bims-kimdis 2022-10-23 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–10–23
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Longitudinal changes in circulating ketone body levels in patients with acute heart failure: A post-hoc analysis of the EMPA-Response-AHF Trial.
Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions.
Ketogenic diet restrains herpes simplex encephalitis via gut microbes.
The effects of a 6-week controlled, hypocaloric ketogenic diet, with and without exogenous ketone salts, on cognitive performance and mood states in overweight and obese adults.
Validation of ketogenic diet adherence questionnaire: Keto-check.
Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study.
Single muscle fibre contractile function with ageing.
Fatty acid oxidation: A neglected factor in understanding the adjustment of mitochondrial function to cold temperatures.
Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities.
Elevated muscle mass accompanied by transcriptional and nuclear alterations several months following cessation of resistance-type training in rats.
The exercise metabolome: acute aerobic and anaerobic signatures.
Ketones: the double-edged sword of SGLT2 inhibitors?
Myostatin: A Skeletal Muscle Chalone.
Sex, lean body mass, and cardiac performance.
Pax7+ Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis.
Assessment of Mitochondrial Dysfunctions After Sirtuin Inhibition.
Reduced intestinal butyrate availability is associated with the vascular remodeling in resistance arteries of hypertensive rats.
Real life evaluation of sodium-glucose cotransporter 2 inhibition in type 1 diabetes and the risk of diabetic ketoacidosis.
Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages.
Beyond ATP, new roles of mitochondria.
Taking mitochondria to heart.
We are all aging, and here's why.
The ROS/NF-κB/HK2 axis is involved in the arsenic-induced Warburg effect in human L-02 hepatocytes.
Disturbing NLRP3 acetylation and inflammasome assembly inhibits androgen receptor-promoted inflammatory responses and prostate cancer progression.
Endocannabinoids effect on oxidative status of human platelets.

J Card Fail. 2022 Oct 13. pii: S1071-9164(22)00728-X. [Epub ahead of print]

Longitudinal changes in circulating ketone body levels in patients with acute heart failure: A post-hoc analysis of the EMPA-Response-AHF Trial.

S N Voorrips, E M Boorsma, J C Beusekamp, R A de Boer, M A Connelly, R P F Dullaart, P van der Meer, D J van Veldhuisen, A A Voors, K Damman, B D Westenbrink.

   AIMS: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF.
METHODS AND RESULTS: This was a post-hoc analysis of 79 acute HF patients included in the EMPA-RESPONSE-AHF trial which compared sodium-dependent glucose-cotransporter protein 2 (SGLT2) inhibitor treatment with empagliflozin for 30 days to placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, β-hydroxybutyrate and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures ANOVA. In the total cohort, median total ketone body (TKB) concentration was 251 [178-377] µmol/L at baseline, which gradually decreased to 202 [156-240] µmol/L at day 30 (p=0.041). Acetone decreased from 60 [34-94] µmol/L at baseline to 30 [21-42] µmol/L (p<0.001), whereas β-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher NT-pro BNP levels (r=0.234; p=0.039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. Higher acetone concentration at baseline was univariately associated with a greater risk of the composite endpoint including in-hospital worsening HF, HF rehospitalizations and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined endpoint.
CONCLUSION: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared to after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in subjects with acute HF.

Keywords:  Acetone; Acute Heart failure; Empagliflozin; Ketone Bodies; NT-pro BNP; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.cardfail.2022.09.009
Front Hum Neurosci. 2022 ;16 846183

Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions.

Naomi Elyse Omori, Geoffrey Hubert Woo, Latt Shahril Mansor.

  Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies.

Keywords:  brain; exogenous; injury; ketones; lactate; metabolism dysfunction; neurodegenerative; traumatic

DOI:  https://doi.org/10.3389/fnhum.2022.846183
Microbes Infect. 2022 Oct 18. pii: S1286-4579(22)00131-9. [Epub ahead of print] 105061

Ketogenic diet restrains herpes simplex encephalitis via gut microbes.

Tianhao Shan, Yanling Huang, Zibo Zhao, Feng Li, Yifei Wang, Cuifang Ye, Kai Zheng, Zhe Ren.

  Herpes simplex virus type 1 (HSV-1) infection-associated herpes simplex encephalitis (HSE) is an occasionally but severe neuronal disease that causes behavioral disorder and impairs cognition. Herein, we demonstrate that the consumption of ketogenic diet (KD), a low-carbohydrate high-fat diet, restricts the neurotropic infection of HSV-1 and HSE progression in mice. KD reduced weight loss, neurodegenerative symptoms, virus production and neuroinflammation, resulting in the enhanced survival rate of HSE mice. Notably, depletion of gut microbes by antibiotics attenuated the protective function of KD on HSV-1-related neuroinflammation and HSE development. Therefore, KD represents as an alternative therapeutic strategy to alleviate or prevent HSE via gut microbiota.

Keywords:  gut microbes; herpes simplex encephalitis; herpes simplex virus type 1; inflammation; ketogenic diet

DOI:  https://doi.org/10.1016/j.micinf.2022.105061
Front Neurosci. 2022 ;16 971144

The effects of a 6-week controlled, hypocaloric ketogenic diet, with and without exogenous ketone salts, on cognitive performance and mood states in overweight and obese adults.

Madison L Kackley, Milene L Brownlow, Alex Buga, Chris D Crabtree, Teryn N Sapper, Annalouise O'Connor, Jeff S Volek.

   Background: Ketogenic diets are a commonly used weight loss method, but little is known how variations in sodium content and ketones influence cognition and mood during the early keto-adaptation period.
Objectives: To investigate the effects of an exogenous ketone salt (KS) as part of a hypocaloric KD on mood and cognitive outcomes in overweight and obese adults. A secondary objective was to evaluate changes in biochemical markers associated with inflammatory and cognitive responses.
Materials and methods: Adults who were overweight or obese participated in a 6-week controlled-feeding intervention comparing hypocaloric diets (∼75% of energy expenditure). KD groups received twice daily ketone salt (KD + KS; n = 12) or a flavor-matched placebo, free of minerals (KD + PL; n = 13). A separate group of age and BMI matched adults were later assigned to an isoenergetic low-fat diet (LFD; n = 12) as comparison to KD. Mood was assessed by shortened Profile of Mood States and Visual Analog Mood Scale surveys. Cognitive function was determined by the Automated Neuropsychological Assessment Metrics mental test battery.
Results: Both KD groups achieved nutritional ketosis. Fasting serum glucose decreased in both KD groups, whereas glucose was unaffected in the LFD. Insulin decreased at week 2 and remained lower in all groups. At week 2, depression scores in the KD + PL group were higher compared to KD + KS. Performance in the math processing and go/no-go cognitive tests were lower for KD + PL and LFD participants, respectively, compared to KD + KS. Serum leptin levels decreased for all groups throughout the study but were higher for KD + KS group at week 6. Serum TNF-α steadily increased for LFD participants, reaching significance at week 6.
Conclusion: During a short-term hypocaloric diet, no indication of a consistent decline in mood or cognitive function were seen in participants following either KD, despite KD + PL being relatively low in sodium. WK2 scores of "anger" and "depression" were higher in the LFD and KD + PL groups, suggesting that KS may attenuate negative mood parameters during the early intervention stages.

Keywords:  BDNF; BHB; cognition; keto-adaptation; ketogenic diet; ketone salts; mood; sodium

DOI:  https://doi.org/10.3389/fnins.2022.971144
Arq Neuropsiquiatr. 2022 Aug;80(8): 794-801

Validation of ketogenic diet adherence questionnaire: Keto-check.

Lenycia de Cassya Lopes Neri, Letícia Pereira de Brito Sampaio.

BACKGROUND: The ketogenic diet is a therapeutic option to control drug-resistant epileptic seizures and has difficult compliance standards due to adverse effects, psychosocial factors, or dietary restriction.
OBJECTIVE: To create and validate a ketogenic diet compliance questionnaire.
METHODS: Methodological study, convergent care. The instrument was analyzed (construct validation) by five judges during two cycles of the Delphi technique. The judges assessed the relevance and clarity by using the Likert scale with three levels and made suggestions. The validation of the instrument was calculated using the agreement rate and content validity index (CVI). The application by two nutritionists made it possible to test reproducibility using the Kappa coefficient. When comparing the classification with a template developed by the health professionals who cared for the patients in question, the Pearson correlation and Fisher exact tests were used. For the reliability test, self-applied data were collected and evaluated using Cronbach Alpha coefficient.
RESULTS: The questionnaire initially created with 11 multiple choice questions on a Likert scale was reduced to 10 questions with an agreement rate and the CVI classified as excellent after two rounds with judges. In the application of the tool, a kappa of 0.6087 was obtained, a Pearson that showed no significant difference between evaluators and a Cronbach α of 0.6483, with substantial consistency.
CONCLUSIONS: This work resulted in the creation of an unprecedented and reliable questionnaire on adherence to the national ketogenic diet. Further studies should be performed to extrapolate the use of this questionnaire in different populations.

DOI: https://doi.org/10.1055/s-0042-1755343
Front Nutr. 2022 ;9 955024

Very low calorie ketogenic diet combined with physical interval training for preserving muscle mass during weight loss in sarcopenic obesity: A pilot study.

Elisabetta Camajani, Alessandra Feraco, Stefania Proietti, Sabrina Basciani, Luigi Barrea, Andrea Armani, Mauro Lombardo, Lucio Gnessi, Massimiliano Caprio.

   Background: The prevalence of sarcopenic obesity (SO) is increasing worldwide, posing important challenges to public health and national health care system, especially during the COVID pandemic. In subjects with SO, it is essential to reduce body weight, and to preserve lean mass, to avoid worsening of muscle function. Adequate nutrition and correct physical activity is essential to counteract SO progression. Very Low Calorie Ketogenic Diet (VLCKD), a well-established nutritional intervention for obesity, has been also indicated for the treatment of SO. To date, the effects of physical training during VLCKD have not been investigated.
Aim: This pilot study aims to determine the efficacy of VLCKD combined with interval training, compared to a VLCKD alone, on weight-loss, body composition, and physical performance in participants with SO.
Materials and methods: Twenty-four participants with SO, aged between 50 and 70 years, who met the inclusion criteria, accepted to adhere to a VLCKD (<800 Kcal/die) and to give informed consent, were enrolled in the study. Twelve participants followed a structured VLCKD protocol (VLCKD group) and twelve followed the same VLCKD protocol combined with interval training (IT), twice per week (VLCKD + IT group). Data were collected at baseline (T0) and after 6-week of treatment (T6). Anthropometric indexes, body composition analysis by Bioelectrical Impedance Analysis (BIA), muscle strength and physical performance analysis were assessed at baseline and at the end of treatment.
Results: At the end of the study, body mass index (BMI), body weight, waist circumference, and hip circumference were significantly reduced in both VLCKD group and VLCKD + IT group. Interestingly, a significant improvement in muscle strength and physical performance was observed in both groups. A multiple comparison of delta variations in all parameters between groups was performed. No differences were observed for the majority of anthropometric and biochemical parameters, with the exception of fat free mass (FFM) and fat mass (FM): notably, participants who followed a VLCKD combined with IT preserved FFM (p < 0.001) and reduced FM (p = 0.001) to a greater extent than what observed in VLCKD group. Moreover, high density lipoprotein (HDL) cholesterol plasma levels were significantly higher in the VLCKD + IT group compared to the VLCKD group.
Conclusion: This pilot study confirms that VLCKD is effective in terms of body weight reduction, particularly FM; moreover, the combination of VLCKD and interval training could determine a better preservation of FFM.

Keywords:  VLCKD; fat free mass; fat mass; physical activity; sarcopenia

DOI:  https://doi.org/10.3389/fnut.2022.955024
J Physiol. 2022 Oct 21.

Single muscle fibre contractile function with ageing.

Gregory J Grosicki, Carlos S Zepeda, Christopher W Sundberg.

  Ageing is accompanied by decrements in the size and function of skeletal muscle that compromises independence and quality of life in older adults. Developing therapeutic strategies to ameliorate these changes is critical but requires an in-depth mechanistic understanding of the underlying physiology. Over the past 25 years, studies on the contractile mechanics of isolated human muscle fibres have been instrumental in facilitating our understanding of the cellular mechanisms contributing to age-related skeletal muscle dysfunction. The purpose of this review is to characterize the changes that occur in single muscle fibre size and contractile function with ageing and identify key areas for future research. Surprisingly, most studies observe that the size and contractile function of fibres expressing slow myosin heavy chain (MHC) I are well-preserved with ageing. In contrast, there are profound age-related decrements in the size and contractile function of the fibres expressing the MHC II isoforms. Notably, lifelong aerobic exercise training is unable to prevent most of the decrements in fast fibre contractile function, which have been implicated as a primary mechanism for the age-related loss in whole-muscle power output. These findings reveal a critical need to investigate the effectiveness of other nutritional, pharmaceutical, or exercise strategies, such as lifelong resistance training, to preserve fast fibre size and function with ageing. Moreover, integrating single fibre contractile mechanics with the molecular profile and other parameters important to contractile function (e.g., phosphorylation of regulatory proteins, innervation status, mitochondrial function, fibre economy) is necessary to comprehensively understand the ageing skeletal muscle phenotype. Abstract figure legend Advancing age is accompanied by decrements in whole-muscle strength and power that exceed the losses in muscle mass. The single fibre preparation has been instrumental in facilitating our understanding of the cellular mechanisms contributing to this phenomenon. Surprisingly, and at odds with some of the earlier findings, both size and contractile function (force, power, shortening velocity, Ca2+ sensitivity, and rates of force development [RFD]) of the MHC I fibres appear well-preserved with ageing. In contrast, several studies observe profound age-related decrements in function - namely force and power - of the MHC II fibres. The decrements in MHC II fibre function are primarily attributable to fibre atrophy, rather than age-related alterations in the intrinsic contractile mechanics, per se. Since MHC II fibres can generate greater force and power than MHC I fibres, these findings implicate fast fibre atrophy as an important therapeutic target for attenuating age-related decrements in whole-muscle strength and power. This article is protected by copyright. All rights reserved.

Keywords:  cross-bridge cycle; muscle power; muscle quality; myosin heavy chain; older adult; shortening velocity; skeletal muscle

DOI:  https://doi.org/10.1113/JP282298
J Exp Biol. 2022 Oct 21. pii: jeb.244934. [Epub ahead of print]

Fatty acid oxidation: A neglected factor in understanding the adjustment of mitochondrial function to cold temperatures.

Heather Mast, Claudia D Holody, Hélène Lemieux.

  For ectothermic species, adaptation to thermal changes is of critical importance. Mitochondrial oxidative phosphorylation (OXPHOS), which leverages multiple electron pathways to produce energy needed for survival, is among the crucial metabolic processes impacted by temperature. Our aim in this study was to identify how changes in temperature affect the less-studied electron transferring flavoprotein pathway, fed by fatty acid substrates. We used the planarian, Dugesia tigrina, acclimated for four weeks at 10 (cold-acclimated) or 20°C (normothermic). Respirometry experiments were conducted at either 10 or 20°C assay temperatures to study specific states of the OXPHOS process using the fatty acid substrates palmitoylcarnitine (long-chain), octanoylcarnitine (medium-chain), or acetylcarnitine (short-chain). Following cold acclimation, octanoylcarnitine exhibited increases in both the OXPHOS and ET (electron transfer, noncoupled) states, indicating that the pathway involved in medium-chain length fatty acids adjusts to cold temperatures. Acetylcarnitine only showed an increase in the OXPHOS state due to cold acclimation, but not in the ET state, indicative of a change in phosphorylation system capacity rather than fatty acid β-oxidation. Palmitoylcarnitine oxidation was unaffected. Our results show that cold acclimation in D. tigrina caused a specific adjustment in the capacity to metabolize medium-chain fatty acid rather than an adjustment in the activity of enzymes carnitine-acylcarnitine translocase, carnitine acyltransferase, and carnitine palmitoyltransferase-2. Here, we provide novel evidence of the alterations in fatty acid β-oxidation during cold acclimation in D. tigrina.

Keywords:  Fatty acid oxidation; Mitochondrial respiration; Thermal acclimation

DOI:  https://doi.org/10.1242/jeb.244934
Biomed Pharmacother. 2022 Nov;pii: S0753-3322(22)01222-7. [Epub ahead of print]155 113833

Skeletal muscle mitochondrial remodeling in heart failure: An update on mechanisms and therapeutic opportunities.

Jiayu Lv, Yumeng Li, Shuqing Shi, Xia Xu, Huaqin Wu, Bingxuan Zhang, Qingqiao Song.

  Patients with heart failure (HF) usually present with skeletal muscle diseases of varying severity, ranging from early fatigue on exercise to sarcopenia, sarcopenic obesity or cachexia, and frailty, which are significant predictors of HF prognosis. Abnormal mitochondrial metabolism has been identified as one of the earliest signs of skeletal muscle injury in HF and is associated with pathological alterations in muscle, manifested as muscle wasting, myocyte atrophy and apoptosis, fiber type shift, impaired contractile coupling, and muscle fat infiltration. In this review, we update the evidence for skeletal muscle mitochondrial remodeling in HF patients or animal models, including the impairments in mitochondrial ultrastructure, oxidative metabolism, electron transport chain (ETC), phosphorylation apparatus, phosphotransfer system, and quality control. We also focus on molecular regulatory mechanisms upstream of mitochondria, including circulating factors (e.g., RAAS, TNF-α IL-6, IGF-1, GH, ghrelin, adiponectin, NO) and molecular signals within myocytes (e.g., PGC-1α, PPARs, AMPK, SIRT1/3, ROS, and MuRF1). Besides the therapies targeting the signaling pathways mentioned above, such as AdipoRon and elamipretide, we further summarize other potential pharmacological approaches like inhibitors of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4), as well as some natural products, which may have the beneficial effects on improving the skeletal muscle mitochondrial function of HF. Targeting myocyte mitochondrial biogenesis, oxidative metabolism, oxidative phosphorylation, and reduction of oxidative stress injury are promising future opportunities for the prevention and management of skeletal muscle myopathy in HF.

Keywords:  Heart failure; Mitochondria; Molecular mechanisms; Pharmacological targets; Skeletal muscle

DOI:  https://doi.org/10.1016/j.biopha.2022.113833
Physiol Rep. 2022 Oct;10(20): e15476

Elevated muscle mass accompanied by transcriptional and nuclear alterations several months following cessation of resistance-type training in rats.

Erik P Rader, Brent A Baker.

  Rodent studies investigating long-term effects following termination of hypertrophy-inducing loading have predominantly involved exposures such as synergist ablation and weighted wheel running or ladder climbing. This research yielded a spectrum of results regarding the extent of detraining in terms of muscle mass and myonuclei number. The studies were also limited in their lack of sensitive performance measures and indirect relatedness to resistance training. Our research group developed and validated a relevant rat model of resistance-type training that induces increased muscle mass and performance. The aim of the present study was to determine to what extent these features persist 3 months following the termination of this training. While performance returned to baseline, muscle mass remained elevated by 17% and a shift in distribution to larger muscle fibers persisted. A 16% greater total RNA and heightened mRNA levels of ribosomal protein S6 kinases implicated preserved transcriptional output and ribosomal content. Remodeling of muscle fiber nuclei was consistent with these findings - increased nuclear number and a distribution shift to a more circular nuclear shape. These findings indicate that muscle mass detrains at a slower rate than performance and implicates multiple forms of myonuclear remodeling in muscle memory.

Keywords:  dorsiflexor muscles; dynamometer; skeletal muscle; stretch-shortening contractions

DOI:  https://doi.org/10.14814/phy2.15476
J Int Soc Sports Nutr. 2022 ;19(1): 603-622

The exercise metabolome: acute aerobic and anaerobic signatures.

Joseph K Pellegrino, Tracy G Anthony, Peter Gillies, Shawn M Arent.

   Background: Exercise modality differentially alters body composition and physical performance. Metabolic changes underlying these outcomes can be tracked through assessment of circulating metabolites. Here, global responses to an acute bout of aerobic or anaerobic exercise were compared in the serum of male and female subjects using a discovery-based metabolomics platform.
Methods: On separate days, 40 healthy, active participants completed 45 min of aerobic cycling or resistance exercise, and blood samples were collected at rest, immediately after (T1) and 1 hour post-exercise (T2) to examine the serum metabolomic landscape.
Results: The two exercise metabolomes appeared more similar than different in this healthy cohort. Overall, metabolomic signatures of both exercise modalities were markedly altered from rest at T1, and returned toward baseline by T2. Metabolomic perturbations at T1 and the T1-T2 rate of recovery post-exercise were greater following aerobic cycling than resistance exercise. Shared signatures included elevations in purine metabolism, substrate catabolism and mobilization, and inflammatory signaling. Aerobic exercise resulted in greater substrate diversity and use of fatty acids, whereas resistance exercise displayed higher purine turnover and glycolytic flux.
Discussion: Individual metabolite differences between conditions were seen in magnitude but not direction. Metabolomic signatures of the exercise responses appeared fairly robust across exercise modalities. An initial perturbation and subsequent shift toward recovery by an hour post-exercise defined the signature in our healthy cohort. The expedited recovery following aerobic cycling may be explained by globally elevated lipid metabolism.

Keywords:  Aerobic; Anaerobic; Metabolomics; exercise

DOI:  https://doi.org/10.1080/15502783.2022.2115858
Diabetologia. 2022 Oct 18.

Ketones: the double-edged sword of SGLT2 inhibitors?

Beatrice C Lupsa, Richard G Kibbey, Silvio E Inzucchi.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications used by individuals with type 2 diabetes that reduce hyperglycaemia by targeting glucose transport in the kidney, preventing its reabsorption, thereby inducing glucosuria. Besides improving HbA1c and reducing body weight and blood pressure, the SGLT2 inhibitors have also been demonstrated to improve cardiovascular and kidney outcomes, an effect largely independent of their effect on blood glucose levels. Indeed, the mechanisms underlying these benefits remain elusive. Treatment with SGLT2 inhibitors has been found to modestly increase systemic ketone levels. Ketone bodies are an ancillary fuel source substituting for glucose in some tissues and may also possess intrinsic anti-oxidative and anti-inflammatory effects. Some have proposed that ketones may in fact mediate the cardio-renal benefits of this drug category. However, a rare complication of SGLT2 inhibition is ketoacidosis, sometimes with normal or near-normal blood glucose concentrations, albeit occurring more frequently in patients with type 1 diabetes who are treated (predominately off-label) with one of these agents. We herein explore the notion that an underpinning of one of the more serious adverse effects of SGLT2 inhibitors may, in fact, explain, at least in part, some of their benefits-a potential 'double-edged sword' of this novel drug category.

Keywords:  Cardiovascular; Diabetes; Ketoacidosis; Ketones; Renal; Review; SGLT2 inhibitor

DOI:  https://doi.org/10.1007/s00125-022-05815-1
Annu Rev Physiol. 2022 Oct 20.

Myostatin: A Skeletal Muscle Chalone.

Se-Jin Lee.

Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-β family member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears to have all of the salient properties of a chalone, which is a term proposed over a half century ago to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it also operates in other tissues. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-physiol-012422-112116
Sci Transl Med. 2022 Oct 19. 14(667): eadd5297

Sex, lean body mass, and cardiac performance.

Ambarish Pandey, Kershaw V Patel.

Lower lean body mass associated with reduced cardiovascular reserve at rest and peak exercise in women but not men may underlie sex differences in heart failure with preserved ejection fraction (Diaz-Canestro et al.).

DOI: https://doi.org/10.1126/scitranslmed.add5297
Sports Med. 2022 Oct 20.

Pax7+ Satellite Cells in Human Skeletal Muscle After Exercise: A Systematic Review and Meta-analysis.

Luthfia Dewi, Yin-Chou Lin, Andrew Nicholls, Giancarlo Condello, Chih-Yang Huang, Chia-Hua Kuo.

BACKGROUND: Skeletal muscle has extraordinary regenerative capabilities against challenge, mainly owing to its resident muscle stem cells, commonly identified by Pax7+, which expediently donate nuclei to the regenerating multinucleated myofibers. This local reserve of stem cells in damaged muscle tissues is replenished by undifferentiated bone marrow stem cells (CD34+) permeating into the surrounding vascular system.
OBJECTIVE: The purpose of the study was to provide a quantitative estimate for the changes in Pax7+ muscle stem cells (satellite cells) in humans following an acute bout of exercise until 96 h, in temporal relation to circulating CD34+ bone marrow stem cells. A subgroup analysis of age was also performed.
METHODS: Four databases (Web of Science, PubMed, Scopus, and BASE) were used for the literature search until February 2022. Pax7+ cells in human skeletal muscle were the primary outcome. Circulating CD34+ cells were the secondary outcome. The standardized mean difference (SMD) was calculated using a random-effects meta-analysis. Subgroup analyses were conducted to examine the influence of age, training status, type of exercise, and follow-up time after exercise.
RESULTS: The final search identified 20 studies for Pax7+ cells comprising a total of 370 participants between the average age of 21 and 74 years and 26 studies for circulating CD34+ bone marrow stem cells comprising 494 participants between the average age of 21 and 67 years. Only one study assessed Pax7+ cells immediately after aerobic exercise and showed a 32% reduction in exercising muscle followed by a fast repletion to pre-exercise level within 3 h. A large effect on increasing Pax7+ cell content in skeletal muscles was observed 24 h after resistance exercise (SMD = 0.89, p < 0.001). Pax7+ cells increased to ~ 50% above pre-exercise level 24-72 h after resistance exercise. For a subgroup analysis of age, a large effect (SMD = 0.81, p < 0.001) was observed on increasing Pax7+ cells in exercised muscle among adults aged > 50 years, whereas adults at younger age presented a medium effect (SMD = 0.64, p < 0.001). Both resistance exercise and aerobic exercise showed a medium overall effect in increasing circulating CD34+ cells (SMD = 0.53, p < 0.001), which declined quickly to the pre-exercise baseline level after exercise within 6 h.
CONCLUSIONS: An immediate depletion of Pax7+ cells in exercising skeletal muscle concurrent with a transient release of CD34+ cells suggest a replenishment of the local stem cell reserve from bone marrow. A protracted Pax7+ cell expansion in the muscle can be observed during 24-72 h after resistance exercise. This result provides a scientific basis for exercise recommendations on weekly cycles allowing for adequate recovery time. Exercise-induced Pax7+ cell expansion in muscle remains significant at higher age, despite a lower stem cell reserve after age 50 years. More studies are required to confirm whether Pax7+ cell increment can occur after aerobic exercise.
CLINICAL TRIAL REGISTRATION: Registered at the International Prospective Register of Systematic Reviews (PROSPERO) [identification code CRD42021265457].

DOI: https://doi.org/10.1007/s40279-022-01767-z
Methods Mol Biol. 2023 ;2589 269-291

Assessment of Mitochondrial Dysfunctions After Sirtuin Inhibition.

Christian Marx, Lisa Marx-Blümel, Jürgen Sonnemann, Zhao-Qi Wang.

  Posttranslational modifications are important for protein functions and cellular signaling pathways. The acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs), with the latter being grouped into four phylogenetic classes. The class III of the HDAC family, the sirtuins (SIRTs), contributes to gene expression, genomic stability, cell metabolism, and tumorigenesis. Thus, several specific SIRT inhibitors (SIRTi) have been developed to target cancer cell proliferation. Here we provide an overview of methods to study SIRT-dependent cell metabolism and mitochondrial functionality. The chapter describes metabolic flux analysis using Seahorse analyzers, methods for normalization of Seahorse data, flow cytometry and fluorescence microscopy to determine the mitochondrial membrane potential, mitochondrial content per cell and mitochondrial network structures, and Western blot analysis to measure mitochondrial proteins.

Keywords:  Flow cytometry; Metabolism; Mitochondria; SIRT; Seahorse analysis; Sirtuin inhibition; Western blot

DOI:  https://doi.org/10.1007/978-1-0716-2788-4_18
Front Physiol. 2022 ;13 998362

Reduced intestinal butyrate availability is associated with the vascular remodeling in resistance arteries of hypertensive rats.

Patrizia Dardi, Rosangela Aparecida Dos Santos-Eichler, Sarah de Oliveira, Marco Aurélio Ramirez Vinolo, Niels Olsen Saraiva Câmara, Luciana Venturini Rossoni.

  During hypertension an unbalance of short-chain fatty acids (SCFAs) production by intestinal bacteria is described. However, no data evaluate the association of SCFAs and vascular remodeling in hypertension, which is an important hallmark of this disease. Thus, the present study aims to evaluate the correlations between SCFAs availability and the resistance arteries remodeling in hypertension, as well as to identify the possible pathway by which the SCFAs could exert a structural and mechanical influence. Hence, male spontaneously hypertensive rats (SHR) and normotensive Wistar rats had blood pressure measured by tail-cuff plethysmography; fecal SCFAs content assessed by gas chromatography; gene expression of SCFAs-transporters in gut epithelium and SCFAs-sensing receptors on mesenteric resistance arteries (MRA) quantified by PCR; and MRA structural and mechanical parameters analyzed by pressure myograph. Reduced butyrate fecal content was found in SHR, with no changes in propionate and acetate, as well as decreased mRNA levels of SCFAs-transporters (MCT1, MCT4, and SMCT1) in the intestinal epithelium. In addition, lower gene expression of SCFAs-sensing receptors (GPR41, GPR43, and GPR109a, but not Olfr78) was identified in MRAs of SHR, which also shows inward eutrophic remodeling with stiffness. Butyrate content presented a negative correlation with systolic blood pressure and with the structural alterations found on MRAs, while a positive correlation between butyrate content and mechanical parameters was detected. Altogether the present study suggests that lower butyrate content due to ineffective SCFA bioavailability, associated with lower SCFAs-sensing receptors expression, could favor MRA remodeling, increasing peripheral vascular resistance and worsening hypertension prognosis.

Keywords:  SCFAs-sensing receptors; butyrate; hypertension; resistance arteries; short-chain fatty acids; vascular remodeling

DOI:  https://doi.org/10.3389/fphys.2022.998362
Diab Vasc Dis Res. 2022 Sep-Oct;19(5):19(5): 14791641221130043

Real life evaluation of sodium-glucose cotransporter 2 inhibition in type 1 diabetes and the risk of diabetic ketoacidosis.

Elisabeth B Stougaard, Peter L Kristensen, Urd Kielgast, Henrik U Andersen, Yasmin Hamid, Peter H Gæde, Esben Søndergaard, Gry H Dørflinger, Karen K Fjeldborg, Klavs W Hansen, Henrik H Thomsen, Thuraya M J Al-Imar, Michael Røder, Vikas S Sridhar, David Cherney, Peter Rossing, Frederik Persson.

   BACKGROUND: The indication for treatment of type 1 diabetes(T1D) with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin has been withdrawn in Europe likely because of concern for diabetic ketoacidosis (DKA). We calculated the incidence of DKA in people with T1D treated with SGLT2i in Denmark.
METHODS: Clinical data from adults with T1D in Denmark were collected from nine outpatient clinics. Electronic health records made the search for DKA accurate.
RESULTS: From a population of 10.500 we observed 134 people treated with SGLT2i over a total period of 222 patient-years. Of those 72% were female, mean age (SD) was 51.4 (13.6) years and median duration of treatment (median, IQR) with an SGLT2i were 12.0 (6.0-29.0) months. The incidence of DKA was zero%.
CONCLUSION: In 134 people with T1D treated with SGLT2i we found that none of the participants developed DKA during the treatment.

Keywords:  Type 1 diabetes; diabetic ketoacidosis; sglt2 inhibitors

DOI:  https://doi.org/10.1177/14791641221130043
Front Immunol. 2022 ;13 918551

Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages.

Gisela Jimenez-Duran, Joseph Kozole, Rachel Peltier-Heap, Eleanor R Dickinson, Christopher R Kwiatkowski, Francesca Zappacosta, Roland S Annan, Nicholas W Galwey, Eva-Maria Nichols, Louise K Modis, Martha Triantafilou, Kathy Triantafilou, Lee M Booty.

  The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane attack complex (MAC) is not clear. In this study we focused on determining whether MAC is an immunometabolic regulator of the innate immune response in human monocyte-derived macrophages. Here, we uncover previously uncharacterized metabolic changes and mitochondrial dysfunction occurring downstream of MAC deposition. These alterations in glycolytic flux and mitochondrial morphology and function mediate NLRP3 inflammasome activation, pro-inflammatory cytokine release and gasdermin D formation. Together, these data elucidate a novel signalling cascade, with metabolic alterations at its center, in MAC-stimulated human macrophages that drives an inflammatory consequence in an immunologically relevant cell type.

Keywords:  NLRP3 inflammasome; complement; immunometabolism; macrophage; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3389/fimmu.2022.918551
Biochem (Lond). 2022 Aug;44(4): 2-8

Beyond ATP, new roles of mitochondria.

Ram Prosad Chakrabarty, Navdeep S Chandel.

Mitochondria, special double-membraned intracellular compartments or 'organelles', are popularly known as the 'powerhouses of the cell', as they generate the bulk of ATP used to fuel cellular biochemical reactions. Mitochondria are also well known for generating metabolites for the synthesis of macromolecules (e.g., carbohydrates, proteins, lipids and nucleic acids). In the mid-1990s, new evidence suggesting that mitochondria, beyond their canonical roles in bioenergetics and biosynthesis, can act as signalling organelles began to emerge, bringing a dramatic shift in our view of mitochondria's roles in controlling cell function. Over the next two and half decades, works from multiple groups have demonstrated how mitochondrial signalling can dictate diverse physiological and pathophysiological outcomes. In this article, we will briefly discuss different mechanisms by which mitochondria can communicate with cytosol and other organelles to regulate cell fate and function and exert paracrine effects. Our molecular understanding of mitochondrial communication with the rest of the cell, i.e. mitochondrial signalling, could reveal new therapeutic strategies to improve health and ameliorate diseases.

DOI: https://doi.org/10.1042/bio_2022_119
Sci Signal. 2022 Oct 18. 15(756): eadf2995

Taking mitochondria to heart.

Wei Wong.

Long-chain fatty acids redirect the uptake of mitochondria released from adipocytes from macrophages to the heart.

DOI: https://doi.org/10.1126/scisignal.adf2995
Aging Med (Milton). 2022 Sep;5(3): 211-231

We are all aging, and here's why.

Atharva Shinde, Gargi Deore, Kedar P Navsariwala, Heena Tabassum, Minal Wani.

Here, through this review, we aim to serve this purpose by first discussing the statistics and aging demographics, including the life expectancy of the world and India, along with the gender life expectancy gap observed throughout the world, followed by explaining the hallmarks and integral causes of aging, along with the role played by senescent cells in controlling inflammation and the effect of senescence associated secretory phenotype on longevity. A few of the molecular pathways which are crucial in modulating the process of aging, such as the nutrient-sensing mTOR pathway, insulin signaling, Nrf2, FOXO, PI3-Akt, Sirtuins, and AMPK, and their effects are also covered in paramount detail. A diverse number of ingenious research methodologies are used in the modern era of longevity exploration. We have attempted to cover these methods under the umbrella of three broad categories: in vitro, in vivo, and in silico techniques. The drugs developed to attenuate the aging process, such as rapamycin, metformin, resveratrol, etc. and their interactions with the above-mentioned molecular pathways along with their toxicity have also been reviewed in detail.

DOI: https://doi.org/10.1002/agm2.12223
Int J Environ Health Res. 2022 Oct 20. 1-16

The ROS/NF-κB/HK2 axis is involved in the arsenic-induced Warburg effect in human L-02 hepatocytes.

Fanshuo Yin, Ying Zhang, Xin Zhang, Meichen Zhang, Zaihong Zhang, Yunyi Yin, Haili Xu, Yanmei Yang, Yanhui Gao.

  Arsenic has been identified as a carcinogen, although the molecular mechanism underlying itscarcinogenesis has not been fully elucidated. To date, only a few studies have attempted to confirm a direct link between oxidative stress and the Warburg effect . This study demonstrated that 0.2 μmol/L As3+ induced the Warburg effect to contribute to abnormal proliferation of L-02 cells, that was mediated by upregulation of hexokinase 2 (HK2), a key enzyme in glycolysis. Further study indicated that arsenic-induced accumulation of reactive oxygen species (ROS) activated the nuclear factor kappa B (NF-κB) signaling pathway by phosphorylation of p65 at the Ser536 and Ser276 sites, leading to upregulated expression of HK2. We therefore concluded that the ROS/NF-κB/HK2 axis contributes to the Warburg effect and cell proliferation induced by low doses of arsenic.AbbreviationsROS, Reactive oxygen species; NAC, N-acetyl-L-cysteine; 2-DG, 2-deoxy-D-glucose; 2-NBDG, 2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose.

Keywords:  Arsenic; Warburg effect; cell proliferation; hexokinase 2; nuclear factor kappa B; reactive oxygen species

DOI:  https://doi.org/10.1080/09603123.2022.2134559
FASEB J. 2022 Nov;36(11): e22602

Disturbing NLRP3 acetylation and inflammasome assembly inhibits androgen receptor-promoted inflammatory responses and prostate cancer progression.

An-Ning Zhao, Zhan Yang, Dan-Dan Wang, Bei Shi, Hong Zhang, Yang Bai, Bo-Wen Yan, Yong Zhang, Jin-Kun Wen, Xiao-Lu Wang, Chang-Bao Qu.

  Chronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa tumorigenesis and inflammatory response. However, little is known about the AR-regulated NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high-grade PCa and observed that NLRP3 inflammasome-associated genes were upregulated in high-grade PCa compared with that in low-grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR-3-a circRNA derived from the AR gene-which is involved in the AR-regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR-3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR-3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression.

Keywords:  KAT2B; NLRP3; acetylation; androgen receptor; inflammasome; prostate cancer

DOI:  https://doi.org/10.1096/fj.202200673RRR
J Cell Biochem. 2022 Oct 19.

Endocannabinoids effect on oxidative status of human platelets.

Maria Grazia Signorello, Silvia Ravera, Giuliana Leoncini.

  Reactive oxygen species (ROS) are known to regulate platelet activation. Since endocannabinoids behave as platelet agonists, we investigated the effect of two endocannabinoids, 2-arachidonoylglycerol (2AG) and anandamide (AEA) on the oxidative status of human platelets. We have demonstrated that 2AG and AEA stimulate ROS production, superoxide anion formation and lipid peroxidation. The effect is dose and time dependent and mainly occurs through the involvement of cannabinoid receptor 1 (CB1) since all tested parameters are greatly reduced by SR141716, the CB1 specific inhibitor. The specific inhibitor of cannabinoid receptor 2 (CB2) SR144528 produces a very small inhibition. The involvement of syk/PI3K/AKT/mTor pathway in oxidative stress induced by endocannabinoids is shown. Nicotinamide adenine dinucleotide phosphate oxidase seems to be poorly involved in the endocannabinoids effect. Concerning the aerobic metabolism, it has been demonstrated that endocannabinoids reduce the oxygen consumption and adenosine triphosphate synthesis, both in the presence of pyruvate + malate or succinate. In addition, endocannabinoids inhibit the activity of respiratory complexes II, III and IV and increase the activity of respiratory complex I. The endocannabinoids effect on aerobic metabolism seems to be also a CB1 mediated mechanism. Thus, in human platelets oxidative stress induced by endocannabinoids, mainly generated in the respiratory chain through the activation of complex I and the inhibition of complex II, III and IV, may lead to thrombotic events, contributing to cardiovascular diseases.

Keywords:  2-arachidonoylglycerol; aerobic metabolism; anandamide; endocannabinoids; human platelets; oxidative stress

DOI:  https://doi.org/10.1002/jcb.30341