bims-kimdis 2023-05-14 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–05–14
twenty-six papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketone bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity.
The effect of isocaloric, energy-restrictive, KETOgenic diet on metabolism, inflammation, nutrition deficiencies and oxidative stress in women with overweight and obesity (KETO-MINOX): Study protocol.
Ketogenic diet enhances the effects of oxycodone in mice.
Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.
Fasting ketone levels vary by age: implications for differentiating physiologic from pathologic ketotic hypoglycemia.
Ketogenic Diet Alleviates Brain Iron Deposition and Cognitive Dysfunction via Nrf2-mediated Ferroptosis pathway in APP/PS1 Mouse.
Skeletal Muscle Mitochondrial Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction.
Ketogenic diet-responsive drug-resistant epilepsy in a case of asparagine synthetase deficiency with a novel compound heterozygous missense variant.
Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism.
Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice.
Fuel oxidation under the control of mitochondrial shape and dynamics.
Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology.
Association between obesity, inflammation and insulin resistance: insights into signaling pathways and therapeutic interventions.
Contribution of low skeletal muscle mass in predicting cardiovascular events: A prospective cohort study.
The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders.
Fission-Fueled Nucleoid Dispersion, a Novel Mitochondrial Metabolic Activation Mechanism.
Rapid glycolytic activation accompanying innate immune responses: mechanisms and function.
The athlete's vein: Venous adaptations in the lower limbs of endurance athletes.
Energy Expenditure, Body Composition, and Skeletal Muscle Oxidative Capacity in Patients with Myotonic Dystrophy Type 1.
C. elegans as a model to study mitochondrial biology and disease.
From mitochondria to sarcopenia: role of 17β-estradiol and testosterone.
Women in Metabolic Science.
Myocardial Infarction as a Consequence of Mitochondrial Dysfunction.
Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.
Skeletal Muscle Memory.
The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine.

bioRxiv. 2023 Apr 26. pii: 2023.04.26.538410. [Epub ahead of print]

Ketone bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity.

Madelyn Blake, Patrycja Puchalska, Felipe Kazmirczak, Thenappan Thenappan, Peter A Crawford, Kurt W Prins.

Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics, to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and approaches that increase ketone concentrations exert beneficial effects in rodents and humans. However, the regulation of ketones in right ventricular failure (RVF) are unexplored. Here, we show in human pulmonary arterial hypertension (PAH), a compensatory ketosis is absent in patients with RVF. In the monocrotaline rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. These data suggest ketogenic therapies may particularly effective in RVF, and future studies evaluating the effects of ketones in RVF are warranted.

DOI: https://doi.org/10.1101/2023.04.26.538410
PLoS One. 2023 ;18(5): e0285283

The effect of isocaloric, energy-restrictive, KETOgenic diet on metabolism, inflammation, nutrition deficiencies and oxidative stress in women with overweight and obesity (KETO-MINOX): Study protocol.

Natalia Drabińska, Jerzy Romaszko, Paul White.

Obesity is considered one of the biggest health problems of the 21st century, becoming a worldwide epidemic, leading to the development of many diseases and increasing the risk of premature death. The first step in reducing body weight is a calorie-restricted diet. To date, there are many different diet types available, including the ketogenic diet (KD) which is recently gaining a lot of attention. However, all the physiological consequences of KD in the human body are not fully understood. Therefore, this study aims to evaluate the effectiveness of an eight-week, isocaloric, energy-restricted, KD as a weight management solution in women with overweight and obesity compared to a standard, balanced diet with the same calorie content. The primary outcome is to evaluate the effects of a KD on body weight and composition. The secondary outcomes are to evaluate the effect of KD-related weight loss on inflammation, oxidative stress, nutritional status, profiles of metabolites in breath, which informs about the metabolic changes in the body, obesity and diabetes-associated parameters, including a lipid profile, status of adipokines and hormones. Notably, in this trial, the long-term effects and efficiency of the KD will be studied. In summary, the proposed study will fill the gap in knowledge about the effects of KD on inflammation, obesity-associated parameters, nutritional deficiencies, oxidative stress and metabolism in a single study. ClinicalTrail.gov registration number: NCT05652972.

DOI: https://doi.org/10.1371/journal.pone.0285283
Sci Rep. 2023 May 09. 13(1): 7507

Ketogenic diet enhances the effects of oxycodone in mice.

R Trinko, D M Diaz, E Foscue, S L Thompson, J R Taylor, R J DiLeone.

Opioids have been used to manage pain for thousands of years, but they have significant potential for abuse. Prescription opioids, like oxycodone, are associated with 32% of overdoses, that have reached a total of 75,673 deaths in 2021. A major challenge is maximizing their therapeutic potential while minimizing the negative side effects including opioid use disorder (OUD). The Ketogenic Diet (KD) has been reported to reduce pain and decrease the severity of alcohol use disorder, yet its effects on oxycodone responses remain unknown. KD mice displayed increased oxycodone-induced locomotor activity and enhanced antinociceptive effects of oxycodone, suggesting a dietary effect on opiate sensitivity. Male KD mice exposed to chronic oxycodone exhibited increased naloxone-induced jumps, suggesting a sex-specific effect of diet on opioid withdrawal. Consistent with this, male KD mice self-administered less oxycodone while female KD mice did not differ from controls. Finally, no effect of KD on motivation to obtain oxycodone was observed during a progressive ratio schedule. These data suggest sex-biased effects of KD on responses to opioids that should be considered and potentially leveraged in both clinical pain management and treatment of OUD.

DOI: https://doi.org/10.1038/s41598-023-33458-8
JAMA Cardiol. 2023 May 10.

Skeletal Muscle Mitochondrial Respiration and Exercise Intolerance in Patients With Heart Failure With Preserved Ejection Fraction.

Lina Scandalis, Dalane W Kitzman, Barbara J Nicklas, Mary Lyles, Peter Brubaker, M Benjamin Nelson, Michelle Gordon, John Stone, Jaclyn Bergstrom, P Darrell Neufer, Erich Gnaiger, Anthony J A Molina.

Importance: The pathophysiology of exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF) remains incompletely understood. Multiple lines of evidence suggest that abnormal skeletal muscle metabolism is a key contributor, but the mechanisms underlying metabolic dysfunction remain unresolved.
Objective: To evaluate the associations of skeletal muscle mitochondrial function using respirometric analysis of biopsied muscle fiber bundles from patients with HFpEF with exercise performance.
Design, Setting, and Participants: In this cross-sectional study, muscle fiber bundles prepared from fresh vastus lateralis biopsies were analyzed by high-resolution respirometry to provide detailed analyses of mitochondrial oxidative phosphorylation, including maximal capacity and the individual contributions of complex I-linked and complex II-linked respiration. These bioenergetic data were compared between patients with stable chronic HFpEF older than 60 years and age-matched healthy control (HC) participants and analyzed for intergroup differences and associations with exercise performance. All participants were treated at a university referral center, were clinically stable, and were not undergoing regular exercise or diet programs. Data were collected from March 2016 to December 2017, and data were analyzed from November 2020 to May 2021.
Main Outcomes and Measures: Skeletal muscle mitochondrial function, including maximal capacity and respiration linked to complex I and complex II. Exercise performance was assessed by peak exercise oxygen consumption, 6-minute walk distance, and the Short Physical Performance Battery.
Results: Of 72 included patients, 50 (69%) were women, and the mean (SD) age was 69.6 (6.1) years. Skeletal muscle mitochondrial function measures were all markedly lower in skeletal muscle fibers obtained from patients with HFpEF compared with HCs, even when adjusting for age, sex, and body mass index. Maximal capacity was strongly and significantly correlated with peak exercise oxygen consumption (R = 0.69; P < .001), 6-minute walk distance (R = 0.70; P < .001), and Short Physical Performance Battery score (R = 0.46; P < .001).
Conclusions and Relevance: In this study, patients with HFpEF had marked abnormalities in skeletal muscle mitochondrial function. Severely reduced maximal capacity and complex I-linked and complex II-linked respiration were associated with exercise intolerance and represent promising therapeutic targets.

DOI: https://doi.org/10.1001/jamacardio.2023.0957
J Pediatr Endocrinol Metab. 2023 May 11.

Fasting ketone levels vary by age: implications for differentiating physiologic from pathologic ketotic hypoglycemia.

Komalben Parmar, Maua Mosha, David A Weinstein, Rebecca Riba-Wolman.

   OBJECTIVES: Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical as part of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is to measure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast.
METHODS: Children ≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast.
RESULTS: Data from 94 participants (mean 8.3 ± 5.7 years, 54 % male, 46 % female, were analyzed. Children ≤3 years of age (19) have significantly higher mean (0.40 ± 0.06 mmol/L) and median (0.4, IQR 0.2-0.6 mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21 ± 0.02 mmol/L) and median BHB (0.1, IQR 0.1-0.2 mmol/L) (p<0.0001). Fasting BHB levels of >1.0 mmol/L was rare (2 %, N=2) and 74 % (N=70) of participants had BHB levels <0.3 mmol/L.
CONCLUSIONS: BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0 mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.

Keywords:  beta-hydroxybutyrate; fasting ketosis; ketotic hypoglycemia; pathologic ketotic hypoglycemia; pediatrics, idiopathic ketotic hypoglycemia; physiological ketotic hypoglycemia

DOI:  https://doi.org/10.1515/jpem-2022-0589
Brain Res. 2023 May 08. pii: S0006-8993(23)00175-0. [Epub ahead of print] 148404

Ketogenic Diet Alleviates Brain Iron Deposition and Cognitive Dysfunction via Nrf2-mediated Ferroptosis pathway in APP/PS1 Mouse.

Yaya Qin, Dazhang Bai, Ming Tang, Ming Zhang, Li Zhao, Jia Li, Rui Yang, Guohui Jiang.

  Progressive cognitive decline and increased brain iron deposition with age are important features of Alzheimer's disease. Previous studies have found that the short-term ketogenic diet has neuroprotective effects in a variety of neurodegenerative diseases, but the effects of an early and long-term ketogenic diet on brain iron content and cognition of Alzheimer's disease have not been reported. In our study, 8-week-old APP/PS1 mice were given a 12-month ketogenic or standard diet, while C57BL/6 mice matched with the age and genetic background of APP/PS1 mice were used as normal controls to be given a standard diet for the same length of time. We found that 12 months of an early ketogenic diet improved the impaired learning and memory ability of APP/PS1 mice. The improvement of cognitive function may be related to the reduction of amyloid-beta deposition and neuronal ferroptosis. The mechanism was achieved by the regulation of ferroptosis-related pathways after activation of nuclear factor erythroid 2-related factor 2 by ketogenic diet-induced elevated β-hydroxybutyrate. In addition, blood biochemical results showed that compared with the standard diet group of the disease, although the early and long-term ketogenic diet increased blood lipids to some extent, it seemed to reduce liver, renal, and myocardial damage caused by genetic differences. This will provide a piece of positive evidence for the early and long-term use of ketogenic diets in people at risk of Alzheimer's disease.

Keywords:  Alzheimer's disease; brain iron deposition; cognitive dysfunction; ferroptosis; ketogenic diet

DOI:  https://doi.org/10.1016/j.brainres.2023.148404
JAMA Cardiol. 2023 May 10.

Skeletal Muscle Mitochondrial Dysfunction and Exercise Intolerance in Heart Failure With Preserved Ejection Fraction.

Ambarish Pandey, Neil Keshvani, Windy Alonso.

DOI: https://doi.org/10.1001/jamacardio.2023.0963
Clin Neurol Neurosurg. 2023 May 08. pii: S0303-8467(23)00188-9. [Epub ahead of print]230 107772

Ketogenic diet-responsive drug-resistant epilepsy in a case of asparagine synthetase deficiency with a novel compound heterozygous missense variant.

Mert Altıntaş, Miraç Yıldırım, Çiğdem İlter Uçar, Engin Köse, Ömer Bektaş, Serap Teber.

  Asparagine synthetase deficiency (ASNSD) is a rare autosomal recessive neurometabolic disorder caused by homozygous or compound heterozygous mutations in the ASNS gene. Most of the patients have early-onset intractable seizures. A 7-year-old boy was first admitted to our clinic with intractable febrile and afebrile seizures that started when he was 6 months old. He had axial hypotonia with spastic quadriparesis, mild facial dysmorphism, and acquired microcephaly at 1 year-old. Metabolic tests showed a borderline-low serum asparagine level. The electroencephalogram demonstrated epileptic discharges with a high incidence of multifocal spike-wave activity. Brain MRI showed mild cerebral atrophy. His seizures continued despite combinations of multiple antiseizure agents. Whole-exome sequencing (WES) revealed a novel compound heterozygous missense variant of the ASNS gene, and the variants were confirmed by Sanger sequencing. He was started on a ketogenic diet at five years and six months of age. In the first month of the ketogenic diet, we observed that the frequency of seizures significantly decreased. He showed a remarkable improvement in seizures and milder improvement in cognitive skills. To our knowledge, our case is the first report describing significant improvement with a ketogenic diet in intractable seizures due to ASNSD.

Keywords:  Asparagine synthetase deficiency; Epilepsy; Ketogenic diet; Treatment; Whole-exome sequencing

DOI:  https://doi.org/10.1016/j.clineuro.2023.107772
Metabolism. 2023 May 08. pii: S0026-0495(23)00181-6. [Epub ahead of print] 155578

Mitochondria-SR interaction and mitochondrial fusion/fission in the regulation of skeletal muscle metabolism.

Mauricio Castro-Sepulveda, Rodrigo Fernández-Verdejo, Hermann Zbinden-Foncea, Jennifer Rieusset.

  Mitochondria-endoplasmic/sarcoplasmic reticulum (ER/SR) interaction and mitochondrial fusion/fission are critical processes that influence substrate oxidation. This narrative review summarizes the evidence on the effects of substrate availability on mitochondrial-SR interaction and mitochondria fusion/fission dynamics to modulate substrate oxidation in human skeletal muscle. Evidence shows that an increase in mitochondria-SR interaction and mitochondrial fusion are associated with elevated fatty acid oxidation. In contrast, a decrease in mitochondria-SR interaction and an increase in mitochondrial fission are associated with an elevated glycolytic activity. Based on the evidence reviewed, we postulate two hypotheses for the link between mitochondrial dynamics and insulin resistance in human skeletal muscle. First, glucose and fatty acid availability modifies mitochondria-SR interaction and mitochondrial fusion/fission to help the cell to adapt substrate oxidation appropriately. Individuals with an impaired response to these substrate challenges will accumulate lipid species and develop insulin resistance in skeletal muscle. Second, a chronically elevated substrate availability (e.g. overfeeding) increases mitochondrial production of reactive oxygen species and induced mitochondrial fission. This decreases fatty acid oxidation, thus leading to the accumulation of lipid species and insulin resistance in skeletal muscle. Altogether, we propose mitochondrial dynamics as a potential target for disturbances associated with low fatty acid oxidation.

Keywords:  Fatty acid oxidation; Metabolic flexibility; Mitochondria dynamics; Mitochondria-associated membranes; Organelle dynamics

DOI:  https://doi.org/10.1016/j.metabol.2023.155578
Exp Neurol. 2023 May 05. pii: S0014-4886(23)00117-6. [Epub ahead of print]366 114432

Ketogenic diet ameliorates autism spectrum disorders-like behaviors via reduced inflammatory factors and microbiota remodeling in BTBR T+ Itpr3tf/J mice.

Ilaria Olivito, Ennio Avolio, Damiana Minervini, Teresa Soda, Carmine Rocca, Tommaso Angelone, Francesco Salvatore Iaquinta, Dina Bellizzi, Francesco De Rango, Rosalinda Bruno, Loredana De Bartolo, Raffaella Alò, Marcello Canonaco, Rosa Maria Facciolo.

  Autism Spectrum Disorder (ASD) is increasing, but its complete etiology is still lacking. Recently, application of ketogenic diet (KD) has shown to reduce abnormal behaviors while improving psychological/sociological status in neurodegenerative diseases. However, KD role on ASD and underlying mechanism remains unknown. In this work, KD administered to BTBR T+ Itpr3tf/J (BTBR) and C57BL/6J (C57) mice reduced social deficits (p = 0.002), repetitive behaviors (p < 0.001) and memory impairments (p = 0.001) in BTBR. Behavioral effects were related to reduced expression levels of tumor necrosis factor alpha, interleukin-1β, and interleukin-6 in the plasma (p = 0.007; p < 0.001 and p = 0.023, respectively), prefrontal cortex (p = 0.006; p = 0.04 and p = 0.03) and hippocampus (p = 0.02; p = 0.09 and p = 0.03). Moreover, KD accounted for reduced oxidative stress by changing lipid peroxidation levels and superoxide dismutase activity in BTBR brain areas. Interestingly, KD increased relative abundances of putatively beneficial microbiota (Akkermansia and Blautia) in BTBR and C57 mice while reversing the increase of Lactobacillus in BTBR feces. Overall, our findings suggest that KD has a multifunctional role since it improved inflammatory plus oxidative stress levels together with remodeling gut-brain axis. Hence, KD may turn out be a valuable therapeutic approach for ameliorating ASD-like conditions even though more evidence is required to evaluate its effectiveness especially on a long term.

Keywords:  Inflammatory factors; Microbial community diversity; Oxidative stress; Three-chamber sociability; Tumor necrosis factor alpha

DOI:  https://doi.org/10.1016/j.expneurol.2023.114432
EMBO J. 2023 May 08. e114129

Fuel oxidation under the control of mitochondrial shape and dynamics.

Erin L Seifert, György Hajnóczky.

How mitochondrial shape and substrate-specific metabolism are related has been a difficult question to address. Here, new work by Ngo et al (2023) reports that mitochondrial shape-long versus fragmented-determines the activity of β-oxidation of long-chain fatty acids, supporting a novel role for mitochondrial fission products as β-oxidation hubs.

DOI: https://doi.org/10.15252/embj.2023114129
Front Physiol. 2023 ;14 1151389

Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology.

Rachel M Handy, Graham P Holloway.

  While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling.

Keywords:  bioenergetics; insulin resistance; metabolism; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2023.1151389
Diabetes Res Clin Pract. 2023 May 05. pii: S0168-8227(23)00453-9. [Epub ahead of print] 110691

Association between obesity, inflammation and insulin resistance: insights into signaling pathways and therapeutic interventions.

Sourbh Suren Garg, Kriti Kushwaha, Rupal Dubey, Jeena Gupta.

  Obesity, a metabolic disorder, is becoming a worldwide epidemic that predominantly increases the risk for various diseases including metabolic inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms that link obesity with other metabolic diseases are not completely understood. In obesity, various inflammatory pathways that cause inflammation in adipose tissue of an obese individual become activated and exacerbate the disease. Obesity-induced low-grade metabolic inflammation perturbates the insulin signaling pathway and leads to insulin resistance. Researchers have identified several pathways that link the impairment of insulin resistance through obesity-induced inflammation like activation of Nuclear factor kappa B (NF-κB), suppressor of cytokine signaling (SOCS) proteins, cJun-N-terminal Kinase (JNK), Wingless-related integration site (Wnt), and Toll-like receptor (TLR) signaling pathways. In this review article, the published studies have been reviewed to identify the potential and influential role of different signaling pathways in the pathogenesis of obesity-induced metabolic inflammation and insulin resistance along with the discussion on potential therapeutic strategies. Therapies targeting these signaling pathways show improvements in metabolic diseases associated with obesity, but require further testing and confirmation through clinical trials.

Keywords:  Adipocytes; Inflammation; Insulin resistance; Metabolic diseases; Obesity

DOI:  https://doi.org/10.1016/j.diabres.2023.110691
Eur J Intern Med. 2023 May 08. pii: S0953-6205(23)00151-6. [Epub ahead of print]

Contribution of low skeletal muscle mass in predicting cardiovascular events: A prospective cohort study.

Yiting Xu, Tingting Hu, Yun Shen, Yufei Wang, Yuqian Bao, Xiaojing Ma.

   BACKGROUND: We aimed to explore the association between skeletal muscle mass and cardiovascular events, and its additional value on the assessment of cardiovascular diseases (CVD) over traditional risk scores.
METHODS: The study included 1365 community-based participants aged over 50 years and free of CVDs at baseline. Participants completed detailed assessments at baseline and received a follow-up assessment in 2021-2022 via phone calls or electronic medical records. Skeletal muscle mass was measured using an automatic bioelectric analyzer. Predicted probabilities of 10-year atherosclerotic cardiovascular disease (ASCVD) risk were estimated individually with the China-PAR equation.
RESULTS: After a mean follow-up of 7.6 years, 144 cardiovascular events were identified. The fully-adjusted hazard ratios (HRs) of cardiovascular events were 0.93 (0.88-0.98) and 1.08 (1.04-1.12) for skeletal muscle mass and predicted 10-year risk, respectively. Among participants over 60 years and with two or more risk factors, cardiovascular events risk increased progressively with each decreasing skeletal muscle tertile. Receiver operating characteristic curves showed that the C-statistic of predicting cardiovascular events for a 10-year risk assessment was slightly increased after adding skeletal muscle mass. The categorical net reclassification improvement (NRI) showed a 56.7% increase in the reclassification. The continuous NRI and integrated discrimination improvement increased as well.
CONCLUSION: Participants with low skeletal muscle mass were more likely to have cardiovascular events. Low muscle mass improved the predictive power of CVD incidence over the original risk score, indicating that muscle mass could be a valuable parameter and a declining value needed early detection in the population.

Keywords:  Atherosclerotic cardiovascular disease; Cardiovascular events; Skeletal muscle mass

DOI:  https://doi.org/10.1016/j.ejim.2023.05.007
J Cell Biochem. 2023 May 09.

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders.

Saeid Bagheri-Mohammadi, Mohammad Farjami, Ali Jaafari Suha, Seyed Mohsen Aghaei Zarch, Sajad Najafi, Ali Esmaeili.

  Mitochondrial calcium (Ca2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca2+ signaling at the molecular level. The biological function of Ca2+ channels and transporters as well as the role of mitochondrial Ca2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments. The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

Keywords:  Alzheimer's disease; ageing; calcium signaling; cellular homeostasis; mitochondria-associated ER membrane; therapeutic strategy

DOI:  https://doi.org/10.1002/jcb.30414
Mol Cells. 2023 May 31. 46(5): 278-280

Fission-Fueled Nucleoid Dispersion, a Novel Mitochondrial Metabolic Activation Mechanism.

Jeongah Kim.

DOI: https://doi.org/10.14348/molcells.2023.0043
Front Immunol. 2023 ;14 1180488

Rapid glycolytic activation accompanying innate immune responses: mechanisms and function.

Dmitry Namgaladze, Bernhard Brüne.

  Innate immune responses to pathogens, mediated by activation of pattern recognition receptors and downstream signal transduction cascades, trigger rapid transcriptional and epigenetic changes to support increased expression of pro-inflammatory cytokines and other effector molecules. Innate immune cells also rapidly rewire their metabolism. The most prominent metabolic alteration following innate immune activation is rapid up-regulation of glycolysis. In this mini-review, we summarize recent advances regarding the mechanisms of rapid glycolytic activation in innate immune cells, highlighting the relevant signaling components. We also discuss the impact of glycolytic activation on inflammatory responses, including the recently elucidated links of metabolism and epigenetics. Finally, we highlight unresolved mechanistic details of glycolytic activation and possible avenues of future research in this area.

Keywords:  dendritic cell; glycolysis; inflammation; macrophage; metabolism; pattern recognition receptors

DOI:  https://doi.org/10.3389/fimmu.2023.1180488
Am J Physiol Heart Circ Physiol. 2023 May 12.

The athlete's vein: Venous adaptations in the lower limbs of endurance athletes.

Kate N Thomas, Ashley P Akerman, Travis D Gibbons, Holly A Campbell, James D Cotter, André M van Rij.

  Endurance exercise induces cardiovascular adaptations; the athletic phenotypes of the heart and arteries are well characterised, but few studies have investigated the effects of chronic exercise on the venous system. The aim of this study was to describe the anatomy and function of lower limb deep and superficial veins in athletes compared to controls. Endurance-trained athletes and untrained controls (13 males, 7 females per group) were examined utilising ultrasound to measure vein diameter and flow, and air plethysmography to assess calf venous volume dynamics and muscle pump function at rest, during a single step, ambulation (10 steps) and after acute treadmill exercise (30 min ~80% age-predicted heart rate maximum). Diameters of 3 of the 7 deep veins assessed were larger in athletes (P≤0.0167) and more medial calf perforators were detectable (5 vs. 3, P=0.0039). Calf venous volume was 22% larger in athletes (P=0.0057), calf muscle pump ejection volume and ambulatory venous volume after 10 steps were both greater in athletes (20 and 46% respectively, P≤0.0482). Following acute exercise, flow recovery profiles in deep and superficial veins draining the leg were not different between groups, despite athletes performing ~four times more work. After exercise, venous volume and ejection volume were reduced by ~20% in athletes with no change in controls (interaction P≤0.0372) and while ambulatory venous volume reduced, this remained greater in athletes. These findings highlight venous adaptations that compensate for the demands of regular endurance exercise, all of which are suited to enhance flow through the lower limb venous system.

Keywords:  air plethysmography; exercise; running; training; ultrasound

DOI:  https://doi.org/10.1152/ajpheart.00175.2023
J Neuromuscul Dis. 2023 May 02.

Energy Expenditure, Body Composition, and Skeletal Muscle Oxidative Capacity in Patients with Myotonic Dystrophy Type 1.

Isis B T Joosten, Cas J Fuchs, Milou Beelen, Guy Plasqui, Luc J C van Loon, Catharina G Faber.

   BACKGROUND: Myotonic dystrophy type 1 (DM1) patients are at risk for metabolic abnormalities and commonly experience overweight and obesity. Possibly, weight issues result from lowered resting energy expenditure (EE) and impaired muscle oxidative metabolism.
OBJECTIVES: This study aims to assess EE, body composition, and muscle oxidative capacity in patients with DM1 compared to age-, sex- and BMI-matched controls.
METHODS: A prospective case control study was conducted including 15 DM1 patients and 15 matched controls. Participants underwent state-of-the-art methodologies including 24 h whole room calorimetry, doubly labeled water and accelerometer analysis under 15-days of free-living conditions, muscle biopsy, full body magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DEXA), computed tomography (CT) upper leg, and cardiopulmonary exercise testing.
RESULTS: Fat ratio determined by full body MRI was significantly higher in DM1 patients (56 [49-62] %) compared to healthy controls (44 [37-52] % ; p = 0.027). Resting EE did not differ between groups (1948 [1742-2146] vs (2001 [1853-2425>] kcal/24 h, respectively; p = 0.466). In contrast, total EE was 23% lower in DM1 patients (2162 [1794-2494] vs 2814 [2424-3310] kcal/24 h; p = 0.027). Also, DM1 patients had 63% less steps (3090 [2263-5063] vs 8283 [6855-11485] steps/24 h; p = 0.003) and a significantly lower VO2 peak (22 [17-24] vs 33 [26-39] mL/min/kg; p = 0.003) compared to the healthy controls. Muscle biopsy citrate synthase activity did not differ between groups (15.4 [13.3-20.0] vs 20.1 [16.6-25.8] μM/g/min, respectively; p = 0.449).
CONCLUSIONS: Resting EE does not differ between DM1 patients and healthy, matched controls when assessed under standardized circumstances. However, under free living conditions, total EE is substantially reduced in DM1 patients due to a lower physical activity level. The sedentary lifestyle of DM1 patients seems responsible for the undesirable changes in body composition and aerobic capacity.

Keywords:  Myotonic dystrophy; body composition; energy expenditure; physical activity

DOI:  https://doi.org/10.3233/JND-230036
Semin Cell Dev Biol. 2023 May 04. pii: S1084-9521(23)00101-5. [Epub ahead of print]

C. elegans as a model to study mitochondrial biology and disease.

Tessa Onraet, Steven Zuryn.

  Mitochondria perform a myriad of essential functions that ensure organismal homeostasis, including maintaining bioenergetic capacity, sensing and signalling the presence of pathogenic threats, and determining cell fate. Their function is highly dependent on mitochondrial quality control and the appropriate regulation of mitochondrial size, shape, and distribution during an entire lifetime, as well as their inheritance across generations. The roundworm Caenorhabditis elegans has emerged as an ideal model organism through which to study mitochondria. The remarkable conservation of mitochondrial biology has allowed C. elegans researchers to investigate complex processes that are challenging to study in higher organisms. In this review, we explore the key recent contributions of C. elegans to mitochondrial biology through the lens of mitochondrial dynamics, organellar removal, and mitochondrial inheritance, as well as their involvement in immune responses, various types of stress, and transgenerational signalling.

Keywords:  Aging; Biogenesis; Fission; Fusion; Mitochondrial disease; Mitophagy; MtDNA; Neurodegeneration; Proteotoxicity; UPRmt

DOI:  https://doi.org/10.1016/j.semcdb.2023.04.006
Front Endocrinol (Lausanne). 2023 ;14 1156583

From mitochondria to sarcopenia: role of 17β-estradiol and testosterone.

Xu Tian, Shujie Lou, Rengfei Shi.

  Sarcopenia, characterized by a loss of muscle mass and strength with aging, is prevalent in older adults. Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia. Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells. The accumulation of damaged mitochondria due to age-related impairments in any of the mitochondrial quality control (MQC) processes, such as proteostasis, biogenesis, dynamics, and mitophagy, can contribute to the decline in muscle mass and strength associated with aging. Interestingly, a decrease in sex hormones (e.g., 17β-estradiol and testosterone), which occurs with aging, has also been linked to sarcopenia. Indeed, 17β-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions. Here, we overview the current literature on the key mechanisms by which mitochondrial dysfunction contribute to the development and progression of sarcopenia and the potential modulatory effects of 17β-estradiol and testosterone on mitochondrial function in this context. The advance in its understanding will facilitate the development of potential therapeutic agents to mitigate and manage sarcopenia.

Keywords:  17β-estradiol; aging; mitochondria; sarcopenia; skeletal muscle; testosterone

DOI:  https://doi.org/10.3389/fendo.2023.1156583
Am J Physiol Endocrinol Metab. 2023 May 11.

Women in Metabolic Science.

Hannah Pallubinsky, Anne-Marie Carreau, Natalie Jane Michael.



Keywords:  Diversity; Metabolism; Research; Science; Women

DOI:  https://doi.org/10.1152/ajpendo.00133.2023
Curr Cardiol Rev. 2023 May 08.

Myocardial Infarction as a Consequence of Mitochondrial Dysfunction.

Pranay Wal, Namra Aziz, Yash Kumar Singh, Ankita Wal, Sourabh Kosey, Awani Kumar Rai.

  Acute myocardial infarction is an event of myocardial necrosis caused by unstable ischemic syndrome. Myocardial infarction (MI) occurs when blood stops flowing to the cardiac tissue or myocardium and the heart muscle gets damaged due to poor perfusion and reduced oxygen supply. Mitochondria can serve as the arbiter of cell fate in response to stress. Oxidative metabolism is the function of mitochondria within the cell. Cardiac cells being highly oxidative tissue generates about 90% of their energy through oxidative metabolism. In this review, we focused on the role of mitochondria in energy generation in myocytes as well as its consequences on heart cells causing cell damage. The role of mitochondrial dysfunction due to oxidative stress, production of reactive oxygen species, and anaerobic production of lactate as a failure of oxidative metabolism are also discussed.

Keywords:  IMM; MPTP; Mitochondrial Dysfunction; Myocardial Infarction (MI); OMM; ROS; apoptosis.

DOI:  https://doi.org/10.2174/1573403X19666230508114311
JCI Insight. 2023 May 11. pii: e169789. [Epub ahead of print]

Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans.

Shana O Warner, Yufei Dai, Nicole Sheanon, Michael V Yao, Rebecca L Cason, Shahriar Arbabi, Shailendra B Patel, Diana M Lindquist, Jason J Winnick.

  Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control subjects. Counterregulatory responses to insulin-induced hypoglycemia were measured in twelve healthy people during two metabolic studies. During one study, subjects ate breakfast and lunch, after which they underwent a two-hour bout of insulin-induced hypoglycemia (FED). During the other study, subjects remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.

Keywords:  Diabetes; Endocrinology

DOI:  https://doi.org/10.1172/jci.insight.169789
Am J Physiol Cell Physiol. 2023 May 08.

Skeletal Muscle Memory.

Adam P Sharples, Daniel C Turner.

  Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, and amongst exercise practitioners and the public. Research has demonstrated that skeletal muscle tissue can be 'primed' by earlier positive encounters with exercise training that can enhance adaptation to later training, even following significant periods of exercise cessation or detraining. This review will describe and discuss the most recent research investigating the underlying mechanisms of skeletal muscle memory: 1) 'cellular' muscle memory and, 2) 'epigenetic' muscle memory as well as the emerging evidence of how these theories may work in synergy. We will discuss both 'positive' and 'negative' muscle memory and highlight the importance of investigating muscle memory for optimising exercise interventions and training programmes as well as the development of therapeutic strategies for counteracting muscle wasting conditions and age-related muscle loss. Finally, important directions emerging in the field will be highlighted to advance the next generation of studies in skeletal muscle memory research into the future.

Keywords:  DNA methylation; Epigenetics; atrophy; hypertrophy; myonuclei

DOI:  https://doi.org/10.1152/ajpcell.00099.2023
Front Pharmacol. 2023 ;14 1151196

The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine.

Jia-Xin Long, Meng-Zhi Tian, Xiao-Yi Chen, Huang-He Yu, Huang Ding, Fang Liu, Ke Du.

  Ischemic stroke (IS) is the second leading cause of death and disability in the world. Pyroptosis, a form of programmed cell death initiated by caspases, participates in the occurrence and development of IS. Because it can increase cell membrane permeability, mediate the release of inflammatory factors, and aggravate inflammation, inhibiting this process can significantly reduce the pathological injury of IS. The nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3) is a multiprotein complex whose activation is the core link of pyroptosis. In recent years, studies have reported that traditional Chinese medicine (TCM) could regulate pyroptosis mediated by NLRP3 inflammasome through multi-channel and multi-target networks and thus exert the effect against IS. This article reviews 107 papers published in recent years in PubMed, Chinese National Knowledge Infrastructure (CNKI), and WanFang Data in recent years. It has found that the activation factors of NLRP3 inflammasome include ROS, mitochondrial dysfunction, K+, Ca2+, lysosome rupture, and trans-Golgi breakdown. TLR4/NF-κB/NLRP3, ROS/TXNIP/NLRP3, AMPK/Nrf2/NLRP3, DRP1/NLRP3, TAK1/JNK/NLRP3 signaling pathways regulate the initiation and assembly of the NLRP3 inflammasome, subsequently induce pyroptosis, affecting the occurrence and development of IS. TCM can affect the above signaling pathways and regulate the pyroptosis mediated by NLRP3 inflammasome, so as to play a protective role against IS, which provides a new entry point for discussing the pathological mechanism of IS and a theoretical basis for developing TCM treasure house.

Keywords:  NLRP3; ischemic stroke (IS); pathways; pyroptosis; traditional Chinese medicine (TCM)

DOI:  https://doi.org/10.3389/fphar.2023.1151196