bims-kimdis 2024-08-18 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–08–18
ten papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, placebo-controlled, pilot study.
Influence of Carbohydrate Intake on Caprylic Acid (C8:0)-Induced Ketogenesis-A Systematic Review and Meta-Analysis.
Three Weeks on a Ketogenic Diet Reduces Free Testosterone and Free Estradiol in Middle-Aged Obese Men and Women.
Self-reported menses physiology is positively modulated by a well-formulated, energy-controlled ketogenic diet vs. low fat diet in women of reproductive age with overweight/obesity.
β-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.
"Unlocking Athletic Potential: Exploring Exercise Physiology from Mechanisms to Performance". Acute antioxidant supplementation and performance - should this be considered.
The acute effect of time-restricted feeding (12 & 16 h) and varying exercise intensities on fat-oxidation rate in inactive young adults - a randomized control trial.
Exercise-specific adaptations in human skeletal muscle: Molecular mechanisms of making muscles fit and mighty.
Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.
Epigenetics of Skeletal Muscle Atrophy.

J Nutr Health Aging. 2024 Aug 12. pii: S1279-7707(24)00416-0. [Epub ahead of print]28(9): 100329

Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults in a randomized, parallel arm, double-blind, placebo-controlled, pilot study.

Brianna J Stubbs, Elizabeth B Stephens, Chatura Senadheera, Sawyer Peralta, Stephanie Roa-Diaz, Laura Alexander, Wendie Silverman-Martin, Thelma Y Garcia, Michi Yukawa, Jenifer Morris, Traci M Blonquist, James B Johnson, John C Newman.

   OBJECTIVES: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to assess the tolerability and safety of KE ingestion in a cohort of older adults.
DESIGN: Randomized, placebo-controlled, double-blinded, parallel-arm trial (NCT05585762).
SETTING: General community, Northern California, USA.
PARTICIPANTS: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n = 30; M = 15, F = 15; age = 76 y, range 65-90 y) were randomized and n = 23 (M = 14, F = 9) completed the protocol.
INTERVENTION: Participants were randomly allocated to consume either KE (25 g bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil daily for 12 weeks.
MEASUREMENTS: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events.
RESULTS: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n = 2 (14.3% [90% CI = 2.6-38.5]); PLA n = 1 (7.1% [90% CI = 0.4-29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 and 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group.
CONCLUSIONS: This KE was safe and well-tolerated in this study of healthy older adults. These results provide an initial foundation for use of KEs in clinical research with older adults.

Keywords:  Beta-Hydroxybutyrate; Exogenous ketone; Ketone ester; Ketones; Safety; Tolerance

DOI:  https://doi.org/10.1016/j.jnha.2024.100329
Nutrients. 2024 Jul 29. pii: 2456. [Epub ahead of print]16(15):

Influence of Carbohydrate Intake on Caprylic Acid (C8:0)-Induced Ketogenesis-A Systematic Review and Meta-Analysis.

Marius Frenser, Tobias Fischer, Isabel Albrecht, Thorsten Marquardt.

  The ketogenic diet is used worldwide to treat various diseases, especially drug-resistant epilepsies. Medium-chain triglycerides or medium-chain fatty acids, primarily the major ketogenic compound caprylic acid (C8; C8:0), can significantly support ketogenesis. This review examines the effects of concurrent carbohydrate intake on C8-induced ketogenesis. A systematic literature search (PubMed and Web of Science) with subsequent data extraction was performed according to PRISMA guidelines and the Cochrane Handbook. Studies investigating the metabolic response to C8-containing MCT interventions with carbohydrate intake were included. The studies did not include a ketogenic diet. Three intervention groups were created. The quality of the studies was assessed using the RoB II tool, and the meta-analysis was performed using the Cochrane RevMan software. A total of 7 trials, including 4 RCTs, met the inclusion criteria. Ketone production was lower when C8 was combined with carbohydrates compared to MCT intake alone. The lower C8 dose group (11 g) did not show a significantly lower ketogenic effect than the higher dose group (19 g). Forest plot analysis showed heterogeneous data. The data suggest a non-linear relationship between C8, carbohydrate intake and ketone production. Further studies are needed to investigate the influence of different carbohydrates on C8-induced ketogenesis. Limitations include heterogeneous intervention conditions, such as different types of dispersions, caffeine intake, limited number of studies and variability in study design.

Keywords:  C8:0); caprylic acid (C8; carbohydrates; ketogenic diet; ketone bodies; ketones; medium-chain fatty acids (MCFA); medium-chain triglycerides (MCT); metabolism; ß-hydroxybutyrate

DOI:  https://doi.org/10.3390/nu16152456
J Nutr Metab. 2024 ;2024 9301369

Three Weeks on a Ketogenic Diet Reduces Free Testosterone and Free Estradiol in Middle-Aged Obese Men and Women.

Mads Svart, Nikolaj Rittig, Thien Vinh Luong, Nigopan Gopalasingam, Esben Thyssen Vestergaard, Lars Gormsen, Esben Søndergaard, Henrik Holm Thomsen, Claus H Gravholt.

Background: Beta-hydroxybuturate (β-OHB) supplements are commonly utilized in sports by both recreational and professional athletes. In a recent study, we observed a drop in testosterone levels following the oral ingestion of racemic sodium-β-OHB. In this investigation, we aim to determine whether a single oral dose of ketone ester (study I) and prolonged endogenous ketosis (study II) also reduces testosterone levels.
Design: This investigation integrated samples from two distinct studies. Study I was a randomized, controlled, crossover trial with ten healthy, young male participants receiving either a weight-adjusted ketone ester or control (water, CTR) and vice versa following an overnight fast. Repeated blood sampling was used to monitor plasma β-OHB and testosterone levels. Study II, another randomized, controlled, crossover trial, included 11 middle-aged participants (five males). They followed either a ketogenic diet (KD) characterized by low carbohydrates and high fat content or a standard diet (SDD) for three weeks. After each study period, participants underwent examination following an overnight fast, with repeated measures employed to analyze concentrations of plasma β-OHB and sex hormone levels.
Results: Study I: Testosterone decreased from 23.8 ± 2.4 nmol/l to 22.3 ± 2.5 nmol/l 300 minutes after the ketone ester and increased from 20.9 ± 2.1 nmol/l to 22.2 ± 1.9 300 minutes after CTR. This difference was not significant, p = 0.06. Study II. Total testosterone was unaffected after the KD compared to the SDD in men (20.2 ± 1.23 nmol/l vs. 18.2 ± 1.23 nmol/l (p = 0.1)) and was lower after KD in women (0.87 ± 0.06 vs. 1.1 ± 0.06 nmol/l (p < 0.0001)). Sex hormone-binding globulin (SHBG) increased in men after KD compared with SDD (31.2 ± 2.6 nmol/l vs 25.0 ± 2.6 nmol/l, p < 0.0001) and women (26.5 ± 3.05 nmol/l vs 24.2 ± 3.05 nmol/l, p = 0.003). The free androgen index decreased after KD in men (ratio: 0.65 ± 0.05 vs. ratio: 0.74 ± 0.05, p = 0.04) and in women (ratio: 0.036 ± 0.006 vs. SDD 0.05 ± 0.006, p = 0.0001). Free estradiol index was also found lower after KD in men (ratio: 3.1 ± 0.8 vs. ratio: 4.8 ± 0.8, p = 0.0003) and in women (ratio: 1.2 ± 2.2 vs. 9.8 ± 2.2, p = 0.0001).
Conclusion: Our findings indicate that the acute ingestion of ketone ester may not reduce testosterone levels in healthy young males. However, a three-week exposure to KB from a KD results in an increase in SHBG in men and women with obesity as well as it lowers free testosterone and estradiol for men and women. We thus present evidence of crosstalk between alterations in a metabolite, β-OHB, and the regulation of the hypothalamic-pituitary-gonadal axis from a KD. The clinical impact of this reduction remains to be investigated. This trial is registered with NCT04156477 and NCT05012748.

DOI: https://doi.org/10.1155/2024/9301369
PLoS One. 2024 ;19(8): e0293670

Self-reported menses physiology is positively modulated by a well-formulated, energy-controlled ketogenic diet vs. low fat diet in women of reproductive age with overweight/obesity.

Madison L Kackley, Alex Buga, Milene L Brownlow, Annalouise O'Connor, Teryn N Sapper, Christopher D Crabtree, Bradley T Robinson, Justen T Stoner, Drew D Decker, Loriana Soma, Jeff S Volek.

Weight loss can positively alter female physiology; however, whether dietary carbohydrate- or fat- restriction confer unique effects is less studied. Precisely designed, hypocaloric well-formulated ketogenic diets (KD; ~75% energy for weight maintenance) were compared to isocaloric/isonitrogenous low-fat diet (LFD) on self-reported menses in pre-menopausal overweight and obese women (mean ± SD: 34 ± 10 years, BMI: 32.3 ± 2.7 kg/m2). Women received a precisely-weighed and formulated KD with either twice-daily with ketone salts (KS; n = 6) or a flavor-matched placebo (PL; n = 7) daily for six-weeks. An age and BMI-matched cohort (n = 6) was later assigned to the LFD and underwent the same testing procedures as the KD. Self-reported menses fluctuations were assessed bi-weekly along with measures of body weight, body composition, and fasting serum clinical chemistries using repeated measures ANOVA with Bonferroni post-hoc corrections. Both diets elicited clinically-significant weight-loss (Δ: -7.0 ± 0.5 kg; p < 0.001), primarily from fat-mass (Δ: -4.6 ± 0.3 kg; p < 0.001), and improved insulin-sensitivity and serum lipids (all p < 0.05). Fasting plasma glucose and inflammatory markers were not different between diets. Fasting capillary beta-hydroxybutyrate (R-βHB) increased significantly during the KD, independent of supplementation (Δ: 1.2 ± 0.3 mM R-βHB; p < 0.001). Women randomized to the KD+KS (30%) and KD+PL (43%) reported subjective increases in menses frequency and intensity after 14 days, whereas another third reported a regain of menses (>1 year since the last period) after 28 days. No LFD participants reported menses changes. Nutrient-dense, whole-food KDs and LFD improved weight, BMI, body composition, and blood parameters in pre-menopausal women after six-weeks. Changes in self-reported menses were described by most of the KD participants, but none of the LFD women suggesting there may be unique effects of nutritional ketosis, independent of weight loss.

DOI: https://doi.org/10.1371/journal.pone.0293670
Aging Cell. 2024 Aug 09. e14294

β-Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway.

Huangming Zhuang, Xunshan Ren, Yuelong Zhang, Huajie Li, Panghu Zhou.

  Osteoarthritis (OA) is widely recognized as the prevailing joint disease associated with aging. The ketogenic diet (KD) has been postulated to impede the advancement of various inflammatory ailments. β-Hydroxybutyrate (βOHB), a prominent constituent of ketone bodies, has recently been proposed to possess crucial signaling capabilities. In this study, we propose to explore the role and mechanism of βOHB in OA. Tissue staining and inflammatory factor assay were employed to evaluate the impacts of KD and βOHB on OA rats. The oxidative stress conditions in chondrocytes were induced using tert-butyl hydroperoxide (TBHP). The mechanisms were determined using the siRNA of hydroxycarboxylic acid receptor 2 (HCAR2), the antagonist of adenosine monophosphate-activated protein kinase (AMPK), and the inhibitor of mitophagy. The administration of KD demonstrated a reduction in pathological damage to cartilage, as well as a decrease in plasma levels of inflammatory factors. Furthermore, it resulted in an increase in the concentration of βOHB in the blood and synovial fluid. In vitro experiments showed that βOHB facilitated mitophagy and adenosine triphosphate production. Besides, βOHB mitigated chondrocyte senescence, inflammatory factors secretion, extracellular matrix degradation, and apoptosis induced by TBHP. Subsequent investigations indicated that the protective effects of βOHB were no longer observed following the knockdown of HCAR2, the antagonist of AMPK, or the inhibitor of mitophagy. Moreover, in vivo studies suggested that βOHB played a protective role by targeting the HCAR2-AMPK-PINK1 axis. In conclusion, βOHB enhanced chondrocyte mitophagy through the HCAR2/AMPK/PINK1/Parkin pathway, offering a potential therapeutic approach for the treatment of OA.

Keywords:  hydroxycarboxylic acid receptor 2; mitophagy; osteoarthritis; senescence; β‐Hydroxybutyrate

DOI:  https://doi.org/10.1111/acel.14294
Free Radic Biol Med. 2024 Aug 13. pii: S0891-5849(24)00599-9. [Epub ahead of print]

"Unlocking Athletic Potential: Exploring Exercise Physiology from Mechanisms to Performance". Acute antioxidant supplementation and performance - should this be considered.

Steen Larsen.

  It is well known that a training intervention leads to mitochondrial adaptations with increased skeletal muscle mitochondrial biogenesis and function. Studies have recently indicated that skeletal muscle mitochondrial function is important for athletic performance. During exercise reactive oxygen species are released from skeletal muscle potentially leading to adaptations but maybe also to fatigue. Focus has been on how chronic antioxidant supplementation affects a training adaptation, where some studies are reporting an abolished adaptation. Whether acute antioxidant supplementation could have a positive effect on fatigue and performance is interesting and highly relevant in sports where athletes are competing over several consecutive days or on the same day, with preliminary competitions in the morning and finals in the afternoon, where it is important for the athletes to recover fast. This review provides an overview of the effects of acute antioxidant supplementation and whether it leads to improved performance and/or faster recovery in humans.

Keywords:  Antioxidant supplementation; Mitochondria; Performance

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.013
BMC Sports Sci Med Rehabil. 2024 Aug 13. 16(1): 169

The acute effect of time-restricted feeding (12 & 16 h) and varying exercise intensities on fat-oxidation rate in inactive young adults - a randomized control trial.

Yavelberg Loren, Gledhill Norman, Jamnik Veronica.

   BACKGROUND AND PURPOSE: Time-restricted feeding (TRF) is a dietary pattern that alternates between periods of fasting and feeding, which has gained significant attention in recent years. The 16/8 approach consists of fasting for 16 h and feeding for an 8-h window, while the 12/12 method consists of fasting for 12 h and a 12-h feeding window. Limited research exists comparing the effects of these methods coupled with physical activity (PA). The aim of this investigation was to examine the acute effects between conditions of varying TRF durations (12 and 16 h) and PA intensities on the fat oxidation rate (FOR). It was hypothesized that i) the TRF16 conditions would exhibit higher FORmax and that PA would enhance these effects, and ii) High Intensity Interval Training (HIIT) would result in greater effects on FORmax compared to Low-Moderate Intensity Steady State Continuous Training (MICT) PA.
METHODS AND RESULTS: Eighteen young adults (age: 23 ± 2.0 yrs., body mass index: 23.5 ± 2.8 kg·m-2) were recruited and participated in the supervised intervention. The discrete component open circuit spirometry system was used to measure oxygen consumption (VO2), and Frayne's equation was used to determine the FOR plus FORmax. ANOVA was used to determine pre/post-intervention differences in FORmax. The FORmax for the TRF16 + HIIT intervention was significantly higher than the TRF12 (mean difference = 0.099 g·min-1, p = 0.011, 95% CI 0.017 to 0.180) and TRF16 fast alone (mean difference = 0.093 g·min-1, p = 0.002, 95% CI 0.027 to 0.159). The FORmax for TRF12 + HIIT intervention was significantly higher than the TRF12 fast alone (mean difference = 0.070 g·min-1, p = 0.023, 95% CI 0.007 to 0.134). The TRF16 + HIIT intervention was also significantly higher than the TRF12 fast alone (mean difference = 0.099 g·min-1, p = 0.011, 95% CI 0.017 to 0.180).
CONCLUSION: This study contributes to the ever-growing body of literature on the acute effects of TRF and PA on young adult males and females. The findings suggest that the TRF16 + HIIT PA intervention results in the highest FORmax.
TRIAL REGISTRATION: Retrospective Registration ISRCTN # 10076373 (October 6, 2023).

Keywords:  High Intensity Interval Training; Intermittent Fasting; Metabolic Conditioning; Obesity; Physical Activity Intervention

DOI:  https://doi.org/10.1186/s13102-024-00959-6
Free Radic Biol Med. 2024 Aug 13. pii: S0891-5849(24)00600-2. [Epub ahead of print]223 341-356

Exercise-specific adaptations in human skeletal muscle: Molecular mechanisms of making muscles fit and mighty.

Aaron C Q Thomas, Connor A Stead, Jatin G Burniston, Stuart M Phillips.

  The mechanisms leading to a predominantly hypertrophied phenotype versus a predominantly oxidative phenotype, the hallmarks of resistance training (RT) or aerobic training (AT), respectively, are being unraveled. In humans, exposure of naïve persons to either AT or RT results in their skeletal muscle exhibiting generic 'exercise stress-related' signaling, transcription, and translation responses. However, with increasing engagement in AT or RT, the responses become refined, and the phenotype typically associated with each form of exercise emerges. Here, we review some of the mechanisms underpinning the adaptations of how muscles become, through AT, 'fit' and RT, 'mighty.' Much of our understanding of molecular exercise physiology has arisen from targeted analysis of post-translational modifications and measures of protein synthesis. Phosphorylation of specific residue sites has been a dominant focus, with canonical signaling pathways (AMPK and mTOR) studied extensively in the context of AT and RT, respectively. These alone, along with protein synthesis, have only begun to elucidate key differences in AT and RT signaling. Still, key yet uncharacterized differences exist in signaling and regulation of protein synthesis that drive unique adaptation to AT and RT. Omic studies are required to better understand the divergent relationship between exercise and phenotypic outcomes of training.

Keywords:  Human; Hypertrophy; Mitochondria; Protein signaling; Protein turnover

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.08.010
J Cell Biol. 2024 Nov 04. pii: e202307036. [Epub ahead of print]223(11):

Mitochondrial-derived compartments remove surplus proteins from the outer mitochondrial membrane.

Zachary N Wilson, Sai Sangeetha Balasubramaniam, Sara Wong, Max-Hinderk Schuler, Mitchell J Wopat, Adam L Hughes.

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a mitochondrial remodeling mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here, we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are incorporated into MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface.

DOI: https://doi.org/10.1083/jcb.202307036
Int J Mol Sci. 2024 Jul 31. pii: 8362. [Epub ahead of print]25(15):

Epigenetics of Skeletal Muscle Atrophy.

Jiacheng Du, Qian Wu, Eun Ju Bae.

  Skeletal muscle atrophy, characterized by diminished muscle strength and mass, arises from various causes, including malnutrition, aging, nerve damage, and disease-related secondary atrophy. Aging markedly escalates the prevalence of sarcopenia. Concurrently, the incidence of muscle atrophy significantly rises among patients with chronic ailments such as heart failure, diabetes, and chronic obstructive pulmonary disease (COPD). Epigenetics plays a pivotal role in skeletal muscle atrophy. Aging elevates methylation levels in the promoter regions of specific genes within muscle tissues. This aberrant methylation is similarly observed in conditions like diabetes, neurological disorders, and cardiovascular diseases. This study aims to explore the relationship between epigenetics and skeletal muscle atrophy, thereby enhancing the understanding of its pathogenesis and uncovering novel therapeutic strategies.

Keywords:  epigenetics; skeletal muscle atrophy

DOI:  https://doi.org/10.3390/ijms25158362