bims-kimdis 2024-11-03 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–11–03
twenty-one papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.
Effects of a Carbohydrate Meal on Lipolysis.
Ketogenesis protects against MASLD-MASH progression through fat oxidation-independent mechanisms.
Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance.
Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice.
Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT.
Monitoring the in vitro import and assembly of mitochondrial precursor proteins into mammalian mitochondria.
Mitochondrial proteins as therapeutic targets in diabetic ketoacidosis: evidence from Mendelian randomization analysis.
Calcium ATPase (PMCA) and GLUT-4 Upregulation in the Transverse Tubule Membrane of Skeletal Muscle from a Rat Model of Chronic Heart Failure.
Isolation of yeast mitochondria by affinity purification using magnetic beads.
Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?
Ketogenic diets are associated with an elevated risk of hypertension: Insights from a cross-sectional analysis of the NHANES 2007-2018.
Utility of a high-intensity interval training app as a remote exercise support strategy in children with obesity: An exploratory study of adherence, effect, and perceptions of its use.
Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions.
Changes in lactate concentration are accompanied by opposite changes in the pattern of fat oxidation: Dose-response relationship.
Recent Advances of Exosomes Derived from Skeletal Muscle and Crosstalk with Other Tissues.
Ketone Skeletal Modification via a Metallaphotoredox-Catalyzed Deacylation and Acylation Strategy.
Monitoring mitochondrial protein import by live cell imaging.
Reverse epidemiology of obesity paradox: Fact or fiction?
The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.
Unveiling the proteome of the fasting heart: Insights into HIF-1 pathway regulation.

Nutrients. 2024 Oct 18. pii: 3526. [Epub ahead of print]16(20):

Oral Administration of a Novel, Synthetic Ketogenic Compound Elevates Blood β-Hydroxybutyrate Levels in Mice in Both Fasted and Fed Conditions.

Maricel A Soliven, Christopher Q Rogers, Michael S Williams, Natalya N Thomas, Edward Turos, Dominic P D'Agostino.

   BACKGROUND/OBJECTIVES: Elevating ketone levels with therapeutic nutritional ketosis can help to metabolically manage disease processes associated with epilepsy, diabetes, obesity, cancer, and neurodegenerative disease. Nutritional ketosis can be achieved with various dieting strategies such as the classical ketogenic diet, the modified Atkins diet, caloric restriction, periodic fasting, or the consumption of exogenous ketogenic supplements such as medium-chain triglycerides (MCTs). However, these various strategies can be unpleasant and difficult to follow, so that achieving and sustaining nutritional ketosis can be a major challenge. Thus, investigators continue to explore the science and applications of exogenous ketone supplementation as a means to further augment the therapeutic efficacy of this metabolic therapy.
METHODS: Here, we describe a structurally new synthetic triglyceride, glycerol tri-acetoacetate (Gly-3AcAc), that we prepared from glycerol and an acetoacetate precursor that produces hyperketonemia in the therapeutic range (2-3 mM) when administered to mice under both fasting and non-fasting conditions. Animal studies were undertaken to evaluate the potential effects of eliciting a ketogenic response systemically. Acute effects (24 h or less) were determined in male VM/Dk mice in both fasted and unfasted dietary states.
RESULTS: Concentration levels of β-hydroxybutyrate in blood were elevated (βHB; 2-3 mM) under both conditions. Levels of glucose were reduced only in the fasted state. No detrimental side effects were observed.
CONCLUSIONS: Pending further study, this novel compound could potentially add to the repertoire of methods for inducing therapeutic nutritional ketosis.

Keywords:  diabetes; exogenous ketones; hyperketonemia; hypoglycemia; ketogenic diet; ketone metabolic therapy; ketosis; medium-chain triglycerides; nutritional supplements

DOI:  https://doi.org/10.3390/nu16203526
Nutrients. 2024 Oct 18. pii: 3531. [Epub ahead of print]16(20):

Effects of a Carbohydrate Meal on Lipolysis.

Kerstin Kempf, Stephan Martin.

   BACKGROUND: Due to the increasing prevalence of obesity and type 2 diabetes, effective dietary recommendations are needed. Previously, we developed the low-insulin method: by avoiding insulinogenic, i.e., insulin-release-triggering foods, insulin secretion becomes reduced, lipolysis is stimulated, and energy production is shifted to ketosis with excess ketone bodies exhaled in the form of acetone. Now, we investigate how quickly stable ketosis (defined as fasting breath acetone concentration ≥ 7.0 ppm) is achieved, whether and for how long a carbohydrate meal inhibits ketosis, and whether the responses differ in healthy adults with different insulin levels.
METHODS: An oral glucose tolerance test was conducted, and body composition and fasting insulin were determined at the beginning and end of the 14-day study. Participants (n = 10) followed a ketogenic diet and performed continuous glucose monitoring. Ketosis levels were determined by measuring breath acetone concentrations. On day 8, two white bread rolls with jam (72 g carbohydrates) were consumed for breakfast.
RESULTS: After seven days, all participants achieved stable ketosis (defined as fasting breath acetone concentration ≥ 7.0 ppm), which dropped from 8.2 to 5.7 ppm (p = 0.0014) after the carbohydrate meal. It took five days to achieve stable ketosis again. The stratification of participants into tertiles according to their fasting insulin levels demonstrated that individuals with low fasting insulin levels achieved stable ketosis again after two days and those with medium insulin levels after five days, while those with high baseline values did not reach stable ketosis by the end of the study.
CONCLUSIONS: By carbohydrate restriction, stable ketosis can be achieved within one week. However, a single carbohydrate meal inhibits ketosis for several days. This effect is pronounced in individuals with elevated fasting insulin levels.

Keywords:  acetone; carbohydrates; insulin; ketogenic diet; ketone; ketosis; lipolysis; obesity; overweight; type 2 diabetes; weight loss

DOI:  https://doi.org/10.3390/nu16203531
bioRxiv. 2024 Oct 17. pii: 2024.10.17.618895. [Epub ahead of print]

Ketogenesis protects against MASLD-MASH progression through fat oxidation-independent mechanisms.

Eric D Queathem, David B Stagg, Alisa B Nelson, Alec B Chaves, Scott B Crown, Kyle Fulghum, D Andre d'Avignon, Justin R Ryder, Patrick J Bolan, Abdirahman Hayir, Jacob R Gillingham, Shannon Jannatpour, Ferrol I Rome, Ashley S Williams, Deborah M Muoio, Sayeed Ikramuddin, Curtis Hughey, Patrycja Puchalska, Peter A Crawford.

The progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) involves complex alterations in both liver-autonomous and systemic metabolism that influence the liver's balance of fat accretion and disposal. Here, we quantify the relative contribution of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. We found in humans with MASH, that liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. The use of loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Furthermore, disruption of mitochondrial β-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of hepatic ketogenesis could serve a protective role through alternative fat oxidation-independent mechanisms.

DOI: https://doi.org/10.1101/2024.10.17.618895
Korean J Physiol Pharmacol. 2024 Nov 01. 28(6): 515-526

Exercise improves muscle mitochondrial dysfunction-associated lipid profile under circadian rhythm disturbance.

Yu Gu, Dong-Hun Seong, Wenduo Liu, Zilin Wang, Yong Whi Jeong, Jae-Cheol Kim, Dae Ryong Kang, Rose Ji Eun Lee, Jin-Ho Koh, Sang Hyun Kim.

  We investigated whether endurance exercise training (EXT) ameliorates circadian rhythm (CR)-induced risk factors by improving skeletal muscle (SKM) mitochondrial biogenesis, reducing oxidative stress, and modulating apoptotic protein expression. We distinguished between regular and shift workers using the National Health and Nutrition Examination Survey (NHANES) and investigated the health problems caused by shift work (CR disturbance) and the potential therapeutic effects of exercise. In our animal study, 36 rats underwent 12 weeks of CR disturbance, divided into regular and irregular CR groups. These groups were further split into EXT (n = 12) and sedentary (n = 12) for an additional 8 weeks. We analyzed SKM tissue to understand the molecular changes induced by CR and EXT. NHANES data were analyzed using SAS 9.4 and Prism 8 software, while experimental animal data were analyzed using Prism 8 software. The statistical procedures used in each experiment are indicated in the figure legends. Our studies showed that CR disturbance increases dyslipidemia, alters circadian clock proteins (BMAL1, PER2), raises apoptotic protein levels, and reduces mitochondrial biogenesis in SKM. EXT improved LDL-C and HDLC levels without affecting muscle BMAL1 expression. It also enhanced mitochondrial biogenesis (AMPK, PGC-1α, Tfam, NADH-UO, COX-I), antioxidant levels (Catalase, SOD1, SOD2), and apoptotic protein (p53, Bax/Bcl2) expression or activity in SKM. We demonstrated that shift work-induced CR disturbance leads to dyslipidemia, diminished mitochondrial biogenesis, and reduced antioxidant capacity in SKM. However, EXT can counteract dyslipidemia under CR disturbance, potentially lowering the risk of cardiovascular disorders.

Keywords:  Circadian rhythm; Exercise; Lipids; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.4196/kjpp.2024.28.6.515
J Cachexia Sarcopenia Muscle. 2024 Oct 31.

Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice.

Chaoran Liu, Pui Yan Wong, Qianjin Wang, Hei Yuet Wong, Tao Huang, Can Cui, Ning Zhang, Wing Hoi Cheung, Ronald Man Yeung Wong.

   BACKGROUND: Sarcopenia is a prevalent muscle disorder in old people leading to higher fracture rate, mortality, and other adverse clinical outcomes. Evidence indicates that short-chain fatty acids (SCFAs), which are beneficial gut microbial metabolites, were reduced in old people with sarcopenia. This study aimed to determine whether the use of SCFAs as a supplement can be a therapeutic strategy of sarcopenia in a pre-clinical model.
METHODS: Seven-month-old pre-sarcopenic senescent accelerated mouse prone 8 (SAMP8) mice received daily SCFAs cocktail (acetate, butyrate, and propionate) for 3 months. Age-matched senescence accelerated mouse resistant 1 (SAMR1) and SAMP8 mice receiving sodium-matched drinking water were control groups. The gut microbiota composition analysis of aged mice with or without sarcopenia was conducted by 16S rDNA sequencing. Gut barrier-related proteins and lipopolysaccharide (LPS) concentration were biomarkers of gut permeability. Colon inflammation levels, circulatory SCFAs concentration, muscle quality, function, and underlying pathways were detected by cell number counting, RT-qPCR, gas chromatography-mass spectrometry, measurements of muscle wet weight and grip strength, ex vivo functional test, treadmill endurance test, transcriptomic sequencing, morphological and immunofluorescent staining, as well as western blot. To investigate the role of mTOR signalling pathways in SCFAs treatment, C2C12 myotubes were treated with rapamycin.
RESULTS: Aged SAMP8 mice had different microbiota composition, and lower serum butyric acid compared with SAMR1 mice (P < 0.05). SCFAs treatment reversed the increment of colon inflammation (2.8-fold lower of il-1β) and gut barrier permeability (1.7-fold lower of LPS) in SAMP8 mice. Increased muscle mass, myofibre cross-sectional area, grip strength, twitch and tetanic force were found in SCFAs-treated mice compared with control SAMP8 mice (P < 0.05). Anti-fatigue capacity (1.6-fold) and muscle glycogen (2-fold) also improved after SCFAs treatment (P < 0.05). Transcriptomic analysis showed that AMPK, insulin, and mTOR pathways were involved in SCFAs treatment (P < 0.05). Regulation of AKT/mTOR/S6K1 and AMPK/PGC1α pathways were found. SCFAs attenuated fat infiltration and improved mitochondria biogenesis of atrophic muscle. In vitro studies indicated that SCFAs inhibited FoxO3a/Atrogin1 and activated mTOR pathways to improve myotube growth (P < 0.05), and rapamycin attenuated the effect of SCFAs through the inhibition of mTOR pathways.
CONCLUSIONS: This study demonstrated that bacterial metabolites SCFAs could attenuate age-related muscle loss and dysfunction, and protein synthesis-related mTOR signalling pathways were involved both in vivo and in vitro.

Keywords:  Aging; Gut microbiota; Muscle; Sarcopenia; Short‐chain fatty acids

DOI:  https://doi.org/10.1002/jcsm.13573
Cell Rep Med. 2024 Oct 22. pii: S2666-3791(24)00548-2. [Epub ahead of print] 101801

Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT.

Lin Li, Rui Li, Qingying Tian, Yaogan Luo, Ruyi Li, Xiaoyu Lin, Yunjing Ou, Tianyu Guo, Xue Chen, An Pan, JoAnn E Manson, Gang Liu.

  The effect of a healthy low-carbohydrate diet (HLCD) and time-restricted eating (TRE), alone or in combination, on body weight and gut microbiome beyond caloric restriction remains unclear. In this 12-week two-by-two factorial randomized trial with a 28-week follow-up among 96 participants with overweight or obesity, isocaloric-restricted feeding yields significant weight loss, ranging from 2.57 to 4.11 kg across different groups. Beyond caloric restriction, HLCD and TRE lead to additional reduction in body mass index. HLCD results in additional fat mass loss while TRE yields more lean mass loss. Additionally, HLCD leads to decreased fecal branched-chain amino acids, and TRE tends to yield an increased abundance of probiotic species involved in synthesizing short-chain fatty acids. Moreover, the effect of HLCD on reducing fat mass is sustained during the post-intervention follow-up. Overall, HLCD and TRE are effective in weight management and yield profound gut microbiome and metabolome alteration beyond caloric restriction. This study was registered at ChiCTR.org.cn (ChiCTR2200056363).

Keywords:  body composition; feeding trial; gut microbiome; healthy low-carbohydrate diet; metabolome; obesity; overweight; time-restricted eating; weight; weight regain

DOI:  https://doi.org/10.1016/j.xcrm.2024.101801
Methods Enzymol. 2024 ;pii: S0076-6879(24)00370-7. [Epub ahead of print]706 365-390

Monitoring the in vitro import and assembly of mitochondrial precursor proteins into mammalian mitochondria.

Jordan J Crameri, Diana Stojanovski.

  Mitochondrial protein import is a complex process governing the delivery of the organelle's proteome. This process, in turn, is essential for maintaining mitochondrial function and cellular homeostasis. Initiated by protein synthesis in the cytoplasm, precursor proteins destined for the mitochondria possess targeting signals that guide them to the mitochondrial surface. At mitochondria, the translocation of proteins across the mitochondrial membranes involves an intricate interplay between translocases, chaperones, and receptors. The mitochondrial import assay offers researchers the opportunity to recapitulate the process of protein import in vitro. The assay has served as an indispensable tool in helping decipher the intricacies of protein translocation into mitochondria, first in fungal models, and subsequently in higher eukaryotic models. In this chapter, we will describe how protein import can be assayed using mammalian mitochondria and provide insight into the types of questions that can be addressed in mammalian mitochondrial biology using this experimental approach.

Keywords:  in vitro; mitochondria; protein import; translocase

DOI:  https://doi.org/10.1016/bs.mie.2024.07.034
Front Pharmacol. 2024 ;15 1448505

Mitochondrial proteins as therapeutic targets in diabetic ketoacidosis: evidence from Mendelian randomization analysis.

Ruiqiang Xie, Hongyan Xie, Hong Gao, Chunguang Xie, Haipo Yuan, Zhijun Feng.

   Introduction: Diabetic ketoacidosis (DKA) is a severe and potentially fatal acute complication in diabetic patients, commonly occurring in type 1 diabetes (T1D) but also seen in type 2 diabetes (T2D). The pathogenesis of DKA involves complex physiological processes that are not fully understood, especially the role of mitochondria. Mitochondria, known as the powerhouse of cells, plays a crucial role in oxidative phosphorylation and ATP production, which is vital in various metabolic diseases, including diabetes. However, the exact causal relationship between mitochondrial dysfunction and DKA remains unclear.
Methods: This study employed Mendelian randomization (MR) analysis and protein-protein interaction (PPI) networks to systematically explore the causal relationships between mitochondrial DNA copy number (mtDNA-CN) and specific mitochondrial proteins with DKA. We used bidirectional MR analysis and genome-wide association study (GWAS) data from openGWAS database to investigate the causal effects of mtDNA-CN and 64 mitochondrial-related proteins on DKA and its subtypes (T1DKA, T2DKA, unspecified-DKA).
Results: The study revealed that increased mtDNA-CN significantly reduces the risk of DKA, whereas the effect of DKA on mtDNA-CN was not significant. Mitochondrial-related proteins such as MRPL32, MRPL33, COX5B, DNAJC19, and NDUFB8 showed a negative causal relationship with DKA, indicating their potential protective roles. Conversely, ATP5F1B and COX4I2 have a positive causal relationship with DKA, indicating that excessive ATP production in diabetic patients may be detrimental to health and increase the risk of severe complications such as DKA.
Discussion: The results emphasize the necessity of protecting mitochondrial function in order to reduce the risk of DKA. The study offers novel perspectives on the molecular pathways involved in DKA, emphasizing the critical functions of mt-DNA and distinct proteins. These evidences not only enhance our comprehension of the implications of mitochondrial dysfunction in diabetes-related complications but also identify potential therapeutic targets for individualized treatment approaches, thereby making a substantial contribution to clinical care and public health initiatives.

Keywords:  Mendelian randomization; causal relationship; diabetic ketoacidosis; mitochondrial dysfunction; mitochondrial proteins; therapeutic targets

DOI:  https://doi.org/10.3389/fphar.2024.1448505
Int J Mol Sci. 2024 Oct 17. pii: 11180. [Epub ahead of print]25(20):

Calcium ATPase (PMCA) and GLUT-4 Upregulation in the Transverse Tubule Membrane of Skeletal Muscle from a Rat Model of Chronic Heart Failure.

Sofia Gitler, Ibrahim Ramirez-Soto, Aura Jiménez-Graduño, Alicia Ortega.

  Intolerance to exercise is a symptom associated with chronic heart failure (CHF) resulting in SM waste and weakness in humans. The effect of CHF on skeletal muscle (SM) arose from experimental evidence in rat models to explain the underlying mechanism. We investigated SM mechanical and metabolic properties in sham rats and with coronary ligation-induced CHF. After twelve weeks of CHF, rats were catheterized to measure right auricular pressure, SM mechanical properties, SERCA-ATPase activity and plasma membrane Ca2+-ATPase (PMCA) hydrolytic activity in isolated sarcoplasmic reticulum (SR) and transverse tubule (TT membrane), respectively, in the sham and CHF. The right auricular pressure and plasma nitrite concentration in CHF increased two-fold with respect to the sham. Pleural effusion and ascites were detected in CHF, confirming CHF. SERCA activity was conserved in CHF. In TT membranes from CHF, the glucose transporter GLUT4 increased seven-fold, and the PMCA hydrolytic activity increased five-fold, but in isolated muscle, the mechanical properties were unaffected. The absence of a deleterious effect of coronary ligation-induced CHF in the rat model on SM could be explained by the increased activity of PMCA and increased presence of GLUT-4 on the TT membrane, which may be involved in the mechanical outcome of the EDL.

Keywords:  GLUT4; PMCA; chronic heart failure; sarcoplasmic reticulum; skeletal muscle; transverse tubule membrane

DOI:  https://doi.org/10.3390/ijms252011180
Methods Enzymol. 2024 ;pii: S0076-6879(24)00368-9. [Epub ahead of print]706 19-36

Isolation of yeast mitochondria by affinity purification using magnetic beads.

Tzu-Ying Lin, Shih-Hung Chien, Liza A Pon, Pin-Chao Liao.

  Isolated mitochondria have been widely utilized in various model organisms to investigate the diverse functions of the organelle. Techniques such as differential centrifugation, density gradient ultracentrifugation and antibody-coated magnetic beads are employed for isolation of the organelle from whole cells. However, mitochondria isolated using differential centrifugation are often contaminated with other organelles; isolation using density gradient ultracentrifugation can reduce contamination but is time-intensive and requires large amounts of starting materials; and mitochondria isolated using antibody-coated magnetic beads are irreversibly bound to the beads. Here, we provide a step-by-step protocol for the isolation of highly pure mitochondria from Saccharomyces cerevisiae using a magnetic bead affinity purification method that overcomes these limitations. This protocol describes how to isolate mitochondria, tagged by insertion of 6 histidines (6xHis) into the chromosomal copy of the TOM70 (Translocase of outer membrane 70) gene using Ni-NTA (nickel(II) nitrilotriacetic acid) paramagnetic beads, and the subsequent release of mitochondria from the beads using a buffer containing imidazole. We provide examples of expected results, highlighting the purity, integrity and import activity of isolated mitochondria. These affinity-purified mitochondria are intact and functional, containing less contamination with cytosol and other organelles compared to mitochondria isolated by other methods. Our method is adaptable and can be applied to other model organisms that can be genetically manipulated using CRISPR or other methods.

Keywords:  Affinity purification; Budding yeast; Magnetic beads; Mitochondrial import; Mitochondrial isolation

DOI:  https://doi.org/10.1016/bs.mie.2024.07.032
Int J Mol Sci. 2024 Oct 11. pii: 10932. [Epub ahead of print]25(20):

Aging Skeletal Muscles: What Are the Mechanisms of Age-Related Loss of Strength and Muscle Mass, and Can We Impede Its Development and Progression?

Thomas Gustafsson, Brun Ulfhake.

  As we age, we lose muscle strength and power, a condition commonly referred to as sarcopenia (ICD-10-CM code (M62.84)). The prevalence of sarcopenia is about 5-10% of the elderly population, resulting in varying degrees of disability. In this review we emphasise that sarcopenia does not occur suddenly. It is an aging-induced deterioration that occurs over time and is only recognised as a disease when it manifests clinically in the 6th-7th decade of life. Evidence from animal studies, elite athletes and longitudinal population studies all confirms that the underlying process has been ongoing for decades once sarcopenia has manifested. We present hypotheses about the mechanism(s) underlying this process and their supporting evidence. We briefly review various proposals to impede sarcopenia, including cell therapy, reducing senescent cells and their secretome, utilising targets revealed by the skeletal muscle secretome, and muscle innervation. We conclude that although there are potential candidates and ongoing preclinical and clinical trials with drug treatments, the only evidence-based intervention today for humans is exercise. We present different exercise programmes and discuss to what extent the interindividual susceptibility to developing sarcopenia is due to our genetic predisposition or lifestyle factors.

Keywords:  ageing; dynapenia; motor unit; muscle fibre atrophy; senescence

DOI:  https://doi.org/10.3390/ijms252010932
Int J Cardiol Cardiovasc Risk Prev. 2024 Dec;23 200342

Ketogenic diets are associated with an elevated risk of hypertension: Insights from a cross-sectional analysis of the NHANES 2007-2018.

Xiaolong Qu, Yuping Liu, Lei Huang, Fang Wan.

   Background: The ketogenic diet (KD) is widely used for weight loss in obese individuals; however, its potential impact on hypertension risk remains uncertain.
Methods: We used cross-sectional data from the 2007-2018 to National Health and Nutrition Examination Survey (NHANES) to investigate the association between the dietary ketogenic ratio (DKR) and hypertension prevalence. Dietary intake information was obtained through a comprehensive 24-h dietary recall interview. The DKR values were computed using a specialized formula. Multiple logistic regression analysis was employed to examine this association, whereas nonlinear relationships were assessed using restricted cubic splines. Inflection points were determined using two-piecewise linear regression analysis. Subgroup analyses based on age were also performed.
Results: In a fully adjusted multivariate logistic regression model accounting for confounding variables, DKR was significantly associated with hypertension (OR, 1.24; 95 % CI: 1.00-1.53; P = 0.045). Moreover, individuals in the highest quartile of DKR exhibited a significantly elevated risk of hypertension compared with those in the lowest quartile (OR, 1.15; 95 % CI: 1.07-1.24; P < 0.001). Additionally, restricted cubic spline analysis revealed a linear relationship between DKR and the risk of hypertension, with a turning point identified at 3.4 units on the measurement scale employed for this study's purposes. Subgroup analyses indicated that this association between DKR and hypertension was particularly pronounced among individuals aged ≥40 years, especially those age group-40-60. We further observed that a multivariate linear regression analysis revealed a significant positive correlation between DKR and DBP in a fully adjusted model (β, 0.42; 95 % CI: 0.12-0.87; P = 0.018), indicating that as DKR increased, there was an accompanying increase in DBP. However, no significant correlation was found between SBP and DKR (β, 0.11; 95 % CI: -0.37-0.59; P = 0.655).
Conclusion: The KD may enhance susceptibility to hypertension in middle-aged and elderly populations in the United States, exhibiting a strong association with elevated diastolic blood pressure, while no significant correlation was observed with increased systolic blood pressure.

Keywords:  Cross-sectional study; Hypertension; Ketogenic diet ratios; NHANES

DOI:  https://doi.org/10.1016/j.ijcrp.2024.200342
Digit Health. 2024 Jan-Dec;10:10 20552076241291386

Utility of a high-intensity interval training app as a remote exercise support strategy in children with obesity: An exploratory study of adherence, effect, and perceptions of its use.

Fábio de Freitas, Maria Ângela Antônio, Mariana R Zago, Mariana Zambon, António Videira-Silva.

   Objective: This study aimed to explore the utility of a high-intensity interval training (HIIT) app as a remote exercise support strategy in children with obesity through assessing adherence, possible effects on obesity-related outcomes, and perceptions of its use to support counseling and improve the treatment of children with obesity.
Methods: Thirty-seven children (94.6% with obesity; 45.9% girls), with a mean age of 10.4 (±1.8) years and a mean body mass index (BMI) z-score of 3.31 (±1.09) were recruited to use the app during 6 weeks. Assessments were performed at baseline, 6 (end of intervention), and 12 weeks (follow up).
Results: Thirty-two (86.3%) participants completed both intervention and follow-up assessments and were analyzed. On average, children used the HIIT app 2.5 times per week (95% confidence interval (CI): 1.9 to 3.0), with the highest perceived exertion of 4.1 (95% CI: 3.6 to 4.5). No over-time differences were found in body composition, physical activity, screen time, sleep duration, or water intake after the intervention; however, an over-time decrease in sugary beverages intake (Δ-0.9, 95% CI: -1.6 to -0.1, p = .019). No differences in body composition were found at follow up. Although none of the children or parents perceived impairments in nutritional behavior, general wellbeing, or fitness as a consequence of intervention, most children (64.5%), but not parents, perceived improvements in nutritional behavior and general wellbeing.
Conclusion: Although feasible, the 6-week effect of HIIT app use is modest or absent regarding body composition, movement, and nutritional behavior change, probably due to its low volume. More studies are needed to explore the utility of HIIT apps as a remote exercise support strategy for children with obesity further.

Keywords:  Child; high-intensity interval training; mobile apps; obesity

DOI:  https://doi.org/10.1177/20552076241291386
Molecules. 2024 Oct 17. pii: 4909. [Epub ahead of print]29(20):

Bis(2-butoxyethyl) Ether-Promoted O2-Mediated Oxidation of Alkyl Aromatics to Ketones under Clean Conditions.

Yangyang Xie, Zeping Li, Xudong Xu, Han Jiang, Keyi Chen, Jinhua Ou, Kaijian Liu, Yihui Zhou, Kejun Luo.

  Conventional oxidation processes for alkyl aromatics to ketones employ oxidants that tend to generate harmful byproducts and cause severe equipment corrosion, ultimately creating critical environmental problems. Thus, in this study, a practical, efficient, and green method was developed for the synthesis of aromatic ketones by applying a bis(2-butoxyethyl) ether/O2 system under external catalyst-, additive-, and base-free conditions. This O2-mediated oxidation system can tolerate various functional groups and is suitable for large-scale synthesis. Diverse target ketones were prepared under clean conditions in moderate-to-high yields. The late-stage functionalization of drug derivatives with the corresponding ketones and one-pot sequential chemical conversions to ketone downstream products further broaden the application prospects of this approach.

Keywords:  alkyl aromatics; bis(2-butoxyethyl) ether; ketones; metal-free; oxidation

DOI:  https://doi.org/10.3390/molecules29204909
Eur J Sport Sci. 2024 Oct 30.

Changes in lactate concentration are accompanied by opposite changes in the pattern of fat oxidation: Dose-response relationship.

José Antonio Benítez-Muñoz, Isabel Guisado-Cuadrado, Miguel Ángel Rojo-Tirado, María Alcocer-Ayuga, Nuria Romero-Parra, Ana Belén Peinado, Rocío Cupeiro.

  It is unknown whether changes in lactate concentration produced by different situations (e.g., glycogen depletion or heat) modify fat oxidation. If confirmed, we could determine a dose-response relationship between lactate and fat. The aim of this study was to determine whether changes in lactate concentration (due to glycogen depletion or heat) alter fat oxidation during exercise. 11 males and eight females performed an incremental exercise test under three situations: control, glycogen depletion, and heat. At rest, in the last minute of each step and immediately post-exhaustion, lactate was analyzed and fat oxidation was estimated by indirect calorimetry. Lactate concentration was inversely associated with fat oxidation in the three aforementioned situations (r > 0.88 and p < 0.05). The highest lactate concentration was found in the heat situation, followed by the control situation, and finally the glycogen depletion situation (all p < 0.05). The opposite was found for fat oxidation, with the highest fat oxidation found in the glycogen depletion situation, followed by the control situation, and finally the heat situation (all p < 0.05). There is no association between the changes in lactate concentration between situations at each intensity and the changes in fat oxidation between situations at each intensity in males or females (p > 0.05). In conclusion, lactatemia is strongly and inversely associated with fat oxidation under the three different situations. Furthermore, the lowest lactate concentrations were accompanied by the highest fat oxidations in the glycogen depletion situation, whereas the highest lactate concentrations were accompanied by the lowest fat oxidations in the heat situation.

Keywords:  glycogen depletion; heat; hyperthermia; substrate oxidation

DOI:  https://doi.org/10.1002/ejsc.12211
Int J Mol Sci. 2024 Oct 10. pii: 10877. [Epub ahead of print]25(20):

Recent Advances of Exosomes Derived from Skeletal Muscle and Crosstalk with Other Tissues.

Jia Luo, Qiang Pu, Xiaoqian Wu.

  Skeletal muscle plays a crucial role in movement, metabolism, and energy homeostasis. As the most metabolically active endocrine organ in the body, it has recently attracted widespread attention. Skeletal muscle possesses the ability to release adipocytokines, bioactive peptides, small molecular metabolites, nucleotides, and other myogenic cell factors; some of which have been shown to be encapsulated within small vesicles, particularly exosomes. These skeletal muscle exosomes (SKM-Exos) are released into the bloodstream and subsequently interact with receptor cell membranes to modulate the physiological and pathological characteristics of various tissues. Therefore, SKM-Exos may facilitate diverse interactions between skeletal muscle and other tissues while also serving as biomarkers that reflect the physiological and pathological states of muscle function. This review delves into the pivotal role and intricate molecular mechanisms of SKM-Exos and its derived miRNAs in the maturation and rejuvenation of skeletal muscle, along with their intercellular signaling dynamics and physiological significance in interfacing with other tissues.

Keywords:  adipose; bone; crosstalk; exosome; skeletal muscle

DOI:  https://doi.org/10.3390/ijms252010877
Org Lett. 2024 Oct 28.

Ketone Skeletal Modification via a Metallaphotoredox-Catalyzed Deacylation and Acylation Strategy.

Ke-Han He, Na Jin, Jia-Cai Chen, You-Fen Zheng, Fei Pan.

Herein, we describe a dual catalytic strategy that employs dihydroquinazolinones, derived from ketone analogs, as versatile intermediates for acylation via α C-C cleavage with 2-pyridyl esters, facilitating the efficient synthesis of a variety of ketones. The reaction accommodates a wide range of ketones and carboxylic acids, showing tolerance to various functional groups. The versatility of this synthetic technique is further highlighted through its application in the late-stage modification of pharmaceuticals and biologically active natural products.

DOI: https://doi.org/10.1021/acs.orglett.4c03456
Methods Enzymol. 2024 ;pii: S0076-6879(24)00363-X. [Epub ahead of print]706 437-447

Monitoring mitochondrial protein import by live cell imaging.

F X Reymond Sutandy.

  The majority of mitochondrial proteins are synthesized in the cytosol and must be imported into mitochondria to attain their mature forms and execute their functions. Disruption of mitochondrial functions, whether caused by external or internal stress, may compromise mitochondrial protein import. Therefore, monitoring mitochondrial protein import has become a standard approach to assess mitochondrial health and gain insights into mitochondrial biology, especially during stress. This chapter describes a detailed protocol for monitoring mitochondrial import in live cells using microscopy. Co-localization between mitochondria and a genetic reporter of mitochondrially targeted enhanced GFP (eGFP) is employed to evaluate mitochondrial protein import efficiency under different physiological conditions. Overall, this technique provides a simple and robust approach to assess mitochondrial protein import efficiency within its native cellular environment.

Keywords:  MTS; mitochondria; protein import; stress response

DOI:  https://doi.org/10.1016/bs.mie.2024.07.027
Physiol Rep. 2024 Nov;12(21): e70107

Reverse epidemiology of obesity paradox: Fact or fiction?

Bellamkonda K Kishore.

  Obesity paradox refers to the clinical observation that when acute cardiovascular decompensation occurs, patients with obesity may have a survival benefit. This apparently runs counter to the epidemiology of obesity, which may increase the risk for non-communicable diseases (NCDs). The scientific community is split on obesity paradox, with some supporting it, while others call it BMI paradox. This review: (a) defines the obesity paradox, and its proposed role in overall mortality in NCDs; (b) delineates evidence for and against obesity paradox; (c) presents the importance of using different indices of body mass to assess the risk in NCDs; (d) examines the role of metabolically healthy obesity in obesity paradox, and emerging importance of cardio-respiratory fitness (CRF) as an independent predictor of CVD risk and all-cause mortality in patients with/without obesity. Evidence suggests that the development of obesity and insulin resistance are influenced by genetic (or ethnic) make up and dietary habits (culture) of the individuals. Hence, this review presents lean diabetes, which has higher total CVD and non-CVD mortality as compared to diabetics with obesity and the possibility of maternal factors programming cardiometabolic risk during fetal development, which may lead to a paradigm shift in our understanding of obesity.

Keywords:  BMI paradox; cardiovascular decompensation; cardio‐respiratory fitness; lean diabetes; metabolically healthy obesity; non‐communicable diseases; obesity paradox

DOI:  https://doi.org/10.14814/phy2.70107
EMBO Rep. 2024 Oct 31.

The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.

Sebastian Edman, Ronald G Jones Iii, Paulo R Jannig, Rodrigo Fernandez-Gonzalo, Jessica Norrbom, Nicholas T Thomas, Sabin Khadgi, Pieter J Koopmans, Francielly Morena, Toby L Chambers, Calvin S Peterson, Logan N Scott, Nicholas P Greene, Vandre C Figueiredo, Christopher S Fry, Liu Zhengye, Johanna T Lanner, Yuan Wen, Björn Alkner, Kevin A Murach, Ferdinand von Walden.

  A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influence the exercise-related hypertrophic transcriptional landscape.

Keywords:  Biopsy; Methylome; Time Course; Transcription Factors; Transcriptome

DOI:  https://doi.org/10.1038/s44319-024-00299-z
Front Physiol. 2024 ;15 1462014

Unveiling the proteome of the fasting heart: Insights into HIF-1 pathway regulation.

Daniel Benak, Kristyna Holzerova, Frantisek Kolar, Miloslava Chalupova, Marketa Hlavackova.

  Fasting is a common dietary intervention known for its protective effects against metabolic and cardiovascular diseases. While its effects are mostly systemic, understanding tissue-specific changes in the heart is crucial for the identification of the mechanisms underlying fasting-induced cardioprotection. In this study, we performed a proteomic analysis of the fasting heart and attempted to clarify the molecular basis of fasting-induced cardioprotection. Our investigation identified a total of 4,652 proteins, with 127 exhibiting downregulation and 118 showing upregulation after fasting. Annotation analysis highlighted significant changes in processes such as lipid metabolism, the peroxisome pathway, and reactive oxygen species metabolism. Notably, the HIF-1 signaling pathway emerged as one of the focal points, with various HIF-1 targets exhibiting differential responses to fasting. Further experiments demonstrated downregulation of HIF-1α at both transcript and protein levels. Intriguingly, while gene expression of Egln3 decreased, its protein product PHD3 remained unaffected by fasting. The unchanged levels of pro-inflammatory cytokines indicated that the observed reduction in Hif1a expression did not stem from a decrease in basal inflammation. These findings underscore the complex regulation of the well-established cardioprotective HIF-1 signaling within the heart during 3-day fasting.

Keywords:  HIF-1; PHD3; fasting; heart; proteome

DOI:  https://doi.org/10.3389/fphys.2024.1462014