bims-kimdis 2022-10-09 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2022–10–09
27 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats.
Ketogenic diet may be a new approach to treatment stress urinary incontinence in obese elderly women: report of five cases.
Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.
Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy.
New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure.
Effects of different modes of exercise on skeletal muscle mass and function and IGF-1 signaling during early aging in mice.
Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications.
SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.
Modified Atkins diet versus ketogenic diet in children with drug-resistant epilepsy: A meta-analysis of comparative studies.
Aerobic exercise alleviates pyroptosis-related diseases by regulating NLRP3 inflammasome.
Medium-chain triglycerides and conjugated linolenic acids in functional yogurts: impact of GIT and potential biological activities.
Hydroxycarboxylic acid receptor 2 (HCA2) agonists induce NET formation and MMP-9 release from bovine polymorphonuclear leukocytes.
All About Oxygen: Using Near-Infrared Spectroscopy To Understand Bioenergetics.
The effect of intermittent fasting diets on body weight and composition.
NLRP3 inflammasome: The rising star in cardiovascular diseases.
Mitochondria-Targeted Antioxidant Mitoquinone Maintains Mitochondrial Homeostasis through the Sirt3-Dependent Pathway to Mitigate Oxidative Damage Caused by Renal Ischemia/Reperfusion.
Muscle atrophy in CKD: A historical perspective of advancements in its understanding.
The key to managing HFpEF? Fun, exercise, diet & sun.
Nutritional entrainment of circadian rhythms under alignment and misalignment: A mechanistic review.
Defining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction.
Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans.
Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice.
Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.
NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis.
Effect Of Exercise on Muscle Mass, Fat Mass, Bone Mass, Muscular Strength and Physical Performance in Community Dwelling Older Adults: Systematic Review and Meta-Analysis.
The Mitochondrial Unfolded Protein Response: A Novel Protective Pathway Targeting Cardiomyocytes.
Low-fat dairy consumption improves intestinal immune function more than high-fat dairy in a diet-induced swine model of insulin resistance.

J Nutr Biochem. 2022 Sep 29. pii: S0955-2863(22)00229-7. [Epub ahead of print] 109161

Ketogenic diet modulates cardiac metabolic dysregulation in streptozocin-induced diabetic rats.

Nguyen Ngoc Trang, Ting-Wei Lee, Yu-Hsun Kao, Tze-Fan Chao, Ting-I Lee, Yi-Jen Chen.

  The ketogenic diet (KD) might improve cardiac function in diabetic cardiomyopathy, but the mechanisms remain unclear. This study investigated the effects of KD on myocardial fatty acid (FA), glucose, and ketone metabolism in diabetic cardiomyopathy. Echocardiograms, biochemistry, and micro-positron emission tomography (micro-PET) were performed to evaluate cardiac function and glucose uptake in control rats and streptozotocin-induced DM rats with normal diet (ND) or KD for 6 weeks. Histopathology, ATP measurement, and Western blot were performed in the ventricular myocytes to analyze fibrosis, FA, ketone body, and glucose utilization. The ND-fed DM rats exhibited impaired left ventricular systolic function and increased chamber dilatation, whereas control and KD-fed DM rats did not. The KD reduced myocardial fibrosis and apoptosis in the DM rats. Myocardial glucose uptake in the micro-PET was similar between ND-fed DM rats and KD-fed DM rats and was substantially lower than the control rats. Compared with the control rats, ND-fed DM rats had increased phosphorylation of acetyl CoA carboxylase and higher expressions of CD-36, carnitine palmitoyltransferase-1β, tumor necrosis factor-α, interleukin (IL)-1β, IL6, PERK, and e-IF2α as well as more myocardial fibrosis and apoptosis (assessed by Bcl-2, BAX, and caspase-3 expression); these increases were attenuated in the KD-fed DM rats. Moreover, ND-fed DM rats had significantly lower myocardial ATP, BHB, and OXCT1 levels than the control and KD-fed DM rats. The KD may improve the condition of diabetic cardiomyopathy by suppressing FA metabolism, increasing ketone utilization, and decreasing endoplasmic reticulum stress and inflammation.

Keywords:  diabetes mellitus; diabetic cardiomyopathy; fatty acid metabolism; inflammation; ketogenic diet

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109161
BMC Womens Health. 2022 Oct 04. 22(1): 402

Ketogenic diet may be a new approach to treatment stress urinary incontinence in obese elderly women: report of five cases.

Yu Sun, Haixia Chen, Yueran Bai, Tingyue Zhang, Wenpei Bai, Bo Jiang.

   BACKGROUND: Stress urinary incontinence (SUI) as a serious social problem restricted women's daily life and affect their quality of life, especially for obese women. The mechanism of stress urinary incontinence is unclear. Weight loss is the first line of treatment for stress incontinence in obese women. Ketogenic diet is a special diet with high fat, low carbohydrate and moderate protein, which can reduce body mass faster than the traditional diet. There exist no reports on the therapeutic effect of ketogenic diet on SUI in obese women.
CASE PRESENTATION: Five postmenopausal obese women are diagnosed as mild to moderate stress urinary incontinence, which affected their quality of life for medical treatment. After 4 weeks ketogenic diet, we found that ketogenic diet can significantly improve urine leakage, reduce body weight, decrease visceral fat area, reduce body fat percentage, and reduce BMI.
CONCLUSION: Reports in this case reveal that ketogenic diet may become one of the effective methods for the treatment of stress urinary incontinence in obese women in the future, providing a minimally invasive, highly profitable and highly compliant treatment for stress urinary incontinence in obese women.

Keywords:  Ketogenic diet; Obese; Stress urinary incontinence; Urine leakage

DOI:  https://doi.org/10.1186/s12905-022-01987-5
Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00464-8. [Epub ahead of print]51 1-6

Effect of caffeine on mitochondrial biogenesis in the skeletal muscle - A narrative review.

André K Yamada, Gustavo D Pimentel, Craig Pickering, André V Cordeiro, Vagner R R Silva.

  Caffeine is one of the most widely used substances as recreational drug for performance-enhancement in sport, underpinned by a strong evidence base. Although the effects of caffeine are widely investigated within the scope of performance physiology, the molecular effects of caffeine within skeletal muscle remain unclear. Evidence from in vitro and in vivo models suggest that caffeine regulates the glucose metabolism in the skeletal muscle. Moreover, caffeine seems to stimulate CaMKII, PPARδ/β, AMPK and PGC1α, classical markers of exercise-adaptations, including mitochondrial biogenesis and mitochondrial content. This review summarizes evidence to suggest caffeine-effects within skeletal muscle fibers, focusing on the putative role of caffeine on mitochondrial biogenesis to explore whether caffeine supplementation might be a strategy to enhance mitochondrial biogenesis.

Keywords:  Caffeine; Exercise; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1016/j.clnesp.2022.09.001
Neuropsychiatr Dis Treat. 2022 ;18 2181-2198

Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy.

Qi Qiao, Zhenzhen Qu, Shuang Tian, Huifang Cao, Yange Zhang, Can Sun, Lijing Jia, Weiping Wang.

   Background: The ketogenic diet (KD) is a proven therapy for refractory epilepsy. Although the anti-seizure properties of this diet are understood to a certain extent, the exploration of its neuroprotective effects and underlying mechanisms is still in its infancy. Tissue acidosis is a common feature of epileptogenic foci. Interestingly, the activation of acid-sensing ion channel 1a (ASIC1a), which mediates Ca2+-dependent neuronal injury during acidosis, has been found to be inhibited by ketone bodies in vitro. This prompted us to investigate whether the neuroprotective effects induced by the KD occur via ASIC1a and interconnected downstream mechanisms in a rat model of temporal lobe epilepsy.
Methods: Male Sprague-Dawley rats were fed either the KD or a normal diet for four weeks after undergoing pilocarpine-induced status epilepticus (SE). The effects of KD on epileptogenesis, cognitive impairment and hippocampal neuron injury in the epileptic rats were subsequently evaluated by video electroencephalogram, Morris water maze test and Nissl staining, respectively. The expression of ASIC1a and cleaved caspase-3 in the hippocampus were determined using Western blot analysis during the chronic period following SE. Moreover, the intracellular Ca2+ concentration, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mROS) and cell apoptosis of hippocampal cells were detected by flow cytometry.
Results: We found that the KD treatment strongly attenuated the spontaneous recurrent seizures, ameliorated learning and memory impairments and prevented hippocampal neuronal injury and apoptosis. The KD was also shown to inhibit the upregulation of ASIC1a and the ensuing intracellular Ca2+ overload in the hippocampus of the epileptic rats. Furthermore, the seizure-induced structure disruption of neuronal mitochondria, loss of MMP and accumulation of mROS were reversed by the KD treatment, suggesting that it has protective effects on mitochondria. Finally, the activation of caspase-3 was also inhibited by the KD.
Conclusion: These findings indicate that the KD suppresses mitochondria-mediated apoptosis possibly by regulating ASIC1a to exert neuroprotective effects. This may provide a mechanistic explanation of the therapeutic effects of KD.

Keywords:  acid-sensing ion channel 1a; ketogenic diet; mitochondrial pathway; neuroprotection; temporal lobe epilepsy

DOI:  https://doi.org/10.2147/NDT.S376979
Front Cardiovasc Med. 2022 ;9 903902

New insights and advances of sodium-glucose cotransporter 2 inhibitors in heart failure.

Juexing Li, Lei Zhou, Hui Gong.

  Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are newly emerging insulin-independent anti-hyperglycemic agents that work independently of β-cells. Quite a few large-scale clinical trials have proven the cardiovascular protective function of SGLT2is in both diabetic and non-diabetic patients. By searching all relevant terms related to our topics over the previous 3 years, including all the names of agents and their brands in PubMed, here we review the mechanisms underlying the improvement of heart failure. We also discuss the interaction of various mechanisms proposed by diverse works of literature, including corresponding and opposing viewpoints to support each subtopic. The regulation of diuresis, sodium excretion, weight loss, better blood pressure control, stimulation of hematocrit and erythropoietin, metabolism remodeling, protection from structural dysregulation, and other potential mechanisms of SGLT2i contributing to heart failure improvement have all been discussed in this manuscript. Although some remain debatable or even contradictory, those newly emerging agents hold great promise for the future in cardiology-related therapies, and more research needs to be conducted to confirm their functionality, particularly in metabolism, Na+-H+ exchange protein, and myeloid angiogenic cells.

Keywords:  diabetes; heart failure; mechanisms; metabolism; sodium-glucose cotransporter 2 inhibitors (SGLT2is)

DOI:  https://doi.org/10.3389/fcvm.2022.903902
J Exp Biol. 2022 Oct 07. pii: jeb.244650. [Epub ahead of print]

Effects of different modes of exercise on skeletal muscle mass and function and IGF-1 signaling during early aging in mice.

Bowen Li, Lili Feng, Xiaonan Wu, Mengxin Cai, JaneJie Yu, Zhenjun Tian.

  Skeletal muscle mass and function tend to decline with increasing age. Insulin-like growth factor 1 (IGF-1) plays a key role in promoting skeletal muscle growth. Exercise improves skeletal muscle mass and function via activating the IGF-1 signaling. The aim of this study was to investigate whether different types of exercise could promote muscle hypertrophy, exercise and metabolic capacities, and activate IGF-1 signaling in early aging mice. 12-month-old male C57/BL6 mice were randomly divided into five groups: control group (CON), aerobic exercise group (AE), resistance exercise group (RE), whole-body vibration group (WBV) and electrical stimulation group (ES). Muscle weight, myofiber size, levels of IGF-1 signaling, oxidative stress, protein synthesis and degradation, and apoptosis in gastrocnemius muscle were detected. C2C12 cells were used to explore the mechanism. In this study, we confirmed that four modes of exercise increased skeletal muscle mass, exercise capacity, indicators of metabolism and protein synthesis, and inhibited oxidative stress and apoptosis via activating the IGF-1 pathway. The most effective intervention was RE. We found that WBV promoted muscle hypertrophy better than AE. Furthermore, in vitro experiment, the importance of IGF-1 / IGF-1R-PI3K / Akt signaling for maintaining skeletal muscle mass was further confirmed. AE, RE, WBV and ES increase skeletal muscle mass, exercise capacities, protein synthesis and metabolic enzyme activities, inhibit protein degradation and apoptosis in mice undergoing early aging via activating IGF-1 signaling. Among them, WBV has been shown to be significantly effective and has a similar effect of conventional exercise in promoting muscle hypertrophy.

Keywords:  Early aging; Exercise; Insulin-like growth factor-1; Skeletal muscle

DOI:  https://doi.org/10.1242/jeb.244650
Evid Based Complement Alternat Med. 2022 ;2022 5277673

Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications.

Junling Gu, Kang Geng, Man Guo, Wei Huang, Tingting Zhao, Xuling Li, You-Hua Xu, Yong Xu.

Pyroptosis is an inflammatory form of programmed cell death that is dependent on inflammatory caspases, leading to the cleavage of gasdermin D (GSDMD) and increased secretion of interleukin (IL)-1β and IL-18. Recent studies have reported that hyperglycemia-induced cellular stress stimulates pyroptosis, and different signaling pathways have been shown to play crucial roles in regulating pyroptosis. This review summarized and discussed the molecular mechanisms, regulation, and cellular effects of pyroptosis in diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. In addition, this review aimed to provide new insights into identifying better treatments for diabetic microvascular complications.

DOI: https://doi.org/10.1155/2022/5277673
Aging Cell. 2022 Oct 05. e13721

SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction.

Rashpal S Dhillon, Yiming Amy Qin, Paul R van Ginkel, Vivian X Fu, James M Vann, Alexis J Lawton, Cara L Green, Fúlvia B Manchado-Gobatto, Claudio A Gobatto, Dudley W Lamming, Tomas A Prolla, John M Denu.

  Mitochondrial NAD+ -dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)-dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR-mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/- ) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/- CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Keywords:  aerobic fitness; calorie restriction; fatty acid oxidation; fuel switching; lifespan; mitochondrial acetylation; mitochondrial respiration; sirtuins

DOI:  https://doi.org/10.1111/acel.13721
Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00467-3. [Epub ahead of print]51 112-119

Modified Atkins diet versus ketogenic diet in children with drug-resistant epilepsy: A meta-analysis of comparative studies.

Asmaa Mhanna, Mohammed Mhanna, Azizullah Beran, Mustafa Al-Chalabi, Nameer Aladamat, Naeem Mahfooz.

   INTRODUCTION: The modified Atkins diet (MAD), a less restrictive form of the ketogenic diet (KD), has gained popularity and is proposed to be an alternative to the traditional KD in the management of drug-resistant epilepsy (DRE). However, the evidence to support this hypothesis remains limited. In this meta-analysis, we aimed to evaluate the efficacy and tolerability of MAD compared to traditional KD in children with DRE.
METHOD: We systematically searched multiple databases through March 2022 for all the studies that evaluated the clinical utility of MAD versus KD for DRE in a pediatric population. The primary outcome was the proportion of children who had seizure frequency reduction (SFR) > 50%. The secondary outcomes were SFR >90%, seizure freedom, and diet-related side effects. All measurements were taken 6 months after starting the regimens. Pooled risk ratio (RR) and corresponding 95% confidence intervals (CIs) were calculated and combined using random-effects model meta-analysis.
RESULTS: Six studies, with 397 patients with DRE (201 followed MAD vs. 196 with KD), were included. There was a significant difference in the proportion of patients who attained SFR >50% favoring the traditional KD (RR: 0.63; 95% CI: 0.47-0.83; P = 0.001). However, there was no significant differences in SFR >90% (RR: 0.73; 95% CI: 0.49-1.10; P = 0.13) or the proportion of patients who had seizure freedom (RR: 0.83; 95% CI: 0.49-1.41; P = 0.49). Furthermore, both regimens had comparable safety profiles (RR: 1.00; 95% CI: 0.95-1.05; P = 0.96).
CONCLUSIONS: Our meta-analysis demonstrated the superiority of traditional KD over MAD in achieving SFR > 50% at 6 months in pediatric patients with DRE. However, SFR > 90% and seizure freedom were comparable between KD and MAD at 6 months. The tolerability profile between the two regimens was similar as well. Large-scale RCTs are necessary to validate our findings.

Keywords:  Drug resistant epilepsy; Efficacy; Ketogenic diet; Modified atkins diet; Refractory epilepsy

DOI:  https://doi.org/10.1016/j.clnesp.2022.09.004
Front Physiol. 2022 ;13 965366

Aerobic exercise alleviates pyroptosis-related diseases by regulating NLRP3 inflammasome.

Shujuan Hu, Xingxia Wan, Xianhui Li, Xianwang Wang.

  Pyroptosis plays a crucial role in a variety of human diseases, including atherosclerosis, obesity, diabetes, depression, and Alzheimer's disease, which usually release pyroptosis-related cytokines due to inflammation. Many studies have demonstrated that aerobic exercise is a good option for decreasing the release of pyroptosis-related cytokines. However, the molecular mechanisms of aerobic exercise on pyroptosis-related diseases remain unknown. In this review, the effects of aerobic exercise on pyroptosis in endothelial cells, adipocytes and hippocampal cells, and their potential mechanisms are summarized. In endothelial cells, aerobic exercise could inhibit NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis by improving the endothelial function, while reducing vascular inflammation and oxidative stress. In adipocytes, aerobic exercise has been shown to inhibit pyroptosis by ameliorating inflammation and insulin resistance. Moreover, aerobic exercise could restrict pyroptosis by attenuating microglial activation, neuroinflammation, and amyloid-beta deposition in hippocampal cells. In summary, aerobic exercise alleviates the pyroptosis-related diseases by regulating the NLRP3 inflammation si0067naling.

Keywords:  NLRP3 inflammasome; aerobic exercise; mechanisms; pyroptosis; pyroptosis-related diseases

DOI:  https://doi.org/10.3389/fphys.2022.965366
Food Funct. 2022 Oct 07.

Medium-chain triglycerides and conjugated linolenic acids in functional yogurts: impact of GIT and potential biological activities.

Manuela Machado, Sérgio Sousa, Pilar Morais, Arménio Miranda, Luís M Rodriguez-Alcalá, Ana Maria Gomes, Manuela Pintado.

In recent years, bioactive lipids particularly medium-chain triglycerides and conjugated linolenic fatty acids have obtained more attention due to their possible applicability in obesity metabolism modulation. These compounds are capable to increase thermogenesis and reduce weight gain through the modulation of key neurohormones such as leptin and adiponectin. The purpose of this work was to develop functional yogurts through the addition of coconut (rich in medium-chain fatty acids) or pomegranate oils (rich in conjugated linolenic acids). The presence of these oils led to a significant alteration in the nutritional value of yogurts, showing a capacity to reduce the accumulation of lipids in hepatocytes and increase the release of triglycerides in adipocytes. These results demonstrate that functional yogurts can be a valuable strategy for obesity prevention.

DOI: https://doi.org/10.1039/d2fo01723g
Dev Comp Immunol. 2022 Sep 29. pii: S0145-305X(22)00224-5. [Epub ahead of print]139 104562

Hydroxycarboxylic acid receptor 2 (HCA2) agonists induce NET formation and MMP-9 release from bovine polymorphonuclear leukocytes.

Daniella Carretta, Paz Creutzburg, Katherine Borquez, John Quiroga, Pablo Alarcón, Andrés Rivera, Rafael Burgos.

  Periparturient cows are commonly fed diets supplemented with Niacin (nicotinic acid, NA) because of its anti-lipolytic properties. NA confers its anti-lipolytic effects by activating the hydroxycarboxylic acid 2 receptor (HCA2). HCA2 is also activated by the ketone body beta-hydroxybutyrate (BHB) and circulating BHB levels are elevated in postpartum dairy cows. The HCA2 receptor is highly expressed in bovine polymorphonuclear leukocytes (PMN) and could link metabolic and innate immune responses in cattle. We investigated how HCA2 agonists affected bovine PMN function in vitro. We studied different PMN responses, such as granule release, surface expression of CD11b and CD47, generation of neutrophil extracellular traps (NETs), and apoptosis. NA, BHB, and 4,4aR,5,5aR-tetrahydro-1H-cyclopropa [4,5] cyclopenta [1,2-c] pyrazole-3-carboxylic acid (MK-1903) treatment triggered the release of matrix metalloproteinase 9 (MMP-9), a component of the tertiary granule, from neutrophils. Additionally, all HCA2 agonists induced NETs formation but did not affect surface expression of CD11b and CD47. Finally, none of the HCA2 agonists triggered apoptosis in bovine PMN. This information will give new insights into the potential role of the HCA2 receptor in the bovine innate immune response.

Keywords:  Beta-hydroxybutyrate; GPR109A; HCA2; Neutrophil extracellular traps; Nicotinic acid

DOI:  https://doi.org/10.1016/j.dci.2022.104562
Adv Physiol Educ. 2022 Oct 06.

All About Oxygen: Using Near-Infrared Spectroscopy To Understand Bioenergetics.

Carrie Ellis, Douglas Burns.

  The interchange among the energy-providing phosphagen, glycolytic and aerobic systems during exercise is often poorly understood by beginning students in exercise physiology. Exercise is oftentimes thought of as being aerobic or anaerobic, with the body progressing sequentially from on system to the next, though the energy systems work synergistically to produce energy from the onset of exercise, and all ultimately use oxygen. Traditional methods of teaching these concepts using only indirect calorimetry and a metabolic cart can be misleading. Using relatively inexpensive non-invasive monitors of muscle oxygenation levels (SmO2) provides a useful tool to help students better understand the contribution and timing of these three systems of ATP generation and convey the concept that ultimately all energy production in the human body is oxygen-dependent. In this laboratory, students use near-infrared spectroscopy (NIRS) visualize oxygen utilization by skeletal muscle during exercise by devising their own three exercise protocols, with each designed to stress a different energy system. Students then perform their protocols, while using NIRS to measure and analyze SmO2. Students generate graphs using collected data, allowing them to visualize and appreciate oxygen consumption during all three protocols, as well as elevated oxygen consumption after exercise, showing that any exercise is really all about oxygen.

Keywords:  Bioenergetics; Near-infrared spectroscopy; Oxygen utilization; Skeletal muscle

DOI:  https://doi.org/10.1152/advan.00106.2022
Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00457-0. [Epub ahead of print]51 207-214

The effect of intermittent fasting diets on body weight and composition.

Nihal Zekiye Erdem, Emre Bayraktaroğlu, Rüken Aslınur Samancı, Eftal Geçgil-Demir, Nadide Gizem Tarakçı, Fatma Mert-Biberoğlu.

   BACKGROUND & AIMS: This study was carried out to determine and compare the effects on anthropometric measurements of the Mediterranean Diet (MD) with daily energy restriction and four different intermittent fasting diets (IFD), which were created as an alternative to MD and gained popularity.
METHODS: 360 people aged 18-65 years, with body mass index (BMI) between 27 and 35 kg/m2 participated to the study. Demographic information, anthropometric measurements, physical activity and food consumption records were obtained by the researcher through weekly face-to-face interviews. The study lasted for 13 weeks, the first of which was a trial. Statistical significance level was accepted as 0.05. Participants were randomly assigned to 5 equal groups: Mediterranean Diet (MD), Week on Week off (WOWO), 6-Hour Time-Restricted Eating (TRE-6), 8-Hour Time-Restricted Eating (TRE-8), Alternative Day Diet (ADD). Of the 360 people who participated in the study, 32 (2 TRE-6, 7 WOWO, 1 MD, 16 ADD, 6 TRE-8) dropped out after the trial week.
RESULTS: It was determined that throughout the study, body weights, BMI, arm circumferences and waist circumferences in all groups decreased significantly. However, trends in changes in body weights and BMIs did not differ between groups. While the energy, carbohydrate, protein and fat intakes of the participants did not change significantly during the study, fiber consumption increased considerably in the MD and WOWO groups.
CONCLUSIONS: It was observed that IFD were not superior to MD in terms of anthropometric measurements. The health effects and long-term consequences are not clear for IFD, unlike MD. For these reasons, it is thought that the most effective nutritional therapy that can be preferred for healthy weight loss is the energy-restricted MD model.

Keywords:  Alternate day diet; Intermittent fasting diet; Weight loss

DOI:  https://doi.org/10.1016/j.clnesp.2022.08.030
Front Cardiovasc Med. 2022 ;9 927061

NLRP3 inflammasome: The rising star in cardiovascular diseases.

Yidan Zheng, Li Xu, Nianguo Dong, Fei Li.

  Cardiovascular diseases (CVDs) are the prevalent cause of mortality around the world. Activation of inflammasome contributes to the pathological progression of cardiovascular diseases, including atherosclerosis, abdominal aortic aneurysm, myocardial infarction, dilated cardiomyopathy, diabetic cardiomyopathy, heart failure, and calcific aortic valve disease. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune response, requiring priming and activation signals to provoke the inflammation. Evidence shows that NLRP3 inflammasome not only boosts the cleavage and release of IL-1 family cytokines, but also leads to a distinct cell programmed death: pyroptosis. The significance of NLRP3 inflammasome in the CVDs-related inflammation has been extensively explored. In this review, we summarized current understandings of the function of NLRP3 inflammasome in CVDs and discussed possible therapeutic options targeting the NLRP3 inflammasome.

Keywords:  NLRP3 inflammasome; cardiovascular diseases; inflammation; interleukins; pyroptosis

DOI:  https://doi.org/10.3389/fcvm.2022.927061
Oxid Med Cell Longev. 2022 ;2022 2213503

Mitochondria-Targeted Antioxidant Mitoquinone Maintains Mitochondrial Homeostasis through the Sirt3-Dependent Pathway to Mitigate Oxidative Damage Caused by Renal Ischemia/Reperfusion.

Hu Mao, Ye Zhang, Yufeng Xiong, Zijing Zhu, Lei Wang, Xiuheng Liu.

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.

DOI: https://doi.org/10.1155/2022/2213503
J Ren Nutr. 2022 Sep 29. pii: S1051-2276(22)00170-4. [Epub ahead of print]

Muscle atrophy in CKD: A historical perspective of advancements in its understanding.

S Russ Price, William E Mitch, Giacomo Garibotto.

   OBJECTIVE: This perspective reviews the seminal clinical and experimental observations that led to today's current mechanistic model of muscle protein loss (wasting) in patients with chronic kidney disease (CKD).
RESULTS AND CONCLUSION: Early International Society of Renal Nutrition and Metabolism (ISRNM) meetings facilitated discussions and hypotheses about the causes of muscle wasting in CKD. It became widely recognized that wasting is common and correlated with increased risks of mortality and morbidity. Although anorexia and dietary restrictions contribute to muscle loss, several features of CKD-associated wasting cannot be explained by malnutrition alone. The protein catabolism-inducing actions of metabolic acidosis, inflammation, insulin resistance, endocrine disorders and uremic toxins were progressively identified. Continued research to understand the interactions of inflammation, anabolic resistance, mitochondrial dysfunction, exercise, and nutrition on muscle protein turnover in patients with CKD will hopefully accelerate discoveries and treatments to ameliorate muscle wasting as well as the progression of CKD.

Keywords:  Chronic kidney disease; muscle atrophy; protein-energy wasting; sarcopenia

DOI:  https://doi.org/10.1053/j.jrn.2022.09.009
Eur J Cardiovasc Nurs. 2022 Sep 22. pii: zvac088. [Epub ahead of print]

The key to managing HFpEF? Fun, exercise, diet & sun.

John Sharpley, Ann Sharpley.

DOI: https://doi.org/10.1093/eurjcn/zvac088
Clin Nutr ESPEN. 2022 Oct;pii: S2405-4577(22)00303-5. [Epub ahead of print]51 50-71

Nutritional entrainment of circadian rhythms under alignment and misalignment: A mechanistic review.

Lydia Chambers, Karin Seidler, Michelle Barrow.

   BACKGROUND AND AIMS: The rising prevalence of obesity is a major international concern and is associated with a substantial burden of disease. Disrupted circadian behaviours, including late and extended eating patterns, are identified as risk factors for obesity. The circadian rhythm synchronises metabolic functions between and within tissues, optimising physiology to integrate with environmental and behavioural cycles. Cellular circadian rhythms also separate poorly compatible processes and enable adaptive integration of energy metabolism with autophagy. The timing of nutritional input is a key and easily controllable variable that influences circadian function. Misalignment of nutritional input with the centrally generated circadian rhythm may dampen and disrupt circadian metabolic function. This review seeks to provide a mechanistic overview of nutritional circadian entrainment and its downstream metabolic effects. The aims are: to characterise the key cellular and physiological mechanisms involved in the nutritional entrainment of circadian rhythms; and to explore the perturbation of these pathways by misaligned nutritional inputs, with relevance to obesity-associated dysmetabolism.
METHODS: A systematic two-tranche search strategy was employed. Searches were conducted within PubMed between March and December 2020. Included studies were formally evaluated for quality. Evidence was extracted and coded into key themes.
RESULTS: 142 records were screened and 50 accepted. The evidence analysed was moderate-to-high quality and enabled the detailed characterisation of cellular pathways involved in nutritional circadian entrainment. Results indicated that diverse nutritional input pathways converge upon key nutrient/redox sensors and nutritionally sensitive core clock genes, which integrate with circadian metabolic pathways, allowing bidirectional communication between circadian clock function and metabolism. Versus alignment, nutritional misalignment was causally associated with dampening and alteration of core clock rhythms, between-tissue rhythmic decoupling, dysmetabolism, and obesity. Signalling through key circadian nodes, such as NAD+/SIRT, was indicated to have importance in these metabolic changes. Misaligned nutritional inputs were associated with altered core circadian temporal dynamics of metabolism and autophagy, and different time division between insulin-sensitive and insulin-resistant metabolic states. Time-restricted feeding protocols aligned with the natural circadian rhythm (light-dark cycle) relatively strengthened circadian oscillatory patterns and protected against diet-induced obesity.
CONCLUSIONS: This review suggests potential value in further investigating circadian-normalising nutritional interventions for obesity, such as circadian-aligned time-restricted feeding.

Keywords:  Chrononutrition; Circadian rhythm; Clock genes; Metabolism; Nutrient sensors; Time-restricted feeding

DOI:  https://doi.org/10.1016/j.clnesp.2022.06.010
Circ Heart Fail. 2022 Oct 06. 101161CIRCHEARTFAILURE122010003

Defining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction.

Wesley J Tucker, Dalane W Kitzman.



Keywords:  Editorials; cardiorespiratory fitness; exercise training; heart failure, preserved ejection fraction; high-intensity interval training; mitochondria; muscular atrophy

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.122.010003
Elife. 2022 Oct 07. pii: e80638. [Epub ahead of print]11

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans.

Yasuyuki Tamai, Akiko Eguchi, Ryuta Shigefuku, Hiroshi Kitamura, Mina Tempaku, Ryosuke Sugimoto, Yoshinao Kobayashi, Motoh Iwasa, Yoshiyuki Takei, Hayato Nakagawa.

   Background: Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate; however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-chain amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition.
Methods: The correlation between serum BA levels and psoas muscle mass index (PMI) was examined in 73 CLD patients. Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy.
Results: In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist.
Conclusions: Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival.
Funding: This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115. Maintaining cirrhotic rats were partially supported by Otsuka Pharmaceutical Company.

Keywords:  bile acids; cell biology; chronic liver diseases; human; lithocholic acid; liver-muscle axis; low muscle mass; medicine; rat; skeletal muscle

DOI:  https://doi.org/10.7554/eLife.80638
Nat Commun. 2022 Oct 05. 13(1): 5655

Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice.

Takayoshi Sasako, Toshihiro Umehara, Kotaro Soeda, Kazuma Kaneko, Miho Suzuki, Naoki Kobayashi, Yukiko Okazaki, Miwa Tamura-Nakano, Tomoki Chiba, Domenico Accili, C Ronald Kahn, Tetsuo Noda, Hiroshi Asahara, Toshimasa Yamauchi, Takashi Kadowaki, Kohjiro Ueki.

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.

DOI: https://doi.org/10.1038/s41467-022-33008-2
Mol Cell. 2022 Oct 06. pii: S1097-2765(22)00895-4. [Epub ahead of print]82(19): 3661-3676.e8

Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex.

Chen-Wei Tsai, Madison X Rodriguez, Anna M Van Keuren, Charles B Phillips, Hannah M Shushunov, Jessica E Lee, Anastacia M Garcia, Amrut V Ambardekar, Joseph C Cleveland, Julie A Reisz, Catherine Proenza, Kathryn C Chatfield, Ming-Feng Tsai.

  Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca2+ uptake properties to support their unique physiological functions.

Keywords:  calcium channels; cardiac pathophysiology; cellular metabolism; intracellular calcium signaling; membrane-transport mechanisms; mitochondrial physiology; mitochondrial proteases; organellar channels; protein complexes

DOI:  https://doi.org/10.1016/j.molcel.2022.09.006
EMBO Rep. 2022 Oct 04. e54446

NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis.

Benedikt Kaufmann, Aleksandra Leszczynska, Agustina Reca, Laela M Booshehri, Janset Onyuru, ZheHao Tan, Alexander Wree, Helmut Friess, Daniel Hartmann, Bettina Papouchado, Lori Broderick, Hal M Hoffman, Ben A Croker, Yanfang Peipei Zhu, Ariel E Feldstein.

  Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil-specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro-inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro-fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation-driven fibrosis.

Keywords:  NLR Family Pyrin Domain Containing 3; fibrosis; liver inflammation; macrophage; neutrophil

DOI:  https://doi.org/10.15252/embr.202154446
Aging Dis. 2022 Oct 01. 13(5): 1421-1435

Effect Of Exercise on Muscle Mass, Fat Mass, Bone Mass, Muscular Strength and Physical Performance in Community Dwelling Older Adults: Systematic Review and Meta-Analysis.

Alejandra González-Rocha, Lucia Mendez-Sanchez, María Araceli Ortíz-Rodríguez, Edgar Denova-Gutiérrez.

  The demographic transition makes it necessary to establish new recommendations about the components that are most affected by aging, such as: muscle mass, fat mass, bone mass, muscle strength, and physical performance. Exercise has been identified as a factor that improves those conditions. The aim of this review is to synthetize and analyze the results of exercise interventions on muscle mass, fat mass, bone mass, strength and physical performance in community dwelling older adults (OA). A systematic search was carried out in eleven databases, using validated terms as "aged", "exercise" and others. For the meta-analysis, we differentiated by type of exercise and outcome. Twenty-nine randomized clinical trials were obtained for the review and 24 clinical trials for meta-analysis. This study identified an increase of 1.0 kg (95% Confidence Interval [CI] 0.3 -1.7) in total muscle mass (TMM) and 0.4 kg (95%CI 0.0,0.7) in appendicular muscle mass (AMM); a decrease of -3.7 kg (95% CI -5.8, -1.5) in total fat mass and -3.7% (95%CI -5.8, -1.5) in fat percentage after the resistance exercise intervention by 2-3 times per week. A -3.0% (95%CI -4.6, -1.3) decrease was observed in fat percentage after the aerobic exercise intervention. The quality of the evidence was ranked from high to very low; the risk of bias most common was performance bias and other bias. This study suggests that resistance exercise is the intervention that shows a positive effect on muscle fat mass, and bone mass. More research is needed for other exercise interventions.

Keywords:  Meta-analysis; fat mass; muscle mass; muscular strength; older adults; physical performance

DOI:  https://doi.org/10.14336/AD.2022.0215
Oxid Med Cell Longev. 2022 ;2022 6430342

The Mitochondrial Unfolded Protein Response: A Novel Protective Pathway Targeting Cardiomyocytes.

Jinfeng Liu, Xinyong He, Sicheng Zheng, Aisong Zhu, Junyan Wang.

Mitochondrial protein homeostasis in cardiomyocyte injury determines not only the normal operation of mitochondrial function but also the fate of mitochondria in cardiomyocytes. Studies of mitochondrial protein homeostasis have become an integral part of cardiovascular disease research. Modulation of the mitochondrial unfolded protein response (UPRmt), a protective factor for cardiomyocyte mitochondria, may in the future become an important treatment strategy for myocardial protection in cardiovascular disease. However, because of insufficient understanding of the UPRmt and inadequate elucidation of relevant mechanisms, few therapeutic drugs targeting the UPRmt have been developed. The UPRmt maintains a series of chaperone proteins and proteases and is activated when misfolded proteins accumulate in the mitochondria. Mitochondrial injury leads to metabolic dysfunction in cardiomyocytes. This paper reviews the relationship of the UPRmt and mitochondrial quality monitoring with cardiomyocyte protection. This review mainly introduces the regulatory mechanisms of the UPRmt elucidated in recent years and the relationship between the UPRmt and mitophagy, mitochondrial fusion/fission, mitochondrial biosynthesis, and mitochondrial energy metabolism homeostasis in order to generate new ideas for the study of the mitochondrial protein homeostasis mechanisms as well as to provide a reference for the targeted drug treatment of imbalances in mitochondrial protein homeostasis following cardiomyocyte injury.

DOI: https://doi.org/10.1155/2022/6430342
Eur J Nutr. 2022 Oct 05.

Low-fat dairy consumption improves intestinal immune function more than high-fat dairy in a diet-induced swine model of insulin resistance.

Yongbo She, Kun Wang, Alexander Makarowski, Rabban Mangat, Sue Tsai, Benjamin P Willing, Spencer D Proctor, Caroline Richard.

   PURPOSE: To understand the effects of consuming high-fat and low-fat dairy products on postprandial cardiometabolic risk factors and intestinal immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance.
METHODS: LBW piglets were randomized to consume one of the 3 experimental high fat diets and were fed for a total of 7 weeks: (1) Control high fat (LBW-CHF), (2) CHF diet supplemented with 3 servings of high-fat dairy (LBW-HFDairy) and (3) CHF diet supplemented with 3 servings of low-fat dairy (LBW-LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). At 11 weeks of age, all piglets underwent an established modified oral glucose and fat tolerance test. At 12 weeks of age, piglets were euthanized and ex vivo cytokine production by cells isolated from mesenteric lymph node (MLN) stimulated with mitogens was assessed.
RESULTS: Dairy consumption did not modulate postprandial plasma lipid, inflammatory markers and glucose concentrations. A lower production of IL-2 and TNF-α after pokeweed mitogen (PWM) stimulation was observed in LBW-CHF vs NBW-Chow (P < 0.05), suggesting impaired MLN T cell function. While feeding high-fat dairy had minimal effects, feeding low-fat dairy significantly improved the production of IL-2 and TNF-α after PWM stimulation (P < 0.05).
CONCLUSIONS: Irrespective of fat content, dairy had a neutral effect on postprandial cardiometabolic risk factors. Low-fat dairy products improved intestinal T cell function to a greater extent than high-fat dairy in this swine model of obesity and insulin resistance.

Keywords:  Dairy; Insulin resistance; Intestinal immune function; Obesity; Postprandial; Swine model

DOI:  https://doi.org/10.1007/s00394-022-03013-8