bims-kimdis 2024-09-08 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–09–08
24 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Sex- and Age-Specific Differences in Mice Fed a Ketogenic Diet.
The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.
Beta-Hydroxybutyrate: A Supplemental Molecule for Various Diseases.
Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.
Nifedipine Improves the Ketogenic Diet Effect on Insulin-Resistance-Induced Cognitive Dysfunction in Rats.
A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.
Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate.
Impact of a ketogenic diet on sleep quality in people with relapsing multiple sclerosis.
Insulin sensitivity and skeletal muscle mitochondrial respiration in Black and White women with obesity.
Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.
Impact of sprint interval training on post-fatigue mitochondrial rate in professional boxers.
STAT3 promotes NLRP3 inflammasome activation by mediating NLRP3 mitochondrial translocation.
Effects of Caloric Restriction and Intermittent Fasting and Their Combined Exercise on Cognitive Functioning: A Review.
NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development.
Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.
The Role and Underlying Mechanisms of Exercise in Heart Failure.
Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.
Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.
Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.
Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites.
Effect of a carbohydrate-restricted diet on weight loss in overweight and obese pediatric population: a meta-analysis of randomized controlled trials.
Time to Moderate and Severe Hyperglycemia and Ketonemia Following an Insulin Pump Occlusion.
Effect of 5:2 intermittent fasting diet versus daily calorie restriction eating on metabolic-associated fatty liver disease-a randomized controlled trial.
Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Nutrients. 2024 Aug 16. pii: 2731. [Epub ahead of print]16(16):

Sex- and Age-Specific Differences in Mice Fed a Ketogenic Diet.

Kenyon W Sprankle, Mya A Knappenberger, Erica J Locke, Jack H Thompson, Madison F Vinovrski, Kaylin Knapsack, Stephen C Kolwicz.

  The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that results in the elevation of serum ketone bodies, known as ketosis. This metabolic consequence has been suggested as a method for treating neurological conditions, improving exercise performance, and facilitating weight loss for overweight individuals. However, since most research primarily uses male populations, little is known about the potential sex differences during the consumption of the KD. In addition, the effects of the KD on aging are relatively unexplored. Therefore, the purpose of this study was to explore sex- and age-specific differences in mice fed the KD. Male and female C57BL/6N mice at either 12 wks or 24 wks of age were randomly assigned to a KD (90% fat, 1% carbohydrate) or chow (13% fat, 60% carbohydrate) group for 6 wks. KD induced weight gain, increased adiposity, induced hyperlipidemia, caused lipid accumulation in the heart and liver, and led to glycogen depletion in the heart, liver, and muscle with varying degrees of changes depending on age and sex. While younger and older male mice on the KD were prone to glucose intolerance, the KD acutely improved rotarod performance in younger females. Overall, this study highlights potential sex and aging differences in the adaptation to the KD.

Keywords:  glucose intolerance; ketone bodies; ketosis; lipid accumulation; metabolism

DOI:  https://doi.org/10.3390/nu16162731
Sports Health. 2024 Sep 04. 19417381241271547

The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.

Kexin Sun, Yee Tung Choi, Clare Chung Wah Yu, Edmund Anthony Severn Nelson, Jorming Goh, Siyu Dai, Lai Ling Hui.

   CONTEXT: Ketogenic diets and ketone supplements have gained popularity among endurance runners given their purported effects: potentially delaying the onset of fatigue by enabling the increased utilization of the body's fat reserve or external ketone bodies during prolonged running.
OBJECTIVE: This systematic review was conducted to evaluate the effects of ketogenic diets (>60% fat and <10% carbohydrates/<50 g carbohydrates per day) or ketone supplements (ketone esters or ketone salts, medium-chain triglycerides or 1,3-butadiol) on the aerobic performance of endurance runners.
DATA SOURCES: A systematic search was conducted in PubMed, Web of Science, Pro Quest, and Science Direct for publications up to October 2023.
STUDY SELECTION: Human studies on the effects of ketogenic diets or ketone supplements on the aerobic performance of adult endurance runners were included after independent screening by 2 reviewers.
STUDY DESIGN: Systematic review.
LEVEL OF EVIDENCE: Level 3.
DATA EXTRACTION: Primary outcomes were markers of aerobic performance (maximal oxygen uptake [VO2max], race time, time to exhaustion and rate of perceived exertion).
RESULTS: VO2max was assessed by incremental test to exhaustion. Endurance performance was assessed by time trials, 180-minute running trials, or run-to-exhaustion trials; 5 studies on ketogenic diets and 7 studies on ketone supplements involving a total of 132 endurance runners were included. Despite the heterogeneity in study design and protocol, none reported benefits of ketogenic diets or ketone supplements on selected markers of aerobic performance compared with controls. Reduction in bodyweight and fat while preserving lean mass and improved glycemic control were reported in some included studies on ketogenic diets.
CONCLUSION: This review did not identify any significant advantages or disadvantages of ketogenic diets or ketone supplements for the aerobic performance of endurance runners. Further trials with larger sample sizes, more gender-balanced participants, longer ketogenic diet interventions, and follow-up on metabolic health are warranted.

Keywords:  aerobic performance; endurance runners; ketogenic diets; ketone supplements

DOI:  https://doi.org/10.1177/19417381241271547
Curr Drug Targets. 2024 Sep 05.

Beta-Hydroxybutyrate: A Supplemental Molecule for Various Diseases.

Navid Reza Shahtaghi, Bindu Soni, Hossamaldeen Bakery, Samira Bigdelitabar, Subheet Kumar Jain.

  β-hydroxybutyrate (BHB) is a ketone body that serves as an alternative energy source for various tissues, including the brain, heart, and skeletal muscle. As a metabolic intermediate and signaling molecule, BHB plays a crucial role in modulating cellular and physiological processes. Notably, BHB supplementation offers a novel and promising strategy to induce nutritional ketosis without the need for strict dietary adherence or causing nutritional deficiencies. This review article provides an overview of BHB metabolism and explores its applications in age-related diseases. This review conducted a comprehensive search of PubMed, ScienceDirect, and other relevant English-language articles. The main findings were synthesized, and discussed the challenges, limitations, and future directions of BHB supplementation. BHB supplementation holds potential benefits for various diseases and conditions, including neurodegenerative disorders, cardiovascular diseases, cancers, and inflammation. BHB acts through multiple mechanisms, including interactions with cell surface receptors, intracellular enzymes, transcription factors, signaling molecules, and epigenetic modifications. Despite its promise, BHB supplementation faces several challenges, such as determining the optimal dosage, ensuring long-term safety, identifying the most effective type and formulation, establishing biomarkers of response, and conducting cost-effectiveness analyses. BHB supplementation opens exciting avenues for research, including investigating molecular mechanisms, refining optimization strategies, exploring innovation opportunities, and assessing healthspan and lifespan benefits. BHB supplementation represents a new frontier in health research, offering a potential pathway to enhance well-being and extend lifespan.

Keywords:  alternative energy sources; disease; ketone bodies.; supplementation; β-hydroxybutyrate

DOI:  https://doi.org/10.2174/0113894501312168240821082224
Biochemistry (Mosc). 2024 Jul;89(7): 1336-1348

Differences in the Effect of Beta-Hydroxybutyrate on the Mitochondrial Biogenesis, Oxidative Stress and Inflammation Markers in Tissues from Young and Old Rats.

Veronika V Nesterova, Polina I Babenkova, Anna A Brezgunova, Natalia A Samoylova, Irina S Sadovnikova, Dmitry S Semenovich, Nadezda V Andrianova, Artem P Gureev, Egor Y Plotnikov.

  One of the therapeutic approaches to age-related diseases is modulation of body cell metabolism through certain diets or their pharmacological mimetics. The ketogenic diet significantly affects cell energy metabolism and functioning of mitochondria, which has been actively studied in various age-related pathologies. Here, we investigated the effect of the ketogenic diet mimetic beta-hydroxybutyrate (BHB) on the expression of genes regulating mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam), quality control (Sqstm1), functioning of the antioxidant system (Nfe2l2, Gpx1, Gpx3, Srxn1, Txnrd2, Slc6a9, Slc7a11), and inflammatory response (Il1b, Tnf, Ptgs2, Gfap) in the brain, lungs, heart, liver, kidneys, and muscles of young and old rats. We also analyzed mitochondrial DNA (mtDNA) copy number, accumulation of mtDNA damage, and levels of oxidative stress based on the concentration of reduced glutathione and thiobarbituric acid-reactive substances (TBARS). In some organs, aging disrupted mitochondrial biogenesis and functioning of cell antioxidant system, which was accompanied by the increased oxidative stress and inflammation. Administration of BHB for 2 weeks had different effects on the organs of young and old rats. In particular, BHB upregulated expression of genes coding for proteins associated with the mitochondrial biogenesis and antioxidant system, especially in the liver and muscles of young (but not old) rats. At the same time, BHB contributed to the reduction of TBARS in the kidneys of old rats. Therefore, our study has shown that administration of ketone bodies significantly affected gene expression in organs, especially in young rats, by promoting mitochondrial biogenesis, improving the functioning of the antioxidant defense system, and partially reducing the level of oxidative stress. However, these changes were much less pronounced in old animals.

Keywords:  aging; beta-hydroxybutyrate; ketogenic diet; mitochondria; mitochondrial DNA; oxidative stress

DOI:  https://doi.org/10.1134/S0006297924070149
Pharmaceuticals (Basel). 2024 Aug 10. pii: 1054. [Epub ahead of print]17(8):

Nifedipine Improves the Ketogenic Diet Effect on Insulin-Resistance-Induced Cognitive Dysfunction in Rats.

Nancy M Abdel-Kareem, Shimaa M Elshazly, May A Abd El Fattah, Afaf A Aldahish, Sawsan A Zaitone, Sahar K Ali, Enas A Abd El-Haleim.

  Insulin resistance, induced by high fructose consumption, affects cognitive function negatively. Nifedipine may be suggested for neurological disorders. This study aimed to assess the effect of nifedipine with either a normal diet (ND) or a ketogenic diet (KD) in cognitive dysfunction. Male Wistar rats received 10% fructose in drinking water for 8 weeks to induce insulin resistance. Rats received nifedipine (5.2 mg/kg/day; p.o.) later with ND or KD for an additional five weeks. One and two-way ANOVAs were used in analyzing the data. Reversion to the ND improved insulin resistance and lipid profile, besides brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 beta (GSK3β), and insulin-degrading enzyme (IDE) levels. Rats fed KD alone and those that received nifedipine with KD did not show similar improvement in the previously mentioned parameters as the ND group. However, nifedipine-ND rats showed improvement in cognitive behavior and insulin resistance. Treatment with nifedipine-KD ameliorated GSK3β, amyloid β (Aβ), and tau protein levels. As the nifedipine-KD combination succeeded in diminishing the accumulated Aβ and tau protein, KD may be used for a while due to its side effects, then nifedipine treatment could be continued with an ND. This conclusion is based on the finding that this combination mitigated insulin resistance with the associated improved behavior.

Keywords:  cognitive dysfunction; fructose; insulin resistance; ketogenic diet; nifedipine

DOI:  https://doi.org/10.3390/ph17081054
bioRxiv. 2024 Jul 23. pii: 2024.07.19.604377. [Epub ahead of print]

A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.

Omid Hajihassani, Mehrdad Zarei, Asael Roichman, Alexander Loftus, Christina S Boutros, Jonathan Hue, Parnian Naji, Jacob Boyer, Soubhi Tahan, Peter Gallagher, William Beegan, James Choi, Shihong Lei, Christine Kim, Moeez Rathore, Faith Nakazzi, Ishan Shah, Kevin Lebo, Helen Cheng, Anusha Mudigonda, Sydney Alibeckoff, Karen Ji, Hallie Graor, Masaru Miyagi, Ali Vaziri-Gohar, Henri Brunengraber, Rui Wang, Peder J Lund, Luke D Rothermel, Joshua D Rabinowitz, Jordan M Winter.

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

DOI: https://doi.org/10.1101/2024.07.19.604377
J Agric Food Chem. 2024 Aug 30.

Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate.

Rasmus N Ottosen, Jacob M Seefeldt, Jakob Hansen, Roni Nielsen, Niels Møller, Mogens Johannsen, Thomas B Poulsen.

  Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Keywords:  N-L-lactoyl-phenylalanine (Lac-Phe); appetite regulation; exercise mimetics; exerkine; ketones; lactate

DOI:  https://doi.org/10.1021/acs.jafc.4c04849
Sleep Med. 2024 Aug 28. pii: S1389-9457(24)00391-5. [Epub ahead of print]122 213-220

Impact of a ketogenic diet on sleep quality in people with relapsing multiple sclerosis.

Jacob Perlman, Emma Wetmore, Diana Lehner-Gulotta, Brenda Banwell, A G Christina Bergqvist, Rachael Coleman, Shanshan Chen, Mark Conaway, Myla D Goldman, Anne Marie Morse, J Nicholas Brenton.

   BACKGROUND: Sleep disturbance in MS is common and can significantly impair overall quality of life. The ketogenic diet (KD) associates with improved sleep quality in people living with epilepsy and may have similar benefits when used within MS; however, the impact of a KD on sleep in this population remains poorly defined.
METHODS: Forty-five patients with relapsing MS enrolled into a 6-month KD intervention trial and completed self-reported assessments of sleep quality and sleep disorder symptoms prior to diet initiation and while on diet, using the Epworth Sleepiness Scale (ESS) and Sleep Disorders Symptom Checklist-25 (SDS). Participants who did not complete sleep assessments at baseline and 6-months were excluded from analysis. In addition to sleep metrics, data collection included anthropometrics and MS-related fatigue scores.
RESULTS: Thirty-nine of 45 (87 %) participants completed the required sleep assessments. There was a mean reduction in ESS score of 1.90 (95 % CI [-2.85, -0.94], p < 0.001). Total SDS score decreased at 6-months on KD (-4.4, 95 % CI [-7.1, -1.7], p = 0.002), with improvements noted in insomnia (-1.55, 95 % CI [-2.66, -0.43], p = 0.008), obstructive sleep apnea (-0.91, 95 % CI [-1.57, -0.25], p = 0.008), and restless leg syndrome screening scores (-1.00, 95 % CI [-1.95, -0.051], p = 0.04). Sleep duration was unchanged on KD.
CONCLUSION: KD associates with improvements in daytime sleepiness, independent of sleep duration, and common comorbid sleep disorders in people living with relapsing MS. The findings herein support the benefits of KD on sleep quality and highlight the potential role of dietary therapeutics for sleep disorders in neurological disease.
TRIAL REGISTRATION INFORMATION: Registered on Clinicaltrials.gov under registration number NCT03718247, posted on Oct 24, 2018. First patient enrollment date: Nov 1, 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.

Keywords:  Apnea; Diet; Insomnia; Obesity; Restless leg; Sleep

DOI:  https://doi.org/10.1016/j.sleep.2024.08.020
J Clin Endocrinol Metab. 2024 Aug 29. pii: dgae600. [Epub ahead of print]

Insulin sensitivity and skeletal muscle mitochondrial respiration in Black and White women with obesity.

Justine M Mucinski, Giovanna Distefano, John Dubé, Frederico G S Toledo, Paul M Coen, Bret H Goodpaster, James P DeLany.

   OBJECTIVES: Non-Hispanic black women (BW) have a greater risk of type 2 diabetes (T2D) and insulin resistance (IR) compared to non-Hispanic white women (WW). The mechanisms leading to these differences are not understood, and it is unclear whether synergistic effects of race and obesity impact disease risk. To understand the interaction of race and weight, hepatic and peripheral IR were compared in WW and BW with and without obesity.
METHODS: Hepatic and peripheral IR was measured by a labeled, hyperinsulinemic-euglycemic clamp in BW (n=32) and WW (n=32) with and without obesity. Measurements of body composition, cardiorespiratory fitness, and skeletal muscle (SM) respiration were completed. Data were analyzed by mixed model ANOVA.
RESULTS: Subjects with obesity had greater hepatic and peripheral IR and lower SM respiration (P<0.001). Despite 14% greater insulin (P=0.066), BW tended to have lower peripheral glucose disposal (Rd; P=0.062), which was driven by women without obesity (P=0.002). BW had significantly lower glucose production (P=0.005), hepatic IR (P=0.024), and maximal coupled and uncoupled respiration (P<0.001) than WW. Maximal coupled and uncoupled SM mitochondrial respiration was strongly correlated with peripheral and hepatic IR (P<0.01).
CONCLUSION: While BW without obesity had lower Rd than WW, race and obesity did not synergistically impact peripheral IR. Paradoxically, WW with obesity had greater hepatic IR compared to BW. Relationships between SM respiration and IR persisted across a range of body weight. These data provide support for therapies in BW, like exercise, that improve SM mitochondrial respiration to reduce IR and T2D risk.

Keywords:  Insulin sensitivity; mitochondrial respiration; racial differences; skeletal muscle

DOI:  https://doi.org/10.1210/clinem/dgae600
Life (Basel). 2024 Jul 31. pii: 962. [Epub ahead of print]14(8):

Mitochondrial Adaptations in Aging Skeletal Muscle: Implications for Resistance Exercise Training to Treat Sarcopenia.

Ilyoung Jeong, Eun-Jeong Cho, Jang-Soo Yook, Youngju Choi, Dong-Ho Park, Ju-Hee Kang, Seok-Hun Lee, Dae-Yun Seo, Su-Jeen Jung, Hyo-Bum Kwak.

  Sarcopenia, the age-related decline in muscle mass and function, poses a significant health challenge as the global population ages. Mitochondrial dysfunction is a key factor in sarcopenia, as evidenced by the role of mitochondrial reactive oxygen species (mtROS) in mitochondrial biogenesis and dynamics, as well as mitophagy. Resistance exercise training (RET) is a well-established intervention for sarcopenia; however, its effects on the mitochondria in aging skeletal muscles remain unclear. This review aims to elucidate the relationship between mitochondrial dynamics and sarcopenia, with a specific focus on the implications of RET. Although aerobic exercise training (AET) has traditionally been viewed as more effective for mitochondrial enhancement, emerging evidence suggests that RET may also confer beneficial effects. Here, we highlight the potential of RET to modulate mtROS, drive mitochondrial biogenesis, optimize mitochondrial dynamics, and promote mitophagy in aging skeletal muscles. Understanding this interplay offers insights for combating sarcopenia and preserving skeletal muscle health in aging individuals.

Keywords:  aging; mitochondria; resistance exercise training; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/life14080962
Eur J Appl Physiol. 2024 Sep 03.

Impact of sprint interval training on post-fatigue mitochondrial rate in professional boxers.

Andrew Usher, John Babraj.

   PURPOSE: Professional boxing is a sport that requires a high aerobic capacity to prevent fatigue and allow athletes to perform over 4-12 rounds. Typically, athletes will go into a heavy training period in a pre-bout camp lasting 6 to 9 weeks. This study investigates the impact of 3 weeks of repeated Wingate sprint interval training, performed on standard gym ergometer bikes, on skeletal muscle endurance and mitochondrial function.
METHODS: Ten male professional boxers (age: 26 ± 4 years, height: 175 ± 5 cm, weight: 70 ± 5 kg) participated in the study. Baseline testing involved a NIRS monitor attached to the rectus femoris muscle prior to an incremental time to exhaustion test on a treadmill. After the treadmill test participants underwent a series of arterial occlusions to determine mitochondrial function post-volitional exhaustion. Participants then continued their own training for 3 weeks and then repeated baseline testing. After the second testing session, participants undertook three weekly sprint sessions consisting of 3 × 30 s maximal sprints with 60 s recovery. Testing was repeated 3 weeks later.
RESULTS: The time to exhaustion increased by > 6% after 3 weeks of sprint interval training as compared to baseline and control (p < 0.05). Skeletal muscle oxygen saturation (SmO2) at exhaustion was increased by 5.5% after 3 weeks of sprint interval training as compared to baseline and control (p = 0.008). Skeletal muscle mitochondrial rate post exhaustion was increased by 160% after 3 weeks of sprint interval training as compared to baseline and control (p < 0.001).
CONCLUSION: The study demonstrated that SIT led to increased incremental time to exhaustion, higher SmO2 levels at volitional exhaustion and increased mitochondrial rates in professional boxers. These findings suggest that SIT should be an integral part of a boxe's conditioning regimen to improve performance and safety within the ring.

Keywords:  Desaturation; Mitochondria; NIRS; Oxygenation; Recovery; Rectus femoris

DOI:  https://doi.org/10.1007/s00421-024-05594-0
Exp Mol Med. 2024 Sep 02.

STAT3 promotes NLRP3 inflammasome activation by mediating NLRP3 mitochondrial translocation.

Ling Luo, Fupeng Wang, Xueming Xu, Mingliang Ma, Guangyan Kuang, Yening Zhang, Dan Wang, Wei Li, Ningjie Zhang, Kai Zhao.

Recognition of the translocation of NLRP3 to various organelles has provided new insights for understanding how the NLRP3 inflammasome is activated by different stimuli. Mitochondria have already been demonstrated to be the site of NLRP3 inflammasome activation, and the latest research suggests that NLRP3 is first recruited to mitochondria, then disassociated, and subsequently recruited to the Golgi network. Although some mitochondrial factors have been found to contribute to the recruitment of NLRP3 to mitochondria, the detailed process of NLRP3 mitochondrial translocation remains unclear. Here, we identify a previously unknown role for Signal transducer and activator of transcription-3 (STAT3) in facilitating the translocation of NLRP3 to mitochondria. STAT3 interacts with NLRP3 and undergoes phosphorylation at Ser727 in response to several NLRP3 agonists, enabling the translocation of STAT3 and thus the bound NLRP3 to mitochondria. Disruption of the interaction between STAT3 and NLRP3 impairs the mitochondrial localization of NLRP3, specifically suppressing NLRP3 inflammasome activation both in vitro and in vivo. In summary, we demonstrate that STAT3 acts as a transporter for mitochondrial translocation of NLRP3 and provide new insight into the spatial regulation of NLRP3.

DOI: https://doi.org/10.1038/s12276-024-01298-9
Curr Nutr Rep. 2024 Sep 06.

Effects of Caloric Restriction and Intermittent Fasting and Their Combined Exercise on Cognitive Functioning: A Review.

Junming Wang, Yifeng Rang, Chunhong Liu.

   PURPOSE OF REVIEW: The impact of dietary habits on cognitive function is increasingly gaining attention. The review is to discuss how caloric restriction (CR) and intermittent fasting (IF) can enhance cognitive function in healthy states through multiple pathways that interact with one another. Secondly, to explore the effects of CR and IF on cognitive function in conditions of neurodegenerative diseases, obesity diabetes and aging, as well as potential synergistic effects in combination with exercise to prevent cognitively related neurodegenerative diseases.
RECENT FINDINGS: With age, the human brain ages and develops corresponding neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and epilepsy, which in turn trigger cognitive impairment. Recent research indicates that the impact of diet and exercise on cognitive function is increasingly gaining attention. The benefits of exercise for cognitive function and brain plasticity are numerous, and future research can examine the efficacy of particular dietary regimens during physical activity when combined with diet which can prevent cognitive decline.

Keywords:  Caloric restriction; Cognitive; Exercise; Intermittent fasting; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s13668-024-00570-8
Int J Mol Sci. 2024 Aug 20. pii: 9018. [Epub ahead of print]25(16):

NLRP3 Negative Regulation Mechanisms in the Resting State and Its Implications for Therapeutic Development.

YeJi Kim, Sumin Lee, Yong Hwan Park.

  The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular sensor of the innate immune system that detects various pathogen- and danger-associated molecular patterns, leading to the assembly of the NLRP3 inflammasome and release of interleukin (IL) 1β and IL-18. However, the abnormal activation of the NLRP3 inflammasome has been implicated in the pathogenesis of autoinflammatory diseases such as cryopyrin-associated autoinflammatory syndromes (CAPS) and common diseases such as Alzheimer's disease and asthma. Recent studies have revealed that pyrin functions as an indirect sensor, similar to the plant guard system, and is regulated by binding to inhibitory 14-3-3 proteins. Upon activation, pyrin transitions to its active form. NLRP3 is predicted to follow a similar regulatory mechanism and maintain its inactive form in the cage model, as it also acts as an indirect sensor. Additionally, newly developed NLRP3 inhibitors have been found to inhibit NLRP3 activity by stabilizing its inactive form. Most studies and reviews on NLRP3 have focused on the activation of the NLRP3 inflammasome. This review highlights the molecular mechanisms that regulate NLRP3 in its resting state, and discusses how targeting this inhibitory mechanism can lead to novel therapeutic strategies for NLRP3-related diseases.

Keywords:  NLRP3 inflammasome; cage model; indirect PRRs; negative regulation; pyrin inflammasome

DOI:  https://doi.org/10.3390/ijms25169018
J Physiol. 2024 Sep 02.

Tic-tac-mito: The relationship between the biological clock with mitochondria dynamics and skeletal muscle function in humans.

Itamar C G Jesus, Flavia M Araujo.



Keywords:  biological clock; metabolism; mitochondria; protein synthesis; skeletal muscle

DOI:  https://doi.org/10.1113/JP287210
Rev Cardiovasc Med. 2024 Aug;25(8): 285

The Role and Underlying Mechanisms of Exercise in Heart Failure.

Chong-Yi Zhang, Ku-Lin Li, Xiao-Xi Zhao, Zhen-Ye Zhang, An-Wen Yin, Ru-Xing Wang.

  Heart failure is a prevalent and life-threatening syndrome characterized by structural and/or functional abnormalities of the heart. As a global burden with high rates of morbidity and mortality, there is growing recognition of the beneficial effects of exercise on physical fitness and cardiovascular health. A substantial body of evidence supports the notion that exercise can play a protective role in the development and progression of heart failure and improve cardiac function through various mechanisms, such as attenuating cardiac fibrosis, reducing inflammation, and regulating mitochondrial metabolism. Further investigation into the role and underlying mechanisms of exercise in heart failure may uncover novel therapeutic targets for the prevention and treatment of heart failure.

Keywords:  cardiac function; exercise; heart failure; mechanism

DOI:  https://doi.org/10.31083/j.rcm2508285
Biochem Biophys Res Commun. 2024 Aug 24. pii: S0006-291X(24)01142-2. [Epub ahead of print]733 150606

Skeletal muscle atrophy induces memory dysfunction via hemopexin action in healthy young mice.

Tsukasa Iki, Chihiro Tohda.

  Age-related morbidity has become an increasingly significant issue worldwide. Sarcopenia, the decline in skeletal muscle mass and strength with age, has been reported to be a risk factor for cognitive impairment. Our previous study revealed that skeletal muscle atrophy shifts the onset of memory dysfunction earlier in young Alzheimer's disease mice and found that hemopexin is a myokine responsible for memory loss. This study aimed to elucidate the occurrence of memory impairment due to skeletal muscle atrophy in non-genetically engineered healthy young mice and the involvement of hemopexin. Closed-colony ddY mice at 12-13 weeks of age were used. Both hind limbs were immobilized by cast attachment for 14 d. Casting for 2 weeks induced a loss of skeletal muscle weight. The memory function of the mice was evaluated using a novel object recognition test. The cast-attached mice exhibited memory impairment. Hemopexin levels in the conditioned medium of the skeletal muscle, plasma, and hippocampus were increased in cast-attached mice. Continuous intracerebroventricular hemopexin infusion induced memory deficits in non-cast mice. To investigate whether hemopexin is the main causative factor of cognitive impairment, cast-attached mice were intracerebroventricularly infused with an anti-hemopexin antibody. Cast-induced memory impairment was reversed by the infusion of an anti-hemopexin antibody. These findings provide new evidence that skeletal muscle atrophy causes memory impairment in healthy young mice through the action of hemopexin in the brain.

Keywords:  Cast model; Cognitive impairment; Hemopexin; Muscle atrophy; Myokine

DOI:  https://doi.org/10.1016/j.bbrc.2024.150606
Traffic. 2024 Sep;25(9): e12951

Intercellular Mitochondrial Transfer: The Novel Therapeutic Mechanism for Diseases.

Huimei Liu, Hui Mao, Xueqian Ouyang, Ruirui Lu, Lanfang Li.

  Mitochondria, the dynamic organelles responsible for energy production and cellular metabolism, have the metabolic function of extracting energy from nutrients and synthesizing crucial metabolites. Nevertheless, recent research unveils that intercellular mitochondrial transfer by tunneling nanotubes, tumor microtubes, gap junction intercellular communication, extracellular vesicles, endocytosis and cell fusion may regulate mitochondrial function within recipient cells, potentially contributing to disease treatment, such as nonalcoholic steatohepatitis, glioblastoma, ischemic stroke, bladder cancer and neurodegenerative diseases. This review introduces the principal approaches to intercellular mitochondrial transfer and examines its role in various diseases. Furthermore, we provide a comprehensive overview of the inhibitors and activators of intercellular mitochondrial transfer, offering a unique perspective to illustrate the relationship between intercellular mitochondrial transfer and diseases.

Keywords:  cell fusion; endocytosis; extracellular vesicles; gap junction intercellular communication; intercellular mitochondrial transfer; tumor microtube; tunneling nanotubes

DOI:  https://doi.org/10.1111/tra.12951
Nat Commun. 2024 Sep 03. 15(1): 7677

Fibre-specific mitochondrial protein abundance is linked to resting and post-training mitochondrial content in the muscle of men.

Elizabeth G Reisman, Javier Botella, Cheng Huang, Ralf B Schittenhelm, David A Stroud, Cesare Granata, Owala S Chandrasiri, Georg Ramm, Viola Oorschot, Nikeisha J Caruana, David J Bishop.

Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

DOI: https://doi.org/10.1038/s41467-024-50632-2
J Gen Physiol. 2024 Oct 07. pii: e202213113. [Epub ahead of print]156(10):

Modeling the mechanism of Ca2+ release in skeletal muscle by DHPRs easing inhibition at RyR I1-sites.

D George Stephenson.

Ca2+ release from the sarcoplasmic reticulum (SR) plays a central role in excitation-contraction coupling (ECC) in skeletal muscles. However, the mechanism by which activation of the voltage-sensors/dihydropyridine receptors (DHPRs) in the membrane of the transverse tubular system leads to activation of the Ca2+-release channels/ryanodine receptors (RyRs) in the SR is not fully understood. Recent observations showing that a very small Ca2+ leak through RyR1s in mammalian skeletal muscle can markedly raise the background [Ca2+] in the junctional space (JS) above the Ca2+ level in the bulk of the cytosol indicate that there is a diffusional barrier between the JS and the cytosol at large. Here, I use a mathematical model to explore the hypothesis that a sudden rise in Ca2+ leak through DHPR-coupled RyR1s, caused by reduced inhibition at the RyR1 Ca2+/Mg2+ inhibitory I1-sites when the associated DHPRs are activated, is sufficient to enable synchronized responses that trigger a regenerative rise of Ca2+ release that remains under voltage control. In this way, the characteristic response to Ca2+ of RyR channels is key not only for the Ca2+ release mechanism in cardiac muscle and other tissues, but also for the DHPR-dependent Ca2+ release in skeletal muscle.

DOI: https://doi.org/10.1085/jgp.202213113
Diabetol Metab Syndr. 2024 Aug 29. 16(1): 210

Effect of a carbohydrate-restricted diet on weight loss in overweight and obese pediatric population: a meta-analysis of randomized controlled trials.

Pejman Rohani, Zahra Rasoulizadeh, Sogand Tavakoli, Hosein Alimadadi, Koroush Vahidshahi, Somaye Fatahi, Mohammad Hassan Sohouli, Nathalia Sernizon Guimarães.

   BACKGROUND: There are conflicting findings regarding the effect of low-carbohydrate diets on obesity-related factors. This study aimed to investigate the effect of a carbohydrate-restricted (CR) diet on changes in anthropometric indicators of adiposity and fat distribution in pediatrics populations.
METHODS: A systematic search was conducted in PubMed/MEDLINE, Web of Science, Scopus, and Embase electronic databases using predefined keywords to identify all randomized controlled trials examining the effects of CR on obesity-related factors. The pooled weighted mean difference (WMD) and 95% confidence intervals (CI) were calculated using a random-effects model.
RESULTS: Findings from 11 studies demonstrated significant reductions in weight (WMD: -2.31 kg; 95% CI: -4.44, -0.18), BMI (WMD:-1.08 kg/m2; 95% CI: -1.91, -0.26), and fat mass (WMD: -1.43%; 95% CI: -2.43 to -0.43) as well as a significant increase in adiponectin levels (WMD: 0.74 ng/ml; 95% CI: 0.02, 1.47) in the CR diet group compared to the control group. However, no significant effect was observed on BMI z-score (WMD:-0.10; 95% CI: -0.21, 0.01), waist circumference (WMD:-3.03 cm; 95% CI: -6.57, 0.51) or leptin levels (WMD: -0.82 ng/ml; 95% CI: -2.26, 0.61). Stratified analysis rrevealed a greater effect of CR on weight and BMI reduction in interventions ≤ 12 weeks and in very low-carbohydrate diets.
CONCLUSIONS: In conclusion, it appears that CR diet, along with other lifestyle factors, can lead to significant improvements in weight loss on pediatrics with obesity/overweight.

Keywords:  Lifestyle; Low-carbohydrate diets; Meta-analysis; Obesity; Weight loss

DOI:  https://doi.org/10.1186/s13098-024-01458-x
J Diabetes Sci Technol. 2024 Sep 06. 19322968241280386

Time to Moderate and Severe Hyperglycemia and Ketonemia Following an Insulin Pump Occlusion.

David C Klonoff, Alessandra T Ayers, Cindy N Ho, Chiara Fabris, María Fernanda Villa-Tamayo, Eleanor Allen, Eda Cengiz, Laya Ekhlaspour, Jenise C Wong, Lutz Heineman, Michael A Kohn.

   INTRODUCTION: Insulin pump therapy can be adversely affected by interruption of insulin flow, leading to a rise in blood glucose (BG) and subsequently of blood beta-hydroxybutyrate (BHB) ketone levels.
METHODS: We performed a PubMed search for English language reports (January 1982 to July 2024) estimating the rate of rise in BG and/or BHB after ≥ 60 minutes of interruption of continuous subcutaneous insulin infusion (CSII) in persons with type 1 diabetes (PwT1D). We also simulated the rise in BG in a virtual population of 100 adults with T1D following suspension of continuous subcutaneous insulin infusion.
RESULTS: We identified eight relevant studies where BG and BHB (seven of these eight studies) were measured following suspension of CSII as a model for occlusion. After 60 minutes post-suspension, the mean extracted rates of rise averaged 0.62 mg/dL/min (37 mg/dL/h) for BG and 0.0038 mmol/L/min (0.20 mmol/L/h) for BHB. Mean estimated time to moderately/severely elevated BG (300/400 mg/dL) or BHB (1.6/3.0 mmol/L) was, respectively, 5.8/8.5 and 8.0/14.2 hours. The simulation model predicted moderately/severely elevated BG (300/400 mg/dL) after 9.25/12, 6.75/8.75, and 4.75/5.75 hours in the virtual subjects post-interruption with small (5th percentile), medium (50th percentile), and large (95th percentile) hyperglycemic changes.
DISCUSSION: Clinical studies and a simulation model similarly predicted that, following CSII interruption, moderate/severe hyperglycemia can occur within 5-9/6-14 hours, and clinical studies predicted that moderate/severe ketonemia can occur within 7-12/13-21 hours. Patients and clinicians should be aware of this timing when considering the risks of developing metabolic complications after insulin pump occlusion.

Keywords:  hyperglycemia; insulin pump; ketoacidosis; occlusion; suspension

DOI:  https://doi.org/10.1177/19322968241280386
Front Nutr. 2024 ;11 1439473

Effect of 5:2 intermittent fasting diet versus daily calorie restriction eating on metabolic-associated fatty liver disease-a randomized controlled trial.

Yuan-Yuan Wang, Fang Tian, Xiao-Lu Qian, Hui-Min Ying, Zhen-Feng Zhou.

   Objective: Both 5:2 IF diet (intermittent fasting) and daily caloric restriction eating had been suggested for management of MAFLD (Metabolic-Associated Fatty Liver Disease), this study aimed to evaluate the effects of 5:2 IF diet on body weight and metabolic parameters in adults with MAFLD, in comparison to daily caloric restriction eating.
Methods: This single-center, double-blind, prospective, randomized controlled trial included 60 patients with MAFLD, who were administered either a 5:2 IF diet limited calories consumed for 2 days each week with no restrictions on the remaining 5 (Group 5:2 IF diet) or a daily calorie restriction eating (Group daily calorie restriction). Fibrotouch-B instrument assessment, ultrasound assessment of hepatic steatosis, anthropometric indices and body composition analysis, blood sample measurements were conducted during two distinct visits: initially on the day of study commencement (T1), and subsequently at the conclusion of the 12-week intervention period (T2).
Results: In comparison to daily calorie restriction eating, the 5:2 IF diet significantly decreased the proportion of hepatic steatosis ≥moderate (29.6% vs. 59.3%, p = 0.028) and the degree of hepatic fibrosis F ≥ 2 (3.7% vs. 25.9%, p = 0.05), and fewer percentage of patients were diagnosed with fatty liver via upper abdominal ultrasound in the 5:2 intermittent fasting diet group (33.3% vs. 63.0%, p = 0.029). Additionally, the CAP (controlled attenuation parameter) and LSM (liver stiffness measurements) value were significantly lower in the 5:2 IF diet group (p < 0.05). No statistically significant differences were observed between the two groups in terms of weight, BMI (body mass index), WC (waist circumference), HC (hip circumference), and WHR (waist to hip ratio). Similarly, there were no significant differences in lipid profile, glycemic indices and adverse events (p > 0.05).
Conclusion: In summary, although both 5:2 IF diet and daily caloric restriction eating achieved similar effect on body weight, liver enzymes, lipid profile and glycemic indices after 12 weeks treatment, 5:2 IF diet demonstrates better improvement in fibrosis and steatosis scores independently from weight regulation. Consequently, it is anticipated to emerge as a viable dietary modality for lifestyle intervention among patients diagnosed with MAFLD.
Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO, identifier ChiCTR2400080292.

Keywords:  5:2 diet; calorie restriction; daily calorie restriction; liver fat; metabolic-associated fatty liver disease

DOI:  https://doi.org/10.3389/fnut.2024.1439473
J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746

Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.

  Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.

Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1016/j.jbc.2024.107746