bims-kimdis 2024-10-06 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024‒10‒06
23 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Do ketone supplements regulate islet hormone secretion?
Putative Role of Adenosine A1 Receptors in Exogenous Ketone Supplements-Evoked Anti-Epileptic Effect.
Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.
Quantification of Total Ketone Bodies in Biological Matrices Using Stable Isotope-Labeled Internal Standards and RP-UHPLC-MS/MS.
The effects of the ketogenic diet on cancer treatment: a narrative review.
Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.
The ketogenic diet has the potential to decrease all-cause mortality without a concomitant increase in cardiovascular-related mortality.
Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.
Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.
Responses to Exercise with Low Carbohydrate Availability on Muscle Glycogen and Cell Signaling: A Systematic Review and Meta-analysis.
The Rate of Leg Fat Oxidation Is Not Attenuated During Incremental Intensity One-Leg Knee Extensor Exercise.
Ursolic Acid Restores Redox Homeostasis and Pro-inflammatory Cytokine Production in Denervation-Induced Skeletal Muscle Atrophy.
Inflammasomes and their role in PANoptosomes.
A reduced carbohydrate diet improves glycemic regulation in hyperglycemic older people in a retirement home: The SAGE study.
Higher skeletal muscle mass associates with higher measured glomerular filtration rate in healthy individuals.
Fasting: A Complex, Double-Edged Blade in the Battle Against Doxorubicin-Induced Cardiotoxicity.
Biogenesis of mitochondrial β-barrel membrane proteins.
NLRP3 blockade by MCC950 suppressed osteoclastogenesis via NF-κB/c-FOS/NFATc1 signal pathway and alleviated bone loss in diabetes mellitus.
Fructose: the sweet(er) side of the Warburg effect.
Characteristics of High-Intensity Interval Training Influence Anthropometrics, Glycemic Control, and Cardiorespiratory Fitness in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Effects of coffee intake on skeletal muscle microvascular reactivity at rest and oxygen extraction during exercise: a randomized cross-over trial.
Does one biopsy cut it? Revisiting human muscle fiber type composition variability using repeated biopsies in the vastus lateralis and gastrocnemius medialis.
Metabolic and Biochemical Effects of Pyrroloquinoline Quinone (PQQ) on Inflammation and Mitochondrial Dysfunction: Potential Health Benefits in Obesity and Future Perspectives.

Endocrinology. 2024 Oct 04. pii: bqae133. [Epub ahead of print]

Do ketone supplements regulate islet hormone secretion?

Jamie W Joseph.

  Ketone supplementation has been gaining interest in improving health and treating some diseases, such as diabetes. However, the mechanism of action of how these ketone supplements work is not fully understood. In a recent paper, Banerjee et al. (2024) showed that physiological concentrations of βHB can affect hormone secretion and signalling within pancreatic islets. They showed that acute treatment with βHB increases insulin secretion and decreases glucagon secretion at physiological glucose concentrations. Their studies also suggest chronic βHB treatment may protect human islet cells from cytokine-induced cell death. Although more work is needed, it is possible that physiological concentrations of βHB may influence hormone secretion and signalling within islets.

Keywords:  Islets; insulin secretion; ketone bodies; type 2 diabetes; β-hydroxybutyrate

DOI:  https://doi.org/10.1210/endocr/bqae133
Int J Mol Sci. 2024 Sep 12. pii: 9869. [Epub ahead of print]25(18):

Putative Role of Adenosine A1 Receptors in Exogenous Ketone Supplements-Evoked Anti-Epileptic Effect.

Zsolt Kovács, Enikő Rauch, Dominic P D'Agostino, Csilla Ari.

  Approximately 30% of patients with epilepsy are drug-refractory. There is an urgent need to elucidate the exact pathophysiology of different types of epilepsies and the mechanisms of action of both antiseizure medication and metabolic therapies to treat patients more effectively and safely. For example, it has been demonstrated that exogenous ketone supplement (EKS)-generated therapeutic ketosis, as a metabolic therapy, may decrease epileptic activity in both animal models and humans, but its exact mechanism of action is unknown. However, it was demonstrated that therapeutic ketosis, among others, can increase adenosine level, which may enhance activity of A1 adenosine receptors (A1Rs) in the brain. It has also been demonstrated previously that adenosine has anti-epileptic effect through A1Rs in different models of epilepsies. Thus, it is possible that (i) therapeutic ketosis generated by the administration of EKSs may exert its anti-epileptic effect through, among other mechanisms, increased adenosine level and A1R activity and that (ii) the enhanced activity of A1Rs may be a necessary anti-epileptic mechanism evoked by EKS administration-generated ketosis. Moreover, EKSs can evoke and maintain ketosis without severe side effects. These results also suggest that the therapeutic application of EKS-generated ketosis may be a promising opportunity to treat different types of epilepsies. In this literature review, we specifically focus on the putative role of A1Rs in the anti-epileptic effect of EKS-induced ketosis.

Keywords:  A1R; epilepsy; exogenous ketone supplement; ketosis

DOI:  https://doi.org/10.3390/ijms25189869
BMC Pediatr. 2024 Sep 28. 24(1): 603

Classic ketogenic diet-induced ketoacidosis in the treatment of pyruvate dehydrogenase deficiency: a case report and literature review.

Rongrong Li, Mingsheng Ma, Wei Chen, Zhengqing Qiu.

  BACKGROUND: As a rare mitochondrial disorder, the pyruvate dehydrogenase complex (PDC) deficiency is a rare inborn disease characterized with glucose metabolism defects, which leads to neurological dysfunction, serum lactic acid buildup and a resultant trend of metabolic acidosis. Although the ketogenic diet (KD) is the first-line treatment for PDC deficiency, there is currently no widely accepted consensus on specific implementation of KD for this condition. Due to the combined effect of pre-existing hyperlactacidemia and KD-induced ketoacidosis that can further exacerbate metabolic disturbances, maintaining metabolic homeostasis should be prioritized during the implementation of KD.CASE PRESENTATION: Herein, the authors present a 6-year-old boy with lactic acidosis, ataxia, hypotonia and neuromotor development retardation. The KD was started after the patient was diagnosed with PDC deficiency based on genetic testing. The initiation with classic KD resulted in severe non-diabetic ketoacidosis with elevated anion gap, which was promptly alleviated by dextrose supplementation and dietary modification to a less-restrictive KD. Long-term supervision demonstrated the efficacy of a modified KD in improving both clinical course and metabolic acidosis of the patient.
CONCLUSIONS: This rare case adds to the limited evidence of KD application in PDC deficiency, and provides valuable insights into the importance of reasonably lowering the ketogenic ratio of KD at the start of treatment to reduce the risk of metabolic acidosis.

Keywords:  Acidosis; Ketogenic diet; Lactic acid; Non-diabetic ketoacidosis; Pyruvate dehydrogenase complex deficiency

DOI:  https://doi.org/10.1186/s12887-024-05054-w
Methods Mol Biol. 2025 ;2855 117-131

Quantification of Total Ketone Bodies in Biological Matrices Using Stable Isotope-Labeled Internal Standards and RP-UHPLC-MS/MS.

Eric D Queathem, Alisa B Nelson, Patrycja Puchalska.

  Acetoacetate (AcAc) and D-beta-hydroxybutyrate (D-βOHB), the two major ketone bodies found in circulation, are linked to multiple physiological and pathophysiological states. Therefore, analytical methodologies surrounding the quantification of total ketone body (TKB) concentrations in biological matrices are paramount. Traditional methods to quantify TKBs relied on indirect spectrophotometric assays with narrow dynamic ranges, which have been significantly improved upon by modern mass spectrometry (MS)-based approaches. However, the lack of stable isotope-labeled internal standards (ISs) for AcAc and the need to distinguish D-βOHB from its closely related structural and enantiomeric isomers pose significant obstacles. Here, we provide a protocol to synthesize and quantify a [13C] stable isotope-labeled IS for AcAc, which, in conjunction with a commercially available [2H] stable isotope-labeled IS for βOHB, allows TKBs to be measured across multiple biological matrices. This rapid (7 min) analysis employs reverse phase ultra-high performance liquid chromatography (RP-UHPLC) coupled to tandem MS (MS/MS) to distinguish βOHB from three structural isomers using parallel reaction monitoring (PRM), providing excellent specificity and selectivity. Finally, a method is provided that distinguishes D-βOHB from L-βOHB using a simple one-step derivatization to produce the corresponding diastereomers, which can be chromatographically resolved using the same rapid RP-UHPLC separation with new PRM transitions. In summary, this method provides a rigorous analytical pipeline for the analysis of TKBs in biological matrices via leveraging two authentic stable isotope-labeled ISs and RP-UHPLC-MS/MS.

Keywords:  Acetoacetate; D-β-hydroxybutyrate; Ketone bodies; L-β-hydroxybutyrate; Stable isotope-labeled internal standards; Tandem mass spectrometry; Ultra-high performance liquid chromatography

DOI:  https://doi.org/10.1007/978-1-0716-4116-3_7
Eur J Cancer Prev. 2024 Sep 20.

The effects of the ketogenic diet on cancer treatment: a narrative review.

Qingxuan Deng, Ruyue Lv, Tangbin Zou.

Despite significant advances in therapy, cancer remains the top cause of death in parts of the globe. For many types of cancer, the typical treatment is a combination of surgery, chemotherapy, and radiotherapy. However, this conventional treatment is not successful on its own. As a consequence, innovative approaches that improve treatment efficacy are urgently needed. The ketogenic diet is a high-fat, moderate protein, and low-carbohydrate diet that appears to sensitize most cancers to conventional therapies by exploiting cancer cells' altered metabolism, making it an effective adjuvant cancer treatment alternative. This diet could decrease glucose metabolism while enhancing lipid metabolism, interfering with the Warburg effect, and inhibiting tumor cell proliferation. The anticancer impact of ketogenic diet has been established in numerous animal trials and clinical investigations on a wide range of tumor types, including glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, invasive rectal cancer, ovarian cancer, and endometrial cancer. In this review, we discussed the various types of ketogenic diets, the mechanism of action for ketogenic diet as a cancer therapy, and the data gathered from continuing preclinical and clinical studies, intending to establish a solid theoretical foundation for future research.

DOI: https://doi.org/10.1097/CEJ.0000000000000918
Mol Cell Biochem. 2024 Oct 04.

Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.

Shunling Yuan, Zhongkai Kuai, Fei Zhao, Diqun Xu, Weijia Wu.

  Heart failure (HF) is associated with the occurrence of mitochondrial dysfunction. ATP produced by mitochondria through the tricarboxylic acid cycle is the main source of energy for the heart. Excessive release of Ca2+ from myocardial sarcoplasmic reticulum (SR) in HF leads to excessive Ca2+ entering mitochondria, which leads to mitochondrial dysfunction and REDOX imbalance. Excessive accumulation of ROS leads to mitochondrial structure damage, which cannot produce and provide energy. In addition, the accumulation of a large number of ROS can activate NF-κB, leading to myocardial inflammation. Energy deficit in the myocardium has long been considered to be the main mechanism connecting mitochondrial dysfunction and systolic failure. However, exercise can improve the Ca2+ imbalance in HF and restore the Ca2+ disorder in mitochondria. Similarly, exercise activates mitochondrial dynamics to improve mitochondrial function and reshape intact mitochondrial structure, rebalance mitochondrial REDOX, reduce excessive release of ROS, and rescue cardiomyocyte energy failure in HF. In this review, we summarize recent evidence that exercise can improve Ca2+ homeostasis in the SR and activate mitochondrial dynamics, improve mitochondrial function, and reduce oxidative stress levels in HF patients, thereby reducing chronic inflammation in HF patients. The improvement of mitochondrial dynamics is beneficial for ameliorating metabolic flow bottlenecks, REDOX imbalance, ROS balance, impaired mitochondrial Ca2+ homeostasis, and inflammation. Interpretation of these findings will lead to new approaches to disease mechanisms and treatment.

Keywords:  Ca2+ ; Exercise; Heart failure; Mitochondrial dynamics; ROS

DOI:  https://doi.org/10.1007/s11010-024-05124-8
Sci Rep. 2024 10 01. 14(1): 22805

The ketogenic diet has the potential to decrease all-cause mortality without a concomitant increase in cardiovascular-related mortality.

Xiaolong Qu, Lei Huang, Jiacheng Rong.

  The impact of the ketogenic diet (KD) on overall mortality and cardiovascular disease (CVD) mortality remains inconclusive.This study enrolled a total of 43,776 adults from the National Health and Nutrition Examination Survey (NHANES) conducted between 2001 and 2018 to investigate the potential association between dietary ketogenic ratio (DKR) and both all-cause mortality as well as cardiovascular disease(CVD) mortality.Three models were established, and Cox proportional hazards regression analysis was employed to examine the correlation. Furthermore, a restricted cubic spline function was utilized to assess the non-linear relationship. In addition, subgroup analysis and sensitivity analysis were performed.In the adjusted Cox proportional hazards regression model, a significant inverse association was observed between DKR and all-cause mortality (HR = 0.76, 95% CI = 0.63-0.9, P = 0.003). However, no significant association with cardiovascular mortality was found (HR = 1.13; CI = 0.79-1.6; P = 0.504). Additionally, a restricted cubic spline(RCS) analysis demonstrated a linear relationship between DKR and all-cause mortality risk. In the adult population of the United States, adherence to a KD exhibits potential in reducing all-cause mortality risk while not posing an increased threat of CVD-related fatalities.

Keywords:  Cohort study; Ketogenic diet ; Mortality ; NHANES

DOI:  https://doi.org/10.1038/s41598-024-73384-x
Immunol Rev. 2024 Oct 01.

Molecular mechanisms of emerging inflammasome complexes and their activation and signaling in inflammation and pyroptosis.

Abhimanu Pandey, Zheyi Li, Manjul Gautam, Aritra Ghosh, Si Ming Man.

  Inflammasomes are multi-protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), driving the secretion of the pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. The best-characterized inflammasome complexes are the NLRP3, NAIP-NLRC4, NLRP1, AIM2, and Pyrin canonical caspase-1-containing inflammasomes, and the caspase-11 non-canonical inflammasome. Newer inflammasome sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, and MxA. These inflammasome sensors can sense PAMPs from bacteria, viruses and protozoa, or DAMPs in the form of mitochondrial damage, ROS, stress and heme. The mechanisms of action, physiological relevance, consequences in human diseases, and avenues for therapeutic intervention for these novel inflammasomes are beginning to be realized. Here, we discuss these emerging inflammasome complexes and their putative activation mechanisms, molecular and signaling pathways, and physiological roles in health and disease.

Keywords:  PANoptosis; PANoptosome; autoimmunity; autoinflammation; bacteria; cancer; caspase‐1; caspase‐11; caspase‐4; caspase‐5; cell death; cytokines; gasdermin D; immunity; infection; inflammatory caspases; interferons; lipopolysaccharide; parasites; pattern‐recognition receptors; viruses

DOI:  https://doi.org/10.1111/imr.13406
Am J Physiol Cell Physiol. 2024 Sep 30.

Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.

Stavroula Tsitkanou, Francielly Morena da Silva, Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Pieter J Koopmans, Sabin Khadgi, Seongkyun Lim, Luca J Delfinis, Tyrone A Washington, Kevin A Murach, Christopher G R Perry, Nicholas P Greene.

  Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1x106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (~250 nmol/kg body weight/day) and administered to mice beginning seven days following tumor induction, while control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post-hoc test when interactions were significant (p≤0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1 and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.

Keywords:  cancer cachexia; protein turnover; reactive oxygen species; sexual dimorphism; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00497.2024
Sports Med. 2024 Oct 01.

Responses to Exercise with Low Carbohydrate Availability on Muscle Glycogen and Cell Signaling: A Systematic Review and Meta-analysis.

Javier Diaz-Lara, Gorka Prieto-Bellver, Amelia Guadalupe-Grau, David J Bishop.

BACKGROUND: The growing interest in how exercise and carbohydrate (CHO) restriction may modify molecular responses that promote endurance adaptations has led to many interesting controversies.OBJECTIVE: We conducted a systematic review and a meta-analysis regarding the effect of low-carbohydrate availability (LOW) pre-, during, or post-exercise, on the mRNA content of commonly measured genes involved in mitochondrial biogenesis (PGC-1α, TFAM mRNA) and metabolism (PDK4, UCP3 and GLUT4 mRNA), and on muscle glycogen levels, compared with a high-CHO (CON) condition.
METHODS: MEDLINE, Scopus, and Web of Science databases were searched following the PRISMA 2020 guidelines (with an end date of November 2023). In total, 19 randomized-controlled studies were considered for inclusion. We evaluated the methodological quality of all studies using the Cochrane Risk of Bias tool for randomized clinical studies. A meta-analysis was performed using a random effects model to calculate the standardized mean difference (SMD), estimated by Hedges' g, and 95% confidence intervals (CIs).
RESULTS: The LOW condition was associated with an increased mRNA content of several genes during the early recovery period post-exercise, such as PDK4 (SMD 1.61; 95% CI 0.80-2.42), GLUT4 (SMD 1.38; 95% CI 0.46-2.30), and UCP3 (SMD 2.05; 95% CI 0.40-3.69). However, overall, there was no significant effect on the mRNA content of PGC-1α or TFAM. Finally, CHO restriction and exercise significantly reduced muscle glycogen levels (SMD 3.69; 95% CI 2.82-5.09). A meta-analysis of subgroups from studies with a difference in muscle glycogen concentration of > 200 mmol kg dw-1 between the LOW and CON conditions showed an increase in exercise-induced PGC-1α mRNA (SMD 2.08; 95% CI 0.64-3.52; p = 0.005; I2 = 75%) and a greater effect in PDK4 and GLUT4 mRNA.
CONCLUSION: The meta-analysis results show that CHO restriction was associated with an increase in the exercise-induced mRNA content of PDK4, UCP3, and GLUT4, but not the exercise-induced mRNA content of PGC-1ɑ and TFAM. However, when there were substantial differences in glycogen depletion between CON and LOW CHO conditions (> 200 mmol kg dw-1), there was a greater effect of CHO restriction on the exercise-induced mRNA content of metabolic genes, and an increase in exercise-induced PGC-1α mRNA.

DOI: https://doi.org/10.1007/s40279-024-02119-9
Scand J Med Sci Sports. 2024 Oct;34(10): e14737

The Rate of Leg Fat Oxidation Is Not Attenuated During Incremental Intensity One-Leg Knee Extensor Exercise.

J W Helge, C E Shannon, B Stallknecht, F B Stephens, P L Greenhaff, F Dela.

  It is not clear if fat oxidation is attenuated at higher exercise intensities, when exercising with a small muscle mass, and therefore, we studied leg fat oxidation during graded one-leg exercise. Ten males (age: 27 ± 2 years, body mass: 82 ± 3 kg, BMI: 24 ± 1 kg m-2, V̇O2max: 49 ± 2 mL min-1 kg-1) performed one-leg exercise at 25% of maximal workload (Wmax) for 30 min, followed by 120-min exercise at 55% Wmax with the contralateral leg, and finally 30-min exercise at 85% Wmax with the first leg. Blood was sampled from an artery and both femoral veins, and blood flow was determined using Doppler ultrasound. Muscle biopsies were obtained before and after 30 min at each workload. One-way RM ANOVA was applied to determine the impact of exercise intensity. Data are expressed as mean ± SEM. From rest through exercise average blood flow (0.4 ± 0.1, 2.1 ± 0.1, 2.6 ± 0.2, 3.7 ± 0.2 L min-1) and oxygen uptake across the leg (0.03 ± 0.01, 0.23 ± 0.02, 0.35 ± 0.03, 0.53 ± 0.04 L min-1) increased with exercise intensity (p < 0.001). Leg RQ (0.76 ± 0.04, 0.86 ± 0.02,0.87 ± 0.01, 0.92 ± 0.01, p < 0.001), leg plasma FA uptake (2 ± 2, 46 ± 8,83 ± 9, 114 ± 16 μmol min-1; p < 0.001) and rate of leg fat oxidation (0.016 ± 0.005, 0.062 ± 0.012, 0.075 ± 0.011, 0.084 ± 0.018 g min-1, p < 0.007) increased with exercise intensity. Muscle-free carnitine content was unchanged from rest at 25% Wmax and decreased after 30 min exercise at 55% and 85% Wmax (17.4 ± 1.6, 16.6 ± 0.7, 14.5 ± 1.2, 10.5 ± 1.0 mmol/kg dry muscle, respectively; p < 0.006). During incremental one-leg exercise, the rate of leg fat oxidation was not attenuated with increasing exercise intensity, probably due to an insufficient muscle metabolic stress response.

Keywords:  carnitine; exercise; metabolism; muscle; one‐leg exercise

DOI:  https://doi.org/10.1111/sms.14737
Appl Biochem Biotechnol. 2024 Oct 03.

Ursolic Acid Restores Redox Homeostasis and Pro-inflammatory Cytokine Production in Denervation-Induced Skeletal Muscle Atrophy.

Aarti Yadav, Rajesh Dabur.

  Skeletal muscle (SkM) atrophy results from metabolic disorders causing body and muscle mass loss, affecting morbidity and mortality. Increased oxidative stress, inflammation, and poor prognosis are the leading causes of involuntary weight loss. Ursolic acid (UA), known for its antioxidant and anti-inflammatory properties, can potentially reduce oxidative stress and inflammation in muscles, but its effects on muscle mass regulation are still unknown. Therefore, the present study investigated the medicinal efficacy of UA and its mode of action against the murine model of SkM atrophy over 7 days of UA supplementation. Denervation-induced SkM atrophy significantly impacts overall body weight and the weight of individual muscles (p < 0.05). However, supplementation with UA can effectively counteract these effects by promoting the synthesis of the slow-myosin heavy chain, thereby restoring body weight and myotube diameter. Moreover, UA also plays a crucial role in reducing the production levels of reactive oxygen species (ROS), lipid peroxidation (LPO), and caspase-3-like activity in atrophied muscles. UA also prevents the leakage of creatine kinase (CK) through the upregulation of superoxide dismutase (SOD) and glutathione peroxidase (GPx) expression. Furthermore, the results obtained from qRT-PCR demonstrated a significant decrease in the levels of pro-inflammatory markers, namely IL-1β, IL-6, TNF-α, and TWEAK, up to four-fold after the third day of the UA intervention. UA also upregulated PGC-1α, Bcl2, and p-Aktser473 expression towards the regulation of redox homeostasis.

Keywords:  Denervation; Sciatic nerve; Signaling; Skeletal muscle atrophy; Ursolic acid

DOI:  https://doi.org/10.1007/s12010-024-05059-2
Curr Opin Immunol. 2024 Sep 27. pii: S0952-7915(24)00079-7. [Epub ahead of print]91 102489

Inflammasomes and their role in PANoptosomes.

Vinod Nadella, Thirumala-Devi Kanneganti.

Inflammasomes are multiprotein signaling structures in the innate immune system that drive cell death and inflammatory responses. These protein complexes generally comprise an innate immune sensor, the adaptor protein ASC, and the inflammatory protease caspase-1. Inflammasomes are formed when a cytosolic sensor, also known as a pattern recognition receptor, senses its cognate ligand, which can include microbial components, endogenous damage/danger signals, or environmental stimuli. Inflammasome assembly leads to autoproteolytic cleavage and activation of caspase-1. This activation, in turn, induces proteolytic maturation and release of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the activation of the pore-forming molecule gasdermin D to induce cell death, known as pyroptosis. Recent studies have identified inflammasomes as integral components of larger cell death complexes, known as PANoptosomes. These PANoptosomes regulate PANoptosis, an innate immune cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting serine/threonine protein kinases. PANoptosome assembly and activation leads to cell lysis, inflammation, and the release of proinflammatory cytokines, damage-associated molecular patterns, and alarmins. In this review, we discuss the current understanding of different inflammasomes and their role in PANoptosomes.

DOI: https://doi.org/10.1016/j.coi.2024.102489
Appl Physiol Nutr Metab. 2024 Oct 04.

A reduced carbohydrate diet improves glycemic regulation in hyperglycemic older people in a retirement home: The SAGE study.

Camille Vandenberghe, Elisabelle Hardy, Marie Christine Morin, Valérie St-Pierre, Karine Groulx, Mélanie Fortier, Daniel Tessier, Paul Leclerc, Stephen C Cunnane.

Poor glucose regulation associated with gradual insulin resistance is a significant risk factor in several age-related chronic diseases. An eating plan that promotes a lower carbohydrate intake may have a beneficial effect on glucose metabolism. This study aimed to evaluate how a diet reduced carbohydrate by 32% (RCHO) over a 2-month period would influence the metabolic profile of older individuals (N = 24) living in a retirement home (RH). A continuous glucose monitor was used to measure blood glucose during four periods: the standard diet before (baseline) and after (washout) the intervention, during the 4 initial days of the RCHO diet (RCHO-early), and the final days of the 2-month intervention (RCHO-end). The blood metabolic profile was also measured (glucose, ketones, insulin, triglycerides and cholesterol). RCHO intake decreased average blood glucose compared to the standard diet in hyperglycemic participants: RCHO-early 7.8 ± 1.0 vs 7.5 ± 1.1 mM (p = 0.012) and RCHO-end 7.8 ± 1.0 vs 7.0 ± 0.9 mM (p = 0.050). In the hyperglycemic participants, the percentage of time spent in hyperglycemia (> 10.0 mM) decreased by 50% during the RCHO-early (p = 0.012) and by 66% at RCHO-end (p = 0.021) compared to baseline. Glycated hemoglobin was significantly lower at RCHO-end in both hyperglycemic and normoglycemic participants compared to baseline (p < 0.008). Plasma ketones increased 3-fold in hyperglycemic participants at RCHO-end compared to baseline (p < 0.028). This study shows that an RCHO diet has metabolic health benefits in an older population and confirms its safety, tolerability, and acceptability in a RH. (NCT06022094).

DOI: https://doi.org/10.1139/apnm-2024-0277
Nephrol Dial Transplant. 2024 Oct 03. pii: gfae217. [Epub ahead of print]

Higher skeletal muscle mass associates with higher measured glomerular filtration rate in healthy individuals.

TransplantLines Investigators

DOI: https://doi.org/10.1093/ndt/gfae217
Cardiovasc Toxicol. 2024 Oct 01.

Fasting: A Complex, Double-Edged Blade in the Battle Against Doxorubicin-Induced Cardiotoxicity.

Yiming Meng, Jing Sun, Guirong Zhang, Tao Yu, Haozhe Piao.

  In recent years, there has been a surge in the popularity of fasting as a method to enhance one's health and overall well-being. Fasting is a customary practice characterized by voluntary refraining from consuming food and beverages for a specified duration, ranging from a few hours to several days. The potential advantages of fasting, including enhanced insulin sensitivity, decreased inflammation, and better cellular repair mechanisms, have been well documented. However, the effects of fasting on cancer therapy have been the focus of recent scholarly investigations. Doxorubicin (Dox) is one of the most widely used chemotherapy medications for cancer treatment. Unfortunately, cardiotoxicity, which may lead to heart failure and other cardiovascular issues, has been linked to Dox usage. This study aims to comprehensively examine the possible advantages and disadvantages of fasting concerning Dox-induced cardiotoxicity. Researchers have investigated the potential benefits of fasting in lowering the risk of Dox-induced cardiac damage to solve this problem. Nevertheless, new studies indicate that prolonged alternate-day fasting may adversely affect the heart's capacity to manage the cardiotoxic properties of Dox. Though fasting may benefit overall health, it is essential to proceed cautiously and consider the potential risks in certain circumstances.

Keywords:  Calorie restriction; Cardiotoxicity; Doxorubicin; Fasting; Left ventricular mass

DOI:  https://doi.org/10.1007/s12012-024-09925-7
FEBS Open Bio. 2024 Oct;14(10): 1595-1609

Biogenesis of mitochondrial β-barrel membrane proteins.

Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.

  β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.

Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein

DOI:  https://doi.org/10.1002/2211-5463.13905
Mol Cell Endocrinol. 2024 Sep 28. pii: S0303-7207(24)00238-7. [Epub ahead of print] 112382

NLRP3 blockade by MCC950 suppressed osteoclastogenesis via NF-κB/c-FOS/NFATc1 signal pathway and alleviated bone loss in diabetes mellitus.

Guoping Cai, Xiaoting Song, Hua Luo, Gaoyuan Dai, Honghao Zhang, Dengteng Jiang, Xinhuan Lei, Haixiao Chen, Liwei Zhang.

  Obesity and type 2 diabetes mellitus (T2DM) are linked to osteoporosis development, with obesity being a significant risk factor for T2DM. T2DM patients with obesity exhibit a higher fracture rate and often have a poor prognosis post-fracture. To address the urgent need for understanding the mechanisms of diabetic osteoporosis (DOP), research is ongoing to explore how obesity and T2DM impact bone metabolism. The NLRP3 inflammasome has been implicated in the pathogenesis of osteoporosis, and MCC950, an NLRP3 inflammasome inhibitor, has shown promise in various diseases but its role in osteoporosis remains unexplored. In this study, BMMs and BMSCs were isolated and cultured to investigate the effects of MCC950 on bone metabolism, and DOP model was used to evaluate the efficacy of MCC950 in vivo. The study demonstrated that MCC950 treatment inhibited osteoclast differentiation, reduced bone resorption capacity in BMMs without suppression for osteoblast differentiation from BMSCs. Additionally, MCC950 suppressed the activation of the NF-κB signaling pathway and downregulated key factors associated with osteoclast differentiation. Additionally, MCC950 alleviated bone loss in DOP mouse. These findings suggest that MCC950, by targeting the NLRP3 inflammasome, may have a protective role in preventing osteoporosis induced by T2DM with obesity. The study highlights the potential therapeutic implications of MCC950 in managing diabetic osteoporosis and calls for further research to explore its clinical application in high-risk patient populations.

Keywords:  MCC950; NLRP3; diabetic osteoporosis; osteoclast

DOI:  https://doi.org/10.1016/j.mce.2024.112382
Cell Death Differ. 2024 Oct 05.

Fructose: the sweet(er) side of the Warburg effect.

Christian Frezza.

DOI: https://doi.org/10.1038/s41418-024-01395-2
Sports Med. 2024 Oct 02.

Characteristics of High-Intensity Interval Training Influence Anthropometrics, Glycemic Control, and Cardiorespiratory Fitness in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Edgardo Opazo-Díaz, Adrián Montes-de-Oca-García, Alejandro Galán-Mercant, Alberto Marín-Galindo, Juan Corral-Pérez, Jesús Gustavo Ponce-González.

BACKGROUND: Exercise is a non-pharmacological intervention for type 2 diabetes mellitus (T2DM), including moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). Despite diverse exercise protocol variations, the impact of these variations in HIIT on T2DM anthropometrics, glycemic control, and cardiorespiratory fitness (CRF) remains unclear.OBJECTIVE: The aim was to examine the influence of HIIT protocol characteristics on anthropometrics, glycemic control, and CRF in T2DM patients and compare it to control (without exercise) and MICT.
METHODS: This review is registered in PROSPERO (CRD42021281398) and follows Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search, employing "high-intensity interval training" and "diabetes mellitus" in PubMed and Web of Science databases, with a "randomized controlled trial" filter, spanned articles up to January 2023.
RESULTS: Of 190 records, 29 trials were included, categorized by HIIT interval duration, training volume, and intervention period. Long-duration, high-volume, and long-term HIIT yields superior outcomes compared to control conditions for body mass, waist circumference, fasting plasma glucose, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), glycosylated hemoglobin (%HbA1c), and CRF. The findings favored HIIT over MICT for body mass in long-duration, high-volume, and short-term intervals (mean difference [MD] - 3.45, - 3.13, and - 5.42, respectively, all p < 0.05) and for CRF in long and medium work intervals and high volume (MD 1.91, 2.55, and 2.43, respectively, all p < 0.05), as well as in medium and long-term intervention (MD 2.66 and 2.21, respectively, all p < 0.05). Regardless of specific HIIT characteristics, no differences were found in the HIIT versus MICT comparison for glycemic control.
CONCLUSIONS: Specific HIIT protocol characteristics influence changes in anthropometrics, glycemic control, and CRF compared to control groups. However, compared to MICT, only longer duration, higher volume, and short-term HIIT improved body mass, waist circumference, and CRF in individuals with T2DM.

DOI: https://doi.org/10.1007/s40279-024-02114-0
J Int Soc Sports Nutr. 2024 Dec;21(1): 2409673

Effects of coffee intake on skeletal muscle microvascular reactivity at rest and oxygen extraction during exercise: a randomized cross-over trial.

Bin Leng, Haizhen Huang, Chuan Zhang.

  PURPOSE: The effects of coffee ingestion on skeletal muscle microvascular function are not well understood. This study aimed to investigate the acute effects of coffee intake with varying levels of caffeine on skeletal muscle microvascular reactivity at rest and oxygen extraction during maximal incremental exercise in physically active individuals.METHODS: Twenty healthy young male participants were administered coffee with low caffeine (3 mg/kg body weight; LC), high caffeine (6 mg/kg body weight; HC), and placebo (decaf) in different sessions. Skeletal muscle reactivity indexes, including tissue saturation index 10s slope (TSI10) and TSI half time recovery (TSI ½) following 5-minute ischemia were measured at rest and were measured at baseline and post-coffee consumption using near-infrared spectroscopy (NIRS). Post-coffee intake, NIRS was also used to measure microvascular oxygen extraction during exercise via maximal incremental exercise. Peak oxygen consumption and peak power output (Wpeak) were simultaneously evaluated.
RESULTS: Post-coffee consumption, TSI10 was significantly higher in the LC condition compared to placebo (p = 0.001) and significantly higher in the HC condition compared to placebo (p < 0.001). However, no difference was detected between LC and HC conditions (p = 0.527). HC condition also showed significant less TSI ½ compared to placebo (p = 0.005). However, no difference was detected for microvascular oxygen extraction during exercise, despite the greater Wpeak found for HC condition (p < 0.001) compared to placebo.
CONCLUSION: Coffee ingestion with high caffeine level (6 mg/kg body weight) significantly enhanced skeletal muscle reactivity at rest. However, the improvement of exercise performance with coffee intake is not accompanied by alterations in muscle oxygen extraction.

Keywords:  Caffeine; exercise performance; microvascular function; near-infrared spectroscopy

DOI:  https://doi.org/10.1080/15502783.2024.2409673
J Appl Physiol (1985). 2024 Oct 03.

Does one biopsy cut it? Revisiting human muscle fiber type composition variability using repeated biopsies in the vastus lateralis and gastrocnemius medialis.

Freek Van de Casteele, Ruud Van Thienen, Oscar Horwath, William Apró, Thibaux Van der Stede, Marcus Moberg, Eline Lievens, Wim Derave.

  Human skeletal muscle fiber type composition varies greatly along the muscle, so one biopsy may not accurately represent the whole muscle. Recommendations on the number of biopsies and fiber counts using immunohistochemistry and whether these findings can be extrapolated to other muscles are lacking. We assessed fiber type composition in the vastus lateralis and gastrocnemius medialis muscles of 40 individuals. Per muscle, we took four biopsy samples from one incision, collecting two samples each from a proximally and distally directed needle. Based on another dataset involving 10 vastus lateralis biopsies per participant (N=7), we calculated 95% limits of agreement for subsets of biopsies and fiber counts compared to the 10-biopsy average. Average absolute differences in type I fiber proportions between proximal and distal, and between within-needle samples were 6.9 and 4.5 percentage points in the vastus lateralis, and 5.5 and 4.4 percentage points in the gastrocnemius medialis, respectively. The 95% limits of agreement narrowed to ±10 percentage points when 200 fibers from at least three biopsies were analyzed, with minimal improvements with greater fiber counts. Type I fiber proportions in the vastus lateralis and gastrocnemius medialis showed a moderate positive association (r²=0.22; p=0.006; at least 200 fibers in each of three to four samples per muscle). In conclusion, three biopsies with a minimum of 200 counted fibers are required to estimate vastus lateralis fiber type composition within ±10 percentage points. Even when using these standards, researchers should be cautious when extrapolating muscle fiber type proportions from one muscle to another.

Keywords:  across-muscle phenotype; cross-sectional area; fiber type composition; immunohistochemistry; myosin heavy chain

DOI:  https://doi.org/10.1152/japplphysiol.00394.2024
Antioxidants (Basel). 2024 Aug 24. pii: 1027. [Epub ahead of print]13(9):

Metabolic and Biochemical Effects of Pyrroloquinoline Quinone (PQQ) on Inflammation and Mitochondrial Dysfunction: Potential Health Benefits in Obesity and Future Perspectives.

Davide Charrier, Giuseppe Cerullo, Roberta Carpenito, Vincenzo Vindigni, Franco Bassetto, Luca Simoni, Tatiana Moro, Antonio Paoli.

  Obesity is defined as a complex, systemic disease characterized by excessive and dysfunctional adipose tissue, leading to adverse health effects. This condition is marked by low-grade inflammation, oxidative stress, and metabolic abnormalities, including mitochondrial dysfunction. These factors promote energy dysregulation and impact body composition not only by increasing body fat but also by promoting skeletal muscle mass atrophy. The decline in muscle mass is associated with an increased risk of all-cause mortality in individuals with this disease. The European Food Safety Authority approved pyrroloquinoline quinone (PQQ), a natural compound, as a dietary supplement in 2018. This narrative review aims to provide a comprehensive overview of the potential role of PQQ, based on its anti-inflammatory and antioxidant properties, in addressing dysfunctional adipose tissue metabolism and related disorders.

Keywords:  adipose tissue; inflammation; mitochondrial dysfunction; oxidative stress; pyrroloquinoline quinone (PQQ)

DOI:  https://doi.org/10.3390/antiox13091027