that a daily intake of D-BHB could promote weight loss, especially through fat reduction. Herein, D-BHB (OKETOATM) was produced via a proprietary fermentation process from sugar. In this randomized, double-blind, placebo-controlled study, we assessed the safety and fat-reduction effects after 12 wk of daily ingestion of D-BHB (2.9 g) in 22 healthy Japanese adults and 22 control participants. Blood samples were collected pre- and post-treatment. Blood chemistry, anthropometric variables, and the body composition of the participants were investigated. Data analysis revealed that visceral fat at 12 wk significantly decreased by 9.0 cm2 (p=0.037), as evidenced by analysis of covariance. Blood parameters and body condition showed no significant differences between the two groups, and the participants reported no adverse effects or discomfort. Furthermore, data were analyzed by regrouping the participants. After removing one suspicious diabetes participant, all others showed significant decreases in visceral fat, body weight, BMI, and fat weight. Additionally, those aged under 50 y old had significantly decreased abdominal circumference and body fat percentage, in addition to visceral fat, body weight, BMI, and fat weight. Overall, our findings indicate that daily D-BHB intake may reduce body fat without dieting or exercise intervention. This study was registered with the UMIN Clinical Trials Registry as UMIN000045322.

Keywords:  D-β-hydroxybutyric acid (D-BHB); ketogenic diet (KD); ketone body; lifestyle-related diseases; obesity

DOI:  https://doi.org/10.3177/jnsv.69.121
J Appl Physiol (1985). 2023 May 04.

Exogenous ketosis increases circulating dopamine concentration and maintains mental alertness in ultra-endurance exercise.

Chiel Poffé, Ruben Robberechts, Myrthe Stalmans, Jan Vanderroost, Stijn Bogaerts, Peter Hespel.

  Exogenous ketosis can improve psychocognitive functioning during exercise as well as stimulate postexercise muscular recovery. Therefore, we hypothesized that ketone ester (KE) supplementation can counteract the decline in psychocognitive functioning during ultra-endurance exercise and stimulate muscular recovery. Eighteen recreational runners participated in a full 100km trail run (RUN, n=8), or ran to premature exhaustion (80km: n=6; 60km: n=4). Before (25g), during (25g·h-1), and after (5*25g in 24h) RUN they received ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE, n=9) supplements or a non-caloric placebo (CON, n=9). Blood samples and muscle biopsies were taken, and mental alertness was assessed by a psychocognitive test battery at different times before, during, and up to 36h after RUN. Compared with CON (<0.3 mM), in KE blood D-ß-hydroxybutyrate concentration was consistently elevated to ~2-3 mM during RUN. In CON, RUN increased visual reaction times from 353±53 to 419±54ms, and movement execution times from 174±47 to 245±64ms. But this effect was fully negated by KE (p<0.05). Plasma dopamine concentrations doubled in KE during RUN but remained stable in CON, resulting in higher concentrations after RUN in KE (4.1±1.7 nM) than in CON (2.4±0.8 nM, p=0.048). KE also inhibited muscular infiltration of macrophages and suppressed AMPK phosphorylation status until 36h post exercise (p<0.05 KE vs. CON). In conclusion, KE increases circulating dopamine concentration and improves mental alertness, as well as improves postexercise muscular inflammation in ultra-endurance exercise.

Keywords:  Cognitive function; Dopamine; Ketone; Skeletal muscle; Ultra marathon

DOI:  https://doi.org/10.1152/japplphysiol.00791.2022
Adv Biol (Weinh). 2023 May 02. e2300095

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions.

Jonathan M Borkum.

  Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high-capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha-ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double-strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia-inducible factor-1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

Keywords:  DNA methylation; DNA repair; aspartate; autophagy; hypoxia; succinate

DOI:  https://doi.org/10.1002/adbi.202300095
Cell Calcium. 2023 Apr 25. pii: S0143-4160(23)00055-6. [Epub ahead of print]112 102743

The ER-mitochondria interface, where Ca2+ and cell death meet.

Ian de Ridder, Martijn Kerkhofs, Fernanda O Lemos, Jens Loncke, Geert Bultynck, Jan B Parys.

  Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca2+ flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca2+-transport system that delivers Ca2+ from the ER towards mitochondria. At the ER-mitochondria contact sites, the IP3Rs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IP3R-GRP75-VDAC1 complex supports the efficient transfer of Ca2+ from the ER into the mitochondrial intermembrane space, from which the Ca2+ ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca2+ oscillations deliver Ca2+ to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca2+ overload occurs, the increase in [Ca2+] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IP3R-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca2+ into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.

Keywords:  Apoptosis; ER-mitochondria tether; IP(3) receptor; Metabolism; Mitochondria-associated membranes

DOI:  https://doi.org/10.1016/j.ceca.2023.102743
Obesity (Silver Spring). 2023 May;31(5): 1338-1346

Lower mitochondrial respiration does not lead to decreased fat oxidation in young African American women without obesity.

John J Dubé, Frederico G S Toledo, Paul M Coen, Bret H Goodpaster, James P DeLany.

OBJECTIVE: The prevalence of type 2 diabetes in African American women (AAW) is nearly twice that of White women. Lower insulin sensitivity and decreased mitochondrial function may be contributing factors. The purpose of this study was to compare fat oxidation in AAW and White women.
METHODS: Participants were 22 AAW and 22 White women, matched for age (18.7-38.3 years) and BMI (< 28 kg/m2). Participants completed two submaximal (50% VO2max) exercise tests with indirect calorimetry and stable isotope tracers to assess total, plasma, and intramyocellular triglyceride fat oxidation.
RESULTS: The respiratory quotient during the exercise test was nearly identical in AAW and White women (0.813 ± 0.008 vs. 0.810 ± 0.008, p = 0.83). Although absolute total and plasma fat oxidation was lower in AAW, adjusting for the lower workload in AAW eliminated these racial differences. There was no racial difference in plasma and intramyocellular triglyceride source of fat for oxidation. No racial differences were observed in rates of ex vivo fat oxidation. Exercise efficiency was lower in AAW when adjusted to leg fat free mass.
CONCLUSIONS: The data suggest that fat oxidation is not lower in AAW compared with White women, but additional studies are needed across exercise intensity, body weight, and age to confirm these results.

DOI: https://doi.org/10.1002/oby.23716
Physiol Int. 2023 May 05.

The effect of electrical stimulation of skeletal muscle on cardioprotection and on muscle-derived myokine levels in rats: A pilot study.

Márton R Szabó, Tamás Csont, Csaba Csonka.

  Electrical muscle stimulation (EMS) is a widely used method in sports and rehabilitation therapies to simulate physical exercise. EMS treatment via skeletal muscle activity improves the cardiovascular functions and the overall physical condition of the patients. However, the cardioprotective effect of EMS has not been proven so far, therefore, the aim of this study was to investigate the potential cardiac conditioning effect of EMS in an animal model. Low-frequency 35-min EMS was applied to the gastrocnemius muscle of male Wistar rats for three consecutive days. Their isolated hearts were then subjected to 30 min global ischemia and 120 min reperfusion. At the end of reperfusion cardiac specific creatine kinase (CK-MB) and lactate dehydrogenase (LDH) enzyme release and myocardial infarct size were determined. Additionally, skeletal muscle-driven myokine expression and release were also assessed. Phosphorylation of cardioprotective signaling pathway members AKT, ERK1/2, and STAT3 proteins were also measured. EMS significantly attenuated cardiac LDH and CK-MB enzyme activities in the coronary effluents at the end of the ex vivo reperfusion. EMS treatment considerably altered the myokine content of the stimulated gastrocnemius muscle without altering circulating myokine levels in the serum. Additionally, phosphorylation of cardiac AKT, ERK1/2, and STAT3 was not significantly different in the two groups. Despite the lack of significant infarct size reduction, the EMS treatment seems to influence the course of cellular damage due to ischemia/reperfusion and favorably modifies skeletal muscle myokine expressions. Our results suggest that EMS may have a protective effect on the myocardium, however, further optimization is required.

Keywords:  cardioprotection; electrical muscle stimulation; heart; myokine; reperfusion injury

DOI:  https://doi.org/10.1556/2060.2023.00198
Elife. 2023 May 02. pii: e84330. [Epub ahead of print]12

Mitochondrial protein import clogging as a mechanism of disease.

Liam P Coyne, Xiaowen Wang, Jiyao Song, Ebbing de Jong, Karin Schneider, Paul T Massa, Frank A Middleton, Thomas Becker, Xin Jie Chen.

  Mitochondrial biogenesis requires the import of >1,000 mitochondrial preproteins from the cytosol. Most studies on mitochondrial protein import are focused on the core import machinery. Whether and how the biophysical properties of substrate preproteins affect overall import efficiency is underexplored. Here, we show that protein traffic into mitochondria can be disrupted by amino acid substitutions in a single substrate preprotein. Pathogenic missense mutations in ADP/ATP translocase 1 (ANT1), and its yeast homolog Aac2, cause the protein to accumulate along the protein import pathway, thereby obstructing general protein translocation into mitochondria. This impairs mitochondrial respiration, cytosolic proteostasis and cell viability independent of ANT1's nucleotide transport activity. The mutations act synergistically, as double mutant Aac2/ANT1 cause severe clogging primarily at the Translocase of the Outer Membrane (TOM) complex. This confers extreme toxicity in yeast. In mice, expression of a super-clogger ANT1 variant led to neurodegeneration and an age-dependent dominant myopathy that phenocopy ANT1-induced human disease, suggesting clogging as a mechanism of disease. More broadly, this work implies the existence of uncharacterized amino acid requirements for mitochondrial carrier proteins to avoid clogging and subsequent disease.

Keywords:  S. cerevisiae; biochemistry; chemical biology; mouse

DOI:  https://doi.org/10.7554/eLife.84330