bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒03‒12
28 papers selected by
Matías Javier Monsalves Álvarez



  1. Front Endocrinol (Lausanne). 2023 ;14 1124576
      Aims: The ketogenic pathway is an effective mechanism by which the liver disposes of fatty acids (FAs) to the peripheral tissues. Impaired ketogenesis is presumed to be related to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), but the results of previous studies have been controversial. Therefore, we investigated the association between ketogenic capacity and MAFLD in subjects with type 2 diabetes (T2D).Methods: A total of 435 subjects with newly diagnosed T2D was recruited for the study. They were classified into two groups based on median serum β-hydroxybutyrate (β-HB) level: intact vs. impaired ketogenesis groups. The associations of baseline serum β-HB and MAFLD indices of hepatic steatosis index, NAFLD liver fat score (NLFS), Framingham Steatosis index (FSI), Zhejian University index, and Chinese NAFLD score were investigated.
    Results: Compared to the impaired ketogenesis group, the intact ketogenesis group showed better insulin sensitivity, lower serum triglyceride level, and higher low-density lipoprotein-cholesterol and glycated hemoglobin levels. Serum levels of liver enzymes were not different between the two groups. Of the hepatic steatosis indices, NLFS (0.8 vs. 0.9, p=0.045) and FSI (39.4 vs. 47.0: p=0.041) were significantly lower in the intact ketogenesis group. Moreover, intact ketogenesis was significantly associated with lower risk of MAFLD as calculated by FSI after adjusting for potential confounders (adjusted odds ratio 0.48, 95% confidence interval 0.25-0.91, p=0.025).
    Conclusions: Our study suggests that intact ketogenesis might be associated with decreased risk of MAFLD in T2D.
    Keywords:  MAFLD; diabetes; ketogenesis; steatosis; β-hydroxybutyrate
    DOI:  https://doi.org/10.3389/fendo.2023.1124576
  2. Nutrients. 2023 Feb 23. pii: 1119. [Epub ahead of print]15(5):
      The classic ketogenic diet (KD) is a high-fat, low-carbohydrate diet that mimics a starvation state with sufficient caloric intake to sustain growth and development. KD is an established treatment for several diseases, and it is currently evaluated in the management of insulin-resistant states, although insulin secretion after a classic ketogenic meal has never been investigated. We measured the insulin secretion to a ketogenic meal in 12 healthy subjects (50% females, age range 19-31 years, BMI range 19.7-24.7 kg/m2) after cross-over administrations of a Mediterranean meal and a ketogenic meal both satisfying ~40% of an individual's total energy requirement, in random order and separated by a 7-day washout period. Venous blood was sampled at baseline and at 10, 20, 30, 45, 60, 90, 120, and 180 min to measure glucose, insulin, and C-peptide concentrations. Insulin secretion was calculated from C-peptide deconvolution and normalized to the estimated body surface area. Glucose, insulin concentrations, and insulin secretory rate were markedly reduced after the ketogenic meal with respect to the Mediterranean meal: glucose AUC in the first OGTT hour -643 mg × dL-1 × min-1, 95% CI -1134, -152, p = 0.015; total insulin concentration -44,943 pmol/L, 95% CI -59,181, -3706, p < 0.001; peak rate of insulin secretion -535 pmol × min-1 × m-2, 95% CI -763, -308, p < 0.001. We have shown that a ketogenic meal is disposed of with only a minimal insulin secretory response compared to a Mediterranean meal. This finding may be of interest to patients with insulin resistance and or insulin secretory defects.
    Keywords:  Mediterranean diet; insulin secretion; ketogenic diet
    DOI:  https://doi.org/10.3390/nu15051119
  3. J Nutr. 2023 Mar 07. pii: S0022-3166(23)35281-7. [Epub ahead of print]
      BACKGROUND: Increasing β-hydroxybutyrate (βHB) availability through ketone monoester plus carbohydrate supplementation is suggested to enhance physical performance by sparing glucose use during exercise. However, no studies have examined the effect of ketone supplementation on glucose kinetics during exercise.OBJECTIVE: This exploratory study primarily aimed to determine the effect of ketone monoester plus carbohydrate (KE + CHO) supplementation on glucose oxidation and physical performance and during steady-state exercise compared with carbohydrate (CHO).
    METHODS: Using a randomized, crossover design (ClinicalTrials.gov, NCT04737694), twelve men consumed KE+CHO (573 mg KE/kg body mass, 110 g glucose) or CHO (110 g glucose) before and during 90 minutes of steady-state treadmill exercise (54±3% V̇O2peak) wearing a weighted vest (30% body mass; 25±3 kg). Glucose oxidation and turnover were determined using indirect calorimetry and stable isotopes. Participants performed an unweighted time to exhaustion (TTE; 85% V̇O2peak) after steady-state exercise, and a weighted (25±3 kg) 6.4 km time trial (TT) the next day after consuming a bolus of KE+CHO or CHO. Data were analyzed by paired t-tests and mixed model ANOVA.
    RESULTS: βHB concentrations were higher (P<0.05) after exercise [2.1 mM(95% CI: 1.6, .6)] and the TT [2.6 mM(2.1, 3.1)] in KE+CHO compared with CHO. TTE was lower [-104 s(-201,-8)] and TT performance was slower [141 s(19,262)] in KE+CHO than CHO (P<0.05). Exogenous [-0.01 g/min (-0.07, 0.04)] and plasma [-0.02 g/min(-0.08,0.04)] glucose oxidation and metabolic clearance rate (MCR [0.38 mg·kg-1·min-1(-0.79,1.54)]) were not different, and glucose rate of appearance [-0.51 mg·kg-1·min-1(-0.97,-0.04)] and disappearance [-0.50 mg·kg-1·min-1(-0.96,-0.04)] were lower (P<0.05) in KE+CHO compared with CHO during steady-state exercise.
    CONCLUSION: Rates of exogenous and plasma glucose oxidation and MCR were not different between treatments during steady-state exercise in the current study suggesting blood glucose utilization is similar between KE+CHO and CHO. KE+CHO supplementation also results in lower physical performance compared with CHO.
    Keywords:  exogenous ketones; glucose oxidation; ketosis; time to exhaustion; time trial; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.tjnut.2023.03.002
  4. Nutrients. 2023 Feb 24. pii: 1148. [Epub ahead of print]15(5):
      MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the perceived potential benefits. However, consumption of carbohydrates with MCTs and untoward gastrointestinal side effects, especially at higher doses, could decrease the sustainability of the ketogenic response. This single-center study investigated the impact of consuming carbohydrate as glucose with MCT oil compared to MCT alone on the BHB response. The effects of MCT oil versus MCT oil plus glucose on blood glucose, insulin response, levels of C8, C10, BHB, and cognitive function were determined, and side effects were monitored. A significant plasma BHB increase with a peak at 60 min was observed in 19 healthy participants (24.4 ± 3.9 years) after consuming MCT oil alone, and a more delayed but slightly higher peak was observed after consuming MCT oil plus glucose. A significant increase in blood glucose and insulin levels occurred only after MCT oil plus glucose intake. The overall mean plasma levels of C8 and C10 were higher with the intake of MCT oil alone. MCT oil plus glucose consumption showed improved scores for the arithmetic and vocabulary subtests.
    Keywords:  beta-hydroxybutyrate; cognitive function; decanoic acid; glucose; insulin; ketogenic diet; medium-chain fatty acids; octanoic acid
    DOI:  https://doi.org/10.3390/nu15051148
  5. Med Sci Sports Exerc. 2023 Feb 24.
      PURPOSE: A ketone body (β-hydroxybutyrate [β-HB]) is used as an energy source in the peripheral tissues. However, the effects of acute β-HB supplementation on different modalities of exercise performance remain unclear. This study aimed to assess the effects of acute β-HB administration on the exercise performance of rats.METHODS: In Study 1, Sprague Dawley rats were randomly divided into six groups: endurance exercise (EE + PL and EE + KE), resistance exercise (RE + PL and RE + KE), and high-intensity intermittent exercise (HIIE+PL and HIIE+KE) with placebo (PL) or β-HB salt (KE) administration. In Study 2, metabolome analysis using capillary electrophoresis mass spectrometry was performed to profile the effects of β-HB salt administration on HIIE-induced metabolic responses in the skeletal and heart muscles.
    RESULTS: The maximal carrying capacity (rest for 3 min after each ladder climb, while carrying heavy weights until the rats could not climb) in the RE + KE group was higher than that in the RE + PL group. The maximum number of HIIE sessions (a 20-s swimming session with a 10-s rest between sessions, while bearing a weight equivalent to 16% of body weight) in the HIIE+KE group was higher than that in the HIIE+PL group. However, there was no significant difference in the time to exhaustion at 30 m/min between the EE + PL and EE + KE groups. Metabolome analysis showed that the overall tricarboxylic acid cycle and creatine phosphate levels in the skeletal muscle were higher in the HIIE+KE group than in the HIIE+PL group.
    CONCLUSIONS: These results indicate that acute β-HB salt administration may accelerate HIIE and RE performance, and the changes in metabolic responses in the skeletal muscle following β-HB salt administration may be involved in the enhancement of HIIE performance.
    DOI:  https://doi.org/10.1249/MSS.0000000000003151
  6. Inflamm Res. 2023 Mar 11.
      BACKGROUND: As an organelle essential for intracellular energy supply, mitochondria are involved in intracellular metabolism and inflammation, and cell death. The interaction of mitochondria with the NLRP3 inflammasome in the development of lung diseases has been extensively studied. However, the exact mechanism by which mitochondria mediate the activation of the NLRP3 inflammasome and trigger lung disease is still unclear.METHODS: The literatures related to mitochondrial stress, NLRP3 inflammasome and lung diseases were searched in PubMed.
    RESULTS: This review aims to provide new insights into the recently discovered mitochondrial regulation of the NLRP3 inflammasome in lung diseases. It also describes the crucial roles of mitochondrial autophagy, long noncoding RNA, micro RNA, altered mitochondrial membrane potential, cell membrane receptors, and ion channels in mitochondrial stress and regulation of the NLRP3 inflammasome, in addition to the reduction of mitochondrial stress by nuclear factor erythroid 2-related factor 2 (Nrf2). The effective components of potential drugs for the treatment of lung diseases under this mechanism are also summarized.
    CONCLUSION: This review provides a resource for the discovery of new therapeutic mechanisms and suggests ideas for the development of new therapeutic drugs, thus promoting the rapid treatment of lung diseases.
    Keywords:  Lung diseases; Mitochondria; NLRP3 inflammasome; Oxidative stress; Potential drugs
    DOI:  https://doi.org/10.1007/s00011-023-01712-4
  7. Cells. 2023 Feb 24. pii: 716. [Epub ahead of print]12(5):
      Mitochondria are cellular organelles that play an essential role in generating the chemical energy needed for the biochemical reactions in cells. Mitochondrial biogenesis, i.e., de novo mitochondria formation, results in enhanced cellular respiration, metabolic processes, and ATP generation, while autophagic clearance of mitochondria (mitophagy) is required to remove damaged or useless mitochondria. The balance between the opposing processes of mitochondrial biogenesis and mitophagy is highly regulated and crucial for the maintenance of the number and function of mitochondria as well as for the cellular homeostasis and adaptations to metabolic demands and extracellular stimuli. In skeletal muscle, mitochondria are essential for maintaining energy homeostasis, and the mitochondrial network exhibits complex behaviors and undergoes dynamic remodeling in response to various conditions and pathologies characterized by changes in muscle cell structure and metabolism, such as exercise, muscle damage, and myopathies. In particular, the involvement of mitochondrial remodeling in mediating skeletal muscle regeneration following damage has received increased attention, as modifications in mitophagy-related signals arise from exercise, while variations in mitochondrial restructuring pathways can lead to partial regeneration and impaired muscle function. Muscle regeneration (through myogenesis) following exercise-induced damage is characterized by a highly regulated, rapid turnover of poor-functioning mitochondria, permitting the synthesis of better-functioning mitochondria to occur. Nevertheless, essential aspects of mitochondrial remodeling during muscle regeneration remain poorly understood and warrant further characterization. In this review, we focus on the critical role of mitophagy for proper muscle cell regeneration following damage, highlighting the molecular mechanisms of the mitophagy-associated mitochondrial dynamics and network reformation.
    Keywords:  exercise; mitochondrial biogenesis; mitochondrial network; mitophagy; muscle damage; myogenesis; regeneration
    DOI:  https://doi.org/10.3390/cells12050716
  8. J Nutr. 2023 Feb;pii: S0022-3166(22)18276-3. [Epub ahead of print]153(2): 459-469
      BACKGROUND: Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared.OBJECTIVES: To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000-2500 kcal/d) and with varying carbohydrate quality or quantity.
    METHODS: We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on "acellular" carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), "cellular" carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at clinicaltrials.gov as NCT03401970.
    RESULTS: Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%-7%) and visceral fat volume (12%-17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: -16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: -39.6 pg/mL; 95% CI: -76, -3.3]). No significant between-group differences were seen in feelings of hunger.
    CONCLUSIONS: Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3-0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss.
    Keywords:  appetite; dietary carbohydrates; ghrelin; ketosis; obesity; randomized controlled trial
    DOI:  https://doi.org/10.1016/j.tjnut.2022.12.030
  9. J Appl Physiol (1985). 2023 Mar 09.
      There is some evidence that the age-associated change in skeletal muscle mass is muscle specific, yet the number of specific muscles that have been studied to form our understanding in this area is limited. In addition, few aging investigations have examined multiple muscles in the same individuals. This longitudinal investigation compared changes in skeletal muscle size via computed tomography of the quadriceps (rectus femoris, vastus lateralis, vastus medialis, vastus intermedius), hamstrings (biceps femoris short and long heads, semitendinosus, semimembranosus), psoas, rectus abdominis, lateral abdominals (obliques and transversus abdominis), and paraspinal muscles (erector spinae and multifidi) of older individuals from the Health ABC study at baseline and 5.0±0.1 years later (n=469, 73±3yr & 78±3yr, 49% women, 33% black). Skeletal muscle size decreased (p<0.05) in quadriceps (-3.3%), hamstrings (-5.9%), psoas (-0.4%), and rectus abdominis (-7.0%). The hamstrings and rectus abdominis atrophied approximately twice as much as the quadriceps (p<0.05), while the quadriceps atrophied substantially more than the psoas (p<0.05). The lateral abdominals (+5.9%) and paraspinals (+4.3%) hypertrophied (p<0.05) to a similar degree (p>0.05) over the 5 years. These data suggest that older individuals experience skeletal muscle atrophy and hypertrophy in a muscle group-specific fashion in the eighth decade, a critical time period in the aging process. A broader understanding of muscle group-specific skeletal muscle aging is needed to better guide exercise programs and other interventions that mitigate decrements in physical function with aging.
    Keywords:  Muscle mass; aging; computed tomography; sarcopenia
    DOI:  https://doi.org/10.1152/japplphysiol.00769.2022
  10. Arch Biochem Biophys. 2023 Mar 05. pii: S0003-9861(23)00057-7. [Epub ahead of print]738 109558
      Ultraviolet B (UVB) irradiation causes skin inflammation and apoptosis. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in skin damages, little is known about the roles of mitochondrial dynamics in these processes. UVB irradiation increases abnormal mitochondrial content but decreases mitochondrial volume in immortalized human keratinocyte HaCaT cells. UVB irradiation resulted in marked upregulation of mitochondrial fission protein dynamin-related protein 1 (DRP1) and downregulation of mitochondrial outer membrane fusion proteins 1 and 2 (MFN1 and MFN2) in HaCaT cells. Mitochondrial dynamics was discovered to be crucial for NLRP3 inflammasome and cGAS-STING pathway activation, as well as the induction of apoptosis. Inhibition of mitochondrial fission by treatments with a DRP1 inhibitor, mdivi-1, or with DRP1-targeted siRNA, efficiently prevented UVB-induced NLRP3/cGAS-STING mediated pro-inflammatory pathways or apoptosis in the HaCaT cells, whereas inhibition of mitochondrial fusion with MFN1and 2 siRNA increased these pro-inflammatory pathways or apoptosis. The enhanced mitochondrial fission and reduced fusion caused the up-regulation of reactive oxygen species (ROS). Application of an antioxidant, N-acetyl-l-cysteine (NAC), which scavenges excessive ROS, attenuated inflammatory responses through suppressing NLRP3 inflammasome and cGAS-STING pathway activation, and rescued cells from apoptosis caused by UVB-irradiation. Together, our findings revealed the regulation of NLRP3/cGAS-STING inflammatory pathways and apoptosis by mitochondrial fission/fusion dynamics in UVB-irradiated HaCaT cells, providing a new strategy for the therapy of UVB skin injury.
    Keywords:  Apoptosis; DRP1; Inflammation; MFN1 and MFN2; Mitochondrial fission; ROS; UVB
    DOI:  https://doi.org/10.1016/j.abb.2023.109558
  11. Inflammation. 2023 Mar 10.
      NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a cytoplasmic multiprotein complex composed of the innate immune receptor protein NLRP3, the adapter protein apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC), and the inflammatory protease cysteine-1. Pathogen-associated molecular patterns (PAMPs) or other endogenous danger-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome. As part of the innate immune response, activated NLRP3 promotes GSDMD-dependent pyroptosis, and IL-1β and IL-18 are released during inflammation. Aberrantly activated NLRP3 is deeply involved in various inflammatory diseases. Due to its interaction with adaptive immunity. NLRP3 inflammation has increasingly received attention in autoimmune diseases. Rheumatoid arthritis (RA) is a classic autoimmune disease, which mainly causes bone and cartilage damage. Elevated levels of NLRP3 can be detected in the synovium of RA patients. NLRP3 overactivation is strongly associated with RA activity. Mouse models of spontaneous arthritis has shown that NLRP3/IL-1β axis is implicated in periarticular inflammation in RA. In this review, we describe the current understanding of NLRP3 activation in RA pathogenesis and dissect its impact on innate and adaptive immunity. We also discuss the potential application of specific inhibitors of NLRP3 to provide new therapeutic strategies for treating RA.
    Keywords:  IL-1β; NLRP3; inflammasome; rheumatoid arthritis
    DOI:  https://doi.org/10.1007/s10753-023-01795-5
  12. Prog Cardiovasc Dis. 2023 Mar 03. pii: S0033-0620(23)00007-5. [Epub ahead of print]
      Despite the emergence of stronger nutritional science over the past two decades, fad diets remain highly popular. However, growing medical evidence has led to the endorsement of healthy eating patterns by medical societies. This thus allows fad diets to be compared to the emerging scientific evidence as to which diets promote or damage health. In this narrative review, the most popular current fad diets are critically analyzed, including low-fat diets, vegan and vegetarian diets, low-carbohydrate diets, ketogenic diets, Paleolithic diets, and intermittent fasting. Each of these diets has some scientific merit, but each has potential deficiencies relative to the findings of nutritional science. This article also presents the common themes that emerge among the dietary guidance of leading health organizations, such as the American Heart Association and the American College of Lifestyle Medicine. While there are important distinctions between dietary recommendations emanating from various medical societies, each recommends eating more unrefined, plant-based foods, while eating fewer highly processed foods and added sugars, and avoiding excessive calorie consumption as an important nutritional strategy for the prevention and management of chronic conditions and promotion of overall health.
    Keywords:  Fad diets; Intermittent fasting; Keto; Paleo; Vegan
    DOI:  https://doi.org/10.1016/j.pcad.2023.02.001
  13. Nutrients. 2023 Feb 23. pii: 1109. [Epub ahead of print]15(5):
      Due to increasingly diverse lifestyles, exercise timings vary between individuals: before breakfast, in the afternoon, or in the evening. The endocrine and autonomic nervous systems, which are associated with metabolic responses to exercise, show diurnal variations. Moreover, physiological responses to exercise differ depending on the timing of the exercise. The postabsorptive state is associated with greater fat oxidation during exercise compared to the postprandial state. The increase in energy expenditure persists during the post-exercise period, known as "Excess Post-exercise Oxygen Consumption". A 24 h evaluation of accumulated energy expenditure and substrate oxidation is required to discuss the role of exercise in weight control. Using a whole-room indirect calorimeter, researchers revealed that exercise performed during the postabsorptive state, but not during the postprandial state, increased accumulated fat oxidation over 24 h. The time course of the carbohydrate pool, as estimated by indirect calorimetry, suggests that glycogen depletion after postabsorptive exercise underlies an increase in accumulated fat oxidation over 24 h. Subsequent studies using 13C magnetic resonance spectroscopy confirmed that the variations in muscle and liver glycogen caused by postabsorptive or postprandial exercise were consistent with indirect calorimetry data. These findings suggest that postabsorptive exercise alone effectively increases 24 h fat oxidation.
    Keywords:  glycogen; postabsorptive state; postprandial state; whole-room indirect calorimeter
    DOI:  https://doi.org/10.3390/nu15051109
  14. J Physiol. 2023 Mar 11.
      This study investigated the role of diacylglycerol (DAG)-mediated protein kinase C (PKC) activation, ceramides accumulation, and inflammation in insulin-resistant female oxidative and glycolytic skeletal muscles induced by an obesogenic high-fat sucrose-enriched (HFS) diet. The HFS diet impaired insulin-stimulated AKTThr308 phosphorylation and glycogen synthesis, whereas rates of fatty acid oxidation and basal lactate production were significantly elevated in soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles. Insulin resistance was accompanied by increases in triacylglycerol (TAG), and DAG contents in Sol and EDL, whereas in Epit muscles only TAG content and markers of inflammation were associated with HFS diet-induced insulin resistance. Analysis of membrane-bound/cytoplasm PKC fractions revealed that the HFS diet promoted activation/translocation of PKCδ and θ isoforms in Sol, EDL, and Epit muscles. However, none of these muscles displayed alterations in ceramides contents in response to HFS feeding. This could be explained by a significant increase in Dgat2 mRNA expression in Sol, EDL, and Epit muscles, which likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis instead of ceramides. Overall, this study helps elucidate the molecular mechanisms underlying insulin resistance caused by diet-induced obesity in female skeletal muscles with distinct fiber type compositions. KEY POINTS: Feeding female Wistar rats a high-fat sucrose-enriched diet (HFS) led to diacylglycerol (DAG)-induced PKC activation and insulin resistance in oxidative and glycolytic skeletal muscles. HFS diet-induced toll-like receptor 4 (Tlr4) expression did not lead to increased ceramide content in female skeletal muscles. In highly glycolytic female muscles, elevated TAG content and markers of inflammation underlied HFS diet-induced insulin resistance. The HFS diet suppressed glucose oxidation and increased lactate production in oxidative and glycolytic female muscles. Increased Dgat2 mRNA expression likely diverted most of the intramyocellular acyl-CoAs toward TAG synthesis and prevented ceramides formation in skeletal muscles of HFS-fed female rats. Abstract figure legend Feeding female Wistar rats for 8 weeks an obesogenic high-fat sucrose-enriched (HFS) caused insulin resistance in Soleus (Sol), Extensor Digitorum Longus (EDL), and Epitrochlearis (Epit) muscles. In all muscles studied, the HFS diet increased diacylglycerol (DAG) content and Dgat2 mRNA expression, but did not affect ceramide levels. PKCθ and PKCδ activities and the expression of inflammatory markers were altered in a fiber type-specific manner by HFS feeding. In Sol and EDL muscles, PKCθ activity was increased, whereas in Epit it remained unaltered by the HFS diet. PKCδ activity was only elevated in Sol muscles by HFS feeding and the mRNA expression of inflammatory markers increased in EDL and Epit, but not in Sol muscles. ↑ = increase; ↔ = no change This article is protected by copyright. All rights reserved.
    Keywords:  AKT; DGAT; TLR4; glucose oxidation; glycogen synthesis; inflammation; intramuscular lipids; obesity
    DOI:  https://doi.org/10.1113/JP284324
  15. Int J Mol Sci. 2023 Feb 21. pii: 4321. [Epub ahead of print]24(5):
      Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.
    Keywords:  endothelial dysfunction; heart failure; molecular mechanisms; pathophysiology
    DOI:  https://doi.org/10.3390/ijms24054321
  16. Nature. 2023 Mar 08.
      
    Keywords:  Cell biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-00596-y
  17. Eur J Intern Med. 2023 Mar 06. pii: S0953-6205(23)00067-5. [Epub ahead of print]
      Obesity is a heterogenous condition with multiple different phenotypes. Among these a particular subtype exists named as metabolically healthy obesity (MHO). MHO has multiple definitions and its prevalence varies according to study. The potential mechanisms underlying the pathophysiology of MHO include the different types of adipose tissue and their distribution, the role of hormones, inflammation, diet, the intestinal microbiota and genetic factors. In contrast to the negative metabolic profile associated with metabolically unhealthy obesity (MUO), MHO has relatively favorable metabolic characteristics. Nevertheless, MHO is still associated with many important chronic diseases including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease as well as certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore, it should not be considered as a benign condition. The major therapeutic alternatives include dietary modifications, exercise, bariatric surgery and certain medications including glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. In this review, we discuss the significance of MHO while comparing this phenotype with MUO.
    Keywords:  Cardiometabolically healthy obesity; GLP-1 analogs; Obesity; SGLT2 inhibitors
    DOI:  https://doi.org/10.1016/j.ejim.2023.02.025
  18. Eur Heart J. 2023 Mar 06. pii: ehad087. [Epub ahead of print]
      AIMS: Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD).METHODS AND RESULTS: This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB].
    CONCLUSION: The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment.
    Keywords:  Cardiovascular disease; Heart failure; Ketone bodies; Mortality
    DOI:  https://doi.org/10.1093/eurheartj/ehad087
  19. Drug Discov Today. 2023 Mar 03. pii: S1359-6446(23)00063-6. [Epub ahead of print] 103547
      Mitochondrial function is essential for maintaining neuronal integrity, because neurons have a high energy demand. Neurodegenerative diseases, such as Alzheimer's disease (AD), are exacerbated by mitochondrial dysfunction. Mitochondrial autophagy (mitophagy) attenuates neurodegenerative diseases by eradicating dysfunctional mitochondria. In neurodegenerative disorders, there is disruption of the mitophagy process. High levels of iron also interfere with the mitophagy process and the mtDNA released after mitophagy is proinflammatory and triggers the cGAS-STING pathway that aids AD pathology. In this review, we critically discuss the factors that affect mitochondrial impairment and different mitophagy processes in AD. Furthermore, we discuss the molecules used in mouse studies as well as clinical trials that could result in potential therapeutics in the future. Teaser: This review reports the novel therapeutic molecules that are underway in clinical trials for neurodegenerative diseases like Alzheimer's disease, demonstrating how mitochondria become dysfunctional and how they can be rescued.
    Keywords:  Alzheimer’s disease; bioenergetics; exosomes; mitochondria; mitophagy; neurodegenerative disorders
    DOI:  https://doi.org/10.1016/j.drudis.2023.103547
  20. Cells. 2023 Feb 24. pii: 715. [Epub ahead of print]12(5):
      Sarcalumenin (SAR) is a luminal Ca2+ buffer protein with high capacity but low affinity for calcium binding found predominantly in the longitudinal sarcoplasmic reticulum (SR) of fast- and slow-twitch skeletal muscles and the heart. Together with other luminal Ca2+ buffer proteins, SAR plays a critical role in modulation of Ca2+ uptake and Ca2+ release during excitation-contraction coupling in muscle fibers. SAR appears to be important in a wide range of other physiological functions, such as Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA) stabilization, Store-Operated-Calcium-Entry (SOCE) mechanisms, muscle fatigue resistance and muscle development. The function and structural features of SAR are very similar to those of calsequestrin (CSQ), the most abundant and well-characterized Ca2+ buffer protein of junctional SR. Despite the structural and functional similarity, very few targeted studies are available in the literature. The present review provides an overview of the role of SAR in skeletal muscle physiology, as well as of its possible involvement and dysfunction in muscle wasting disorders, in order to summarize the current knowledge on SAR and drive attention to this important but still underinvestigated/neglected protein.
    Keywords:  Ca2+ buffer protein; sarcalumenin; sarcalumenin-related skeletal muscle diseases; sarcoplasmic reticulum; skeletal muscle
    DOI:  https://doi.org/10.3390/cells12050715
  21. Int J Mol Sci. 2023 Mar 03. pii: 4903. [Epub ahead of print]24(5):
      Heart failure, a leading cause of hospitalizations and deaths, is a major clinical problem. In recent years, the increasing incidence of heart failure with preserved ejection fraction (HFpEF) has been observed. Despite extensive research, there is no efficient treatment for HFpEF available. However, a growing body of evidence suggests stem cell transplantation, due to its immunomodulatory effect, may decrease fibrosis and improve microcirculation and therefore, could be the first etiology-based therapy of the disease. In this review, we explain the complex pathogenesis of HFpEF, delineate the beneficial effects of stem cells in cardiovascular therapy, and summarize the current knowledge concerning cell therapy in diastolic dysfunction. Furthermore, we identify outstanding knowledge gaps that may indicate directions for future clinical studies.
    Keywords:  cardiology; heart failure; preserved ejection fraction; stem cells
    DOI:  https://doi.org/10.3390/ijms24054903
  22. J Cell Physiol. 2023 Mar 08.
      Atherosclerosis (AS), a chronic inflammatory vascular disease with lipid metabolism abnormalities, is one of the major pathological bases of coronary heart disease. As people's lifestyles and diets change, the incidence of AS increases yearly. Physical activity and exercise training have recently been identified as effective strategies for lowering cardiovascular disease (CVD) risk. However, the best exercise mode to ameliorate the risk factors related to AS is not clear. The effect of exercise on AS is affected by the type of exercise, intensity, and duration. In particular, aerobic and anaerobic exercise are the two most widely discussed types of exercise. During exercise, the cardiovascular system undergoes physiological changes via various signaling pathways. The review aims to summarize signaling pathways related to AS in two different exercise types and provide new ideas for the prevention and treatment of AS in clinical practice.
    Keywords:  aerobic exercise; anaerobic exercise; atherosclerosis; cardiovascular disease; signaling pathway
    DOI:  https://doi.org/10.1002/jcp.30989
  23. Physiol Rep. 2023 Mar;11(5): e15634
      Low-grade inflammation is central to coronary artery disease (CAD) and type 2 diabetes (T2D) and is reduced by exercise training. The objective of this study was to compare the anti-inflammatory potential of moderate-to-vigorous intensity continuous training (MICT) and high-intensity interval training (HIIT) in patients with CAD with or without T2D. The design and setting of this study is based on a secondary analysis of registered randomized clinical trial NCT02765568. Male patients with CAD were randomly assigned to either MICT or HIIT, with subgroups divided according to T2D status (non-T2D-HIIT n = 14 and non-T2D-MICT n = 13; T2D-HIIT n = 6 and T2D-MICT n = 5). The intervention was a 12-week cardiovascular rehabilitation program consisting of either MICT or HIIT (twice weekly sessions) and circulating cytokines measured pre- and post-training as inflammatory markers. The co-occurrence of CAD and T2D was associated with increased plasma IL-8 (p = 0.0331). There was an interaction between T2D and the effect of the training interventions on plasma FGF21 (p = 0.0368) and IL-6 (p = 0.0385), which were further reduced in the T2D groups. An interaction between T2D, training modalities, and the effect of time (p = 0.0415) was detected for SPARC, with HIIT increasing circulating concentrations in the control group, while lowering them in the T2D group, and the inverse occurring with MICT. The interventions also reduced plasma FGF21 (p = 0.0030), IL-6 (p = 0.0101), IL-8 (p = 0.0087), IL-10 (p < 0.0001), and IL-18 (p = 0.0009) irrespective of training modality or T2D status. HIIT and MICT resulted in similar reductions in circulating cytokines known to be increased in the context of low-grade inflammation in CAD patients, an effect more pronounced in patients with T2D for FGF21 and IL-6.
    Keywords:  coronary artery disease; cytokines; exercise; interleukins; type 2 diabetes
    DOI:  https://doi.org/10.14814/phy2.15634
  24. EMBO J. 2023 Mar 06. e113576
      The fate of unimported mitochondrial precursors has been increasingly studied in recent years, mostly focusing on protein degradation. In this issue of the EMBO journal, Krämer et al discovered MitoStores, a new protective mechanism that temporarily stores mitochondrial proteins in cytosolic deposits.
    DOI:  https://doi.org/10.15252/embj.2023113576
  25. Asian J Surg. 2023 Mar 08. pii: S1015-9584(23)00267-1. [Epub ahead of print]
      
    Keywords:  Anatomy; Fist; Heart
    DOI:  https://doi.org/10.1016/j.asjsur.2023.02.094
  26. Exp Gerontol. 2023 Mar 08. pii: S0531-5565(23)00062-1. [Epub ahead of print] 112141
      PURPOSE: To investigate which type, frequency, duration, intensity, and volume of chronic exercise might more strongly reduce pro-inflammatory cytokines and enhance anti-inflammatory cytokines in human and animal models with Mild Cognitive Impairment (MCI) or dementia.DESIGN: A systematic review.
    DATA SOURCE: English-language search of 13 electronic databases: Web of Science, PubMed/Medline, Sport Discus, Scopus, Cochrane, Psych Net, Springer, ScienceDirect, Pascal & Francis, Sage journals, Pedro, Google Scholar, and Sage.
    INCLUSION CRITERIA: (i) human and animal studies that included exercise, physical activity, or fitness training as an experimental intervention, (ii) studies that addressed MCI, dementia, or AD, (iii) studies that focused on measuring cytokines and/or other inflammatory and/or neuroinflammatory immune markers, (iii) studies that examined inflammatory indicators in blood, CSF (Cerebrospinal Fluid), and brain tissue.
    RESULTS: Of the 1290 human and animal studies found, 38 were included for qualitative analysis, 11 human articles, 27 animal articles, and two articles addressing both human and animal protocols. In the animal model, physical exercise decreased pro-inflammatory markers in 70.8 % of the articles and anti-inflammatory cytokines: IL -4, IL -10, IL-4β, IL -10β, and TGF-β in 26 % of articles. Treadmill running, resistance exercise, and swimming exercise reduce pro-inflammatory cytokines and increase anti-inflammatory cytokines. In the human model, 53.9 % of items reduced pro-inflammatory proteins and 23 % increased anti-inflammatory proteins. Cycling exercise, multimodal, and resistance training effectively decreased pro-inflammatory cytokines.
    CONCLUSION: In rodent animal models with AD phenotype, treadmill, swimming, and resistance training remain good interventions that can delay various mechanisms of dementia progression. In the human model, aerobic, multimodal, and resistance training are beneficial in both MCI and AD. Multimodal training of moderate to high intensity multimodal exercise is effective for MCI. Voluntary cycling training, moderate- or high-intensity aerobic exercise is effective in mild AD patients.
    Keywords:  Alzheimer's disease; Chronic exercise; Cognitive decline; Cytokines; Neuro inflammation
    DOI:  https://doi.org/10.1016/j.exger.2023.112141