bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒12‒17
27 papers selected by
Matías Javier Monsalves Álvarez
  1. Fecal transfers from children on the ketogenic diet mimic the anti-seizure effect in mice.
  2. The Ketogenic Diet in the Prevention of Migraines in the Elderly.
  3. Ketogenic diets: A systematic review of current scientific evidence and possible applicability in dogs and cats.
  4. Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans.
  5. Metabolic Messengers: ketone bodies.
  6. Ketogenic Diets Are Not Beneficial for Athletic Performance.
  7. Ketogenic Diets Are Beneficial for Athletic Performance.
  8. Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice.
  9. Ketogenic Diets Are Beneficial for Athletic Performance: Response to Burke and Whitfield.
  10. The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
  11. Mitochondrial-targeted antioxidant ingestion acutely blunts VO2max in physically inactive females.
  12. Fast and Slow Muscle Fiber Transcriptome Dynamics with Lifelong Endurance Exercise.
  13. A detailed molecular network map and model of the NLRP3 inflammasome.
  14. Impact of NLRP3 Depletion on Aging-Related Metaflammation, Cognitive Function, and Social Behavior in Mice.
  15. The critical roles of STING in mitochondrial homeostasis.
  16. Additive Impact of Soy Protein Dietary Intake and Exercise on Visceral Fat Mass Reduction and Mitochondrial Complex I Activation in Skeletal Muscle.
  17. Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia.
  18. The Effect of High-Intensity Interval Training on Mitochondrial-Associated Indices in Overweight and Obese Adults: A Systematic Review and Meta-Analysis.
  19. Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism.
  20. NLRP3 Inflammasome Involvement in Heart, Liver, and Lung Diseases-A Lesson from Cytokine Storm Syndrome.
  21. A Combination of ß-Hydroxybutyrate and Citrate Ameliorates Disease Progression in a Rat Model of Polycystic Kidney Disease.
  22. Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
  23. Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis.
  24. Geroprotector drugs and exercise: friends or foes on healthy longevity?
  25. Mitochondrial Cation Signalling in the Control of Inflammatory Processes.
  26. Butyrate ameliorated ferroptosis in ulcerative colitis through modulating Nrf2/GPX4 signal pathway and improving intestinal barrier.
  27. Arachidonic acid alleviates autoimmune diabetes in NOD mice.
  1. Cell Rep. 2023 Dec 08. pii: S2211-1247(23)01582-6. [Epub ahead of print]42(12): 113570
    Fecal transfers from children on the ketogenic diet mimic the anti-seizure effect in mice.
    Stefanie Prast-Nielsen.
      The ketogenic diet (KD) mediates its anti-seizure effect through the gut microbiota in epilepsy mouse models.1 Lum et al.2 demonstrated that fecal microbiota from children with epilepsy treated with the KD decreases seizure susceptibility in mice after transfer.
    DOI:  https://doi.org/10.1016/j.celrep.2023.113570
  2. Nutrients. 2023 Dec 02. pii: 4998. [Epub ahead of print]15(23):
    The Ketogenic Diet in the Prevention of Migraines in the Elderly.
    Michal Fila, Jan Chojnacki, Elzbieta Pawlowska, Piotr Sobczuk, Cezary Chojnacki, Janusz Blasiak.
      Migraines display atypical age dependence, as the peak of their prevalence occurs between the ages of 20-40 years. With age, headache attacks occur less frequently and are characterized by a lower amplitude. However, both diagnosis and therapy of migraines in the elderly are challenging due to multiple comorbidities and polypharmacy. Dietary components and eating habits are migraine triggers; therefore, nutrition is a main target in migraine prevention. Several kinds of diets were proposed to prevent migraines, but none are commonly accepted due to inconsistent results obtained in different studies. The ketogenic diet is featured by very low-carbohydrate and high-fat contents. It may replace glucose with ketone bodies as the primary source of energy production. The ketogenic diet and the actions of ketone bodies are considered beneficial in several aspects of health, including migraine prevention, but studies on the ketogenic diet in migraines are not standardized and poorly evidenced. Apart from papers claiming beneficial effects of the ketogenic diet in migraines, several studies have reported that increased levels of ketone bodies may be associated with all-cause and incident heart failure mortality in older adults and are supported by research on mice showing that the ketogenic diets and diet supplementation with a human ketone body precursor may cause life span shortening. Therefore, despite reports showing a beneficial effect of the ketogenic diet in migraines, such a diet requires further studies, including clinical trials, to verify whether it should be recommended in older adults with migraines.
    Keywords:  elderly; headache; ketogenic diet; ketone bodies; migraine; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/nu15234998
  3. J Anim Physiol Anim Nutr (Berl). 2023 Dec 13.
    Ketogenic diets: A systematic review of current scientific evidence and possible applicability in dogs and cats.
    Thiago H A Vendramini, Andressa R Amaral, Mariana F Rentas, Juliana P D S Nogueira, Vivian Pedrinelli, Vinicius V de Oliveira, Rafael V A Zafalon, Márcio A Brunetto.
      Ketogenic diets (KD) have been used in the treatment of epilepsy in humans for around a century and, more recently, they have been implanted for cancer patients, as well as in the treatment of obesity. This type of diet consists of high-fat levels, an adequate amount of protein and restricted carbohydrates, or high medium-chain triglycerides. Recently, the ketogenic diet has gained attention in veterinary medicine and studies were published evaluating the effects of KD in dogs with epilepsy. The objective of this review was to highlight recent studies about the application of KD in dogs and cats, to describe the neurobiochemical mechanisms through which KD improves epilepsy crisis, and their adverse effects. Studies were identified by a systematic review of literature available on PubMed, Embase, and Scopus. All cohort and case-control studies were included, and all articles were exported to Mendeley® citation manager, and duplicates were automatically removed. Seven articles and three conference abstracts conducted with dogs were included in the present study. There is evidence that the consumption of diets with medium-chain triglycerides increases the concentration of circulating ketone bodies and improves epilepsy signs, although these diets have higher carbohydrate and lower fat content when compared to the classic KD.
    Keywords:  epilepsy; fasting; ketone bodies; medium chain triglycerides; metabolism; small animals
    DOI:  https://doi.org/10.1111/jpn.13913
  4. Nutrients. 2023 Nov 22. pii: 4876. [Epub ahead of print]15(23):
    Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans.
    Mickey L Bolyard, Christina M Graziano, Kevin R Fontaine, R Drew Sayer, Gordon Fisher, Eric P Plaisance.
      Exogenous ketone ester and ketone ester mixed with ketone free acid formulations are rapidly entering the commercial marketspace. Short-term animal and human studies using these products suggest significant potential for primary or secondary prevention of a number of chronic disease conditions. However, a number of questions need to be addressed by the field for optimal use in humans, including variable responses among available exogenous ketones at different dosages; frequency of dosing; and their tolerability, acceptability, and efficacy in long-term clinical trials. The purpose of the current investigation was to examine the tolerability, acceptability, and circulating R-beta-hydroxybutyrate (R-βHB) and glucose responses to a ketone monoester (KME) and ketone monoester/salt (KMES) combination at 5 g and 10 g total R-βHB compared with placebo control (PC). Fourteen healthy young adults (age: 21 ± 2 years, weight: 69.7 ± 14.2 kg, percent fat: 28.1 ± 9.3%) completed each of the five study conditions: placebo control (PC), 5 g KME (KME5), 10 g KME (KME10), 5 g (KMES5), and 10 g KMES (KMES10) in a randomized crossover fashion. Circulating concentrations of R-βHB were measured at baseline (time 0) following an 8-12 h overnight fast and again at 15, 30, 60, and 120 min following drink ingestion. Participants also reported acceptability and tolerability during each condition. Concentrations of R-βHB rose to 2.4 ± 0.1 mM for KME10 after 15 min, whereas KMES10 similarly peaked (2.1 ± 0.1 mM) but at 30 min. KME5 and KMES5 achieved similar peak R-βHB concentrations (1.2 ± 0.7 vs. 1.1 ± 0.5 mM) at 15 min. Circulating R-βHB concentrations were similar to baseline for each condition by 120 min. Negative correlations were observed between R-βHB and glucose at the 30 min time point for each condition except KME10 and PC. Tolerability was similar among KME and KMES, although decreases in appetite were more frequently reported for KMES. Acceptability was slightly higher for KMES due to the more frequently reported aftertaste for KME. The results of this pilot investigation illustrate that the KME and KMES products used increase circulating R-βHB concentrations to a similar extent and time course in a dose-dependent fashion with slight differences in tolerability and acceptability. Future studies are needed to examine variable doses, frequency, and timing of exogenous ketone administration for individuals seeking to consume ketone products for health- or sport performance-related purposes.
    Keywords:  ketogenic diet; ketones; ketosis; metabolism; obesity
    DOI:  https://doi.org/10.3390/nu15234876
  5. Nat Metab. 2023 Dec 13.
    Metabolic Messengers: ketone bodies.
    Alisa B Nelson, Eric D Queathem, Patrycja Puchalska, Peter A Crawford.
      Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.
    DOI:  https://doi.org/10.1038/s42255-023-00935-3
  6. Med Sci Sports Exerc. 2023 Dec 11.
    Ketogenic Diets Are Not Beneficial for Athletic Performance.
    Louise M Burke, Jamie Whitfield.
      
    DOI:  https://doi.org/10.1249/MSS.0000000000003344
  7. Med Sci Sports Exerc. 2023 Dec 11.
    Ketogenic Diets Are Beneficial for Athletic Performance.
    Timothy David Noakes.
      
    DOI:  https://doi.org/10.1249/MSS.0000000000003343
  8. Cell Rep. 2023 Dec 08. pii: S2211-1247(23)01533-4. [Epub ahead of print]42(12): 113521
    Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice.
    Gregory R Lum, Sung Min Ha, Christine A Olson, Montgomery Blencowe, Jorge Paramo, Beck Reyes, Joyce H Matsumoto, Xia Yang, Elaine Y Hsiao.
      The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid β-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.
    Keywords:  CP: Microbiology; CP: Neuroscience; epilepsy; ketogenic diet; microbiome; seizure
    DOI:  https://doi.org/10.1016/j.celrep.2023.113521
  9. Med Sci Sports Exerc. 2023 Dec 11.
    Ketogenic Diets Are Beneficial for Athletic Performance: Response to Burke and Whitfield.
    Timothy David Noakes.
      
    DOI:  https://doi.org/10.1249/MSS.0000000000003345
  10. J Appl Physiol (1985). 2023 Dec 14.
    The Role of TFE3 in Mediating Skeletal Muscle Mitochondrial Adaptations to Exercise Training.
    Jenna C Wong, Ashley N Oliveira, Priyanka Khemraj, David A Hood.
      TFE3 is a transcription factor that activates the expression of lysosomal genes involved in the clearance of dysfunctional mitochondria, termed mitophagy. With exercise, TFE3 is presumed to optimize the mitochondrial pool through the removal of organelles via lysosomes. However, the molecular mechanisms of the involved pathways remain unknown. Wild-type (WT) and TFE3 knockout (KO) mice were subjected to 6 weeks of voluntary wheel running as an endurance training regimen. This was followed by a 45-minute bout of in situ stimulation of the sciatic nerve innervating hindlimb muscles to evaluate muscle fatigue and contractile properties. A subset of animals was treated with colchicine to measure autophagy and mitophagy flux. Fatigability during stimulation was reduced with training in WT animals, as seen by a 13% increase in percent of maximum force at 5 minutes of stimulation, and a 30% increase at 30 minutes. Permeabilized fiber oxygen consumption was also improved with training. Concurrent with improved muscle and mitochondrial function, COX activity and COX I protein expression were increased in trained WT animals compared to untrained animals, signifying an increase in mitochondrial content. These training adaptations were abolished with the loss of TFE3. Surprisingly, the absence of TFE3 did not affect lysosomal content, nor did it blunt the induction of mitophagy flux with contractile activity compared to WT mice. Our results suggest that the loss of TFE3 compromises beneficial training adaptations that lead to improved muscle endurance and mitochondrial function.
    Keywords:  TFE3; exercise; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00484.2023
  11. Physiol Rep. 2023 Dec;11(23): e15871
    Mitochondrial-targeted antioxidant ingestion acutely blunts VO2max in physically inactive females.
    Ryan P Hughes, Nicholas A Carlini, Bradley S Fleenor, Matthew P Harber.
      PURPOSE: To determine the acute effects of a mitochondrial targeting antioxidant (MitoQ) on the metabolic response during exercise.METHODS: Nine (n = 9) physically inactive females (age 47 ± 22 years) performed two trials (Placebo and MitoQ) in a double-blind randomized cross-over design. In both trials, participants performed an exercise protocol consisting of 3-min stages at submaximal workloads followed by a ramp protocol to volitional exhaustion. Participants received either Placebo or MitoQ (80 mg) 1 h prior to exercise. Indirect calorimetry and cardiovascular measurements were collected throughout the duration of the exercise bout.
    RESULTS: Submaximal metabolic and cardiovascular variables were not different between trials (p > 0.05). VO2max was higher (p = 0.03) during Placebo (23.5 ± 5.7 mL kg min-1 ) compared to MitoQ (21.0 ± 6.6 mL kg min-1 ). Maximal ventilation was also higher (p = 0.02) in Placebo (82.4 ± 17.7 L/min) compared to MitoQ (75.0 ± 16.8 L/min). Maximal cardiovascular variables and blood lactate were not different between trials (p > 0.05).
    CONCLUSION: An acute dose of MitoQ blunted VO2max , which was primarily mediated by impairment of ventilatory function. These data suggest that the acute accumulation of exercise-induced mitochondrial reactive oxygen species (mtROS) are necessary for maximal aerobic capacity. Further research is warranted on mtROS-antioxidant cell signaling cascades, and how they relate to mitochondrial function during exercise.
    Keywords:  cardiorespiratory fitness; exercise; mitochondria
    DOI:  https://doi.org/10.14814/phy2.15871
  12. J Appl Physiol (1985). 2023 Dec 14.
    Fast and Slow Muscle Fiber Transcriptome Dynamics with Lifelong Endurance Exercise.
    Ulrika Raue, Gwenaelle Begue, Kiril Minchev, Bozena Jemiolo, Kevin J Gries, Toby Chambers, Aliza Rubenstein, Elena Zaslavsky, Stuart C Sealfon, Todd Trappe, Scott Trappe.
      We investigated fast and slow muscle fiber transcriptome exercise dynamics among three groups of men: Lifelong exercisers (LLE, n=8, 74±1 y), old healthy non-exercisers (OH, n=9, 75±1 y), and young exercisers (YE, n=8, 25±1 y). Muscle biopsies were obtained pre- and 4h post-resistance exercise (3x10 knee extensions, 70% 1-RM). Fast and slow fiber size and function were assessed pre-exercise with fast and slow RNA-seq examined pre- and post-exercise. LLE fast fiber size was similar to OH, which were ~30% smaller than YE (P<0.05) with contractile function variables among groups resulting in lower power in LLE (P<0.05). LLE slow fibers were ~30% larger and more powerful compared to YE and OH (P<0.05). At the transcriptome level, fast fibers were more responsive to resistance exercise compared to slow fibers among all three cohorts (P<0.05). Exercise induced a comprehensive biological response in fast fibers (P<0.05) including transcription, signaling, skeletal muscle cell differentiation, and metabolism with vast differences among the groups. Fast fibers from YE exhibited a growth and metabolic signature, with LLE being primarily metabolic, and OH showing a strong stress related response. In slow fibers, only LLE exhibited a biological response to exercise (P<0.05), which was related to ketone and lipid metabolism. The divergent exercise transcriptome signatures provide novel insight into the molecular regulation in fast and slow fibers with age and exercise and suggest that the ~5% weekly exercise time commitment of the lifelong exercisers provided a powerful investment for fast and slow muscle fiber metabolic health at the molecular level.
    Keywords:  Aging; Exercise; Masters Athletes; Skeletal Muscle; Transcriptome
    DOI:  https://doi.org/10.1152/japplphysiol.00442.2023
  13. Front Immunol. 2023 ;14 1233680
    A detailed molecular network map and model of the NLRP3 inflammasome.
    Marcus Krantz, Daniel Eklund, Eva Särndahl, Alexander Hedbrant.
      The NLRP3 inflammasome is a key regulator of inflammation that responds to a broad range of stimuli. The exact mechanism of activation has not been determined, but there is a consensus on cellular potassium efflux as a major common denominator. Once NLRP3 is activated, it forms high-order complexes together with NEK7 that trigger aggregation of ASC into specks. Typically, there is only one speck per cell, consistent with the proposal that specks form - or end up at - the centrosome. ASC polymerisation in turn triggers caspase-1 activation, leading to maturation and release of IL-1β and pyroptosis, i.e., highly inflammatory cell death. Several gain-of-function mutations in the NLRP3 inflammasome have been suggested to induce spontaneous activation of NLRP3 and hence contribute to development and disease severity in numerous autoinflammatory and autoimmune diseases. Consequently, the NLRP3 inflammasome is of significant clinical interest, and recent attention has drastically improved our insight in the range of involved triggers and mechanisms of signal transduction. However, despite recent progress in knowledge, a clear and comprehensive overview of how these mechanisms interplay to shape the system level function is missing from the literature. Here, we provide such an overview as a resource to researchers working in or entering the field, as well as a computational model that allows for evaluating and explaining the function of the NLRP3 inflammasome system from the current molecular knowledge. We present a detailed reconstruction of the molecular network surrounding the NLRP3 inflammasome, which account for each specific reaction and the known regulatory constraints on each event as well as the mechanisms of drug action and impact of genetics when known. Furthermore, an executable model from this network reconstruction is generated with the aim to be used to explain NLRP3 activation from priming and activation to the maturation and release of IL-1β and IL-18. Finally, we test this detailed mechanistic model against data on the effect of different modes of inhibition of NLRP3 assembly. While the exact mechanisms of NLRP3 activation remains elusive, the literature indicates that the different stimuli converge on a single activation mechanism that is additionally controlled by distinct (positive or negative) priming and licensing events through covalent modifications of the NLRP3 molecule. Taken together, we present a compilation of the literature knowledge on the molecular mechanisms on NLRP3 activation, a detailed mechanistic model of NLRP3 activation, and explore the convergence of diverse NLRP3 activation stimuli into a single input mechanism.
    Keywords:  NLRP3; NLRP3 triggers; inflammasome; mechanistic model; osmotic stress; rxncon
    DOI:  https://doi.org/10.3389/fimmu.2023.1233680
  14. Int J Mol Sci. 2023 Nov 21. pii: 16580. [Epub ahead of print]24(23):
    Impact of NLRP3 Depletion on Aging-Related Metaflammation, Cognitive Function, and Social Behavior in Mice.
    Elena D Khilazheva, Angelina I Mosiagina, Yulia A Panina, Olga S Belozor, Yulia K Komleva.
      Immunosenescence and chronic inflammation associated with old age accompany brain aging and the loss of complex behaviors. Neuroinflammation in the hippocampus plays a pivotal role in the development of cognitive impairment and anxiety. However, the underlying mechanisms have not been fully explained. In this study, we aimed to investigate the disruption of insulin signaling and the mechanisms underlying metabolic inflammation ("metaflammation") in the brains of wild-type (WT) and NLRP3 knockout (KO) mice of different ages. We found a significant upregulation of the NLRP3 inflammasome in the hippocampus during aging, leading to an increase in the expression of phosphorylated metaflammation proteinases and inflammatory markers, along with an increase in the number of senescent cells. Additionally, metaflammation causes anxiety and impairs social preference behavior in aged mice. On the other hand, deletion of NLRP3 improves some behavioral and biochemical characteristics associated with aging, such as signal memory, neuroinflammation, and metabolic inflammation, but not anxious behavior. These results are associated with reduced IL-18 signaling and the PKR/IKKβ/IRS1 pathway as well as the SASP phenotype. In NLRP3 gene deletion conditions, PKR is down-regulated. Therefore, it is likely that slowing aging through various NLRP3 inhibition mechanisms will lessen the corresponding cognitive decline with aging. Thus, the genetic knockout of the NLRP3 inflammasome can be seen as a new therapeutic strategy for slowing down central nervous system (CNS) aging.
    Keywords:  NLRP3; aging; immunosenescence; inflammasome; inflammation; metaflammasome; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.3390/ijms242316580
  15. Biochem Pharmacol. 2023 Dec 10. pii: S0006-2952(23)00531-2. [Epub ahead of print] 115938
    The critical roles of STING in mitochondrial homeostasis.
    Shishi Zou, Bo Wang, Ke Yi, Dandan Su, Yukai Chen, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology.
    Keywords:  Cell death; Innate immunity; Mitochondrial dynamics; Mitochondrial metabolism; MtDNA; STING
    DOI:  https://doi.org/10.1016/j.bcp.2023.115938
  16. Am J Physiol Endocrinol Metab. 2023 Dec 13.
    Additive Impact of Soy Protein Dietary Intake and Exercise on Visceral Fat Mass Reduction and Mitochondrial Complex I Activation in Skeletal Muscle.
    Kohei Kido, Shinya Watanabe, Masaki Kusano, Ai Ito, Kazuya Sakai, Miki Kosugi, Yayoi Gotoh, Toshio Suzuki, Kentaro Kawanaka, Yasuki Higaki.
      Soy protein has shown remarkable effectiveness in reducing fat mass compared with other protein sources, and exercise has the potential to further enhance this fat loss effect. Previous studies have demonstrated that soy protein intake leads to decreased fatty acid synthesis, which contributes to its fat-loss properties. However, the exact mechanism by which these lipids are consumed remains unclear. To investigate this, we conducted a comprehensive study using C57/BL6 male mice, comparing the effects of soy and casein proteins with and without exercise (Casein-Sed, Casein-Ex, Soy-Sed, and Soy-Ex groups) under high- and low-protein conditions (14% or 40% protein). Our findings revealed that combining soy protein intake with exercise significantly reduced epididymal white adipose tissue (eWAT) weight, particularly in the high-protein diet group. Further analysis revealed that exercise increased the expression of lipid oxidation-regulatory proteins, including mitochondrial oxidative phosphorylation protein (OXPHOS) complexes, in the plantaris muscle regardless of the protein source. Although soy protein intake did not directly affect muscle mitochondrial protein expression, the activity of OXPHOS complex I was additively enhanced by exercise and soy protein under the 40% protein condition. Notably, complex I activity inversely correlated with eWAT weight in the soy protein diet group. These results highlight the potential link between improved complex I activity induced by soy protein and fat mass reduction, which emphasizes the promising benefits of combining soy protein with exercise in promoting fat loss.
    Keywords:  Exercise; OXPHOS complex enzyme activity; Skeletal muscle; Soy protein; Visceral fat mass
    DOI:  https://doi.org/10.1152/ajpendo.00196.2023
  17. J Cachexia Sarcopenia Muscle. 2023 Dec 07.
    Obesity worsens mitochondrial quality control and does not protect against skeletal muscle wasting in murine cancer cachexia.
    Thomas D Cardaci, Brandon N VanderVeen, Brooke M Bullard, Sierra J McDonald, Christian A Unger, Reilly T Enos, Daping Fan, Kandy T Velázquez, Norma Frizzell, Espen E Spangenburg, E Angela Murphy.
      BACKGROUND: More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia.METHODS: Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high-resolution respirometry and transmission electron microscopy (TEM).
    RESULTS: Obese LLC mice experienced significant tumour-free body weight loss similar to lean (-12.8% vs. -11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2  = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (-24%, P < 0.0354) and mCSA (-16%, P = 0.0004) with similar activation of muscle p65 (P = 0.0337), and p38 (P = 0.0008). ADP-dependent coupled respiration was reduced in both Obese and Obese LLC muscle (-30%, P = 0.0072) consistent with reductions in volitional cage activity (-39%, P < 0.0001) and grip strength (-41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: -37%, P = 0.0009; SS: -21%, P = 0.0101) and LLC (IMF: -40%, P = 0.0019; SS: -27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 (P = 0.0029) and DRP1 (P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 (P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle.
    CONCLUSIONS: Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre-existing metabolic conditions when determining the impact of weight status on cancer-induced cachexia and functional mitochondrial deficits.
    Keywords:  Autophagy; High fat diet; Lewis lung carcinoma; Mitochondrial dysfunction; Mitophagy; Muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.13391
  18. Front Biosci (Landmark Ed). 2023 Nov 08. 28(11): 281
    The Effect of High-Intensity Interval Training on Mitochondrial-Associated Indices in Overweight and Obese Adults: A Systematic Review and Meta-Analysis.
    Spyridon Hadjispyrou, Petros C Dinas, Spyridon Marios Delitheos, Ioannis-Alexios Koumprentziotis, Costas Chryssanthopoulos, Anastassios Philippou.
      BACKGROUND: Obesity is a significant health problem with an increasing incidence, causing a low-grade systemic inflammatory state and being implicated in various chronic diseases. Moreover, obesity has been shown to cause mitochondrial dysfunction through oxidative stress and inflammation, eventually affecting energy metabolism. However, high-intensity interval training (HIIT) can improve mitochondrial efficiency through exercise-induced mitochondrial adaptations. This systematic review and meta-analysis aims to examine the potential effects of HIIT on mitochondrial-associated indices in obese and overweight adults.METHODS: PubMed, Scopus, and Web of Science databases were searched.
    RESULTS: Twenty-eight eligible studies were included, involving 530 participants. HIIT was found to significantly improve the activity of citrate synthase (CS), cytochrome C (COX-IV), beta-hydroxyacyl CoA-dehydrogenase (β-HAD), Complexes I-V as well as VO2max in overweight and obese individuals, whereas no significant changes were shown in PGC-1α and SIRT1. Interestingly, subgroup analyses revealed that CS, COX-IV, β-HAD, and Complexes I-V activity exhibited a significant improvement only in the healthy subgroup.
    CONCLUSIONS: Overall, HIIT can be utilized to enhance mitochondrial-associated indices in overweight and obese individuals. However, this improvement may be health status dependent.
    Keywords:  Complex I–V; biogenesis; citrate synthase; cytochrome c; exercise; mitochondria; obesity; physical activity
    DOI:  https://doi.org/10.31083/j.fbl2811281
  19. Int J Mol Sci. 2023 Nov 29. pii: 16951. [Epub ahead of print]24(23):
    Fibroblast Growth Factor 21: A Fascinating Perspective on the Regulation of Muscle Metabolism.
    Shuo Li, Jun Chen, Panting Wei, Tiande Zou, Jinming You.
      Fibroblast growth factor 21 (FGF21) plays a vital role in normal eukaryotic organism development and homeostatic metabolism under the influence of internal and external factors such as endogenous hormone changes and exogenous stimuli. Over the last few decades, comprehensive studies have revealed the key role of FGF21 in regulating many fundamental metabolic pathways, including the muscle stress response, insulin signaling transmission, and muscle development. By coordinating these metabolic pathways, FGF21 is thought to contribute to acclimating to a stressful environment and the subsequent recovery of cell and tissue homeostasis. With the emphasis on FGF21, we extensively reviewed the research findings on the production and regulation of FGF21 and its role in muscle metabolism. We also emphasize how the FGF21 metabolic networks mediate mitochondrial dysfunction, glycogen consumption, and myogenic development and investigate prospective directions for the functional exploitation of FGF21 and its downstream effectors, such as the mammalian target of rapamycin (mTOR).
    Keywords:  FGF21; insulin signaling; muscle metabolism; myogenic development; stress response
    DOI:  https://doi.org/10.3390/ijms242316951
  20. Int J Mol Sci. 2023 Nov 21. pii: 16556. [Epub ahead of print]24(23):
    NLRP3 Inflammasome Involvement in Heart, Liver, and Lung Diseases-A Lesson from Cytokine Storm Syndrome.
    Cecilia Napodano, Valeria Carnazzo, Valerio Basile, Krizia Pocino, Annunziata Stefanile, Stefania Gallucci, Patrizia Natali, Umberto Basile, Mariapaola Marino.
      Inflammation and inflammasomes have been proposed as important regulators of the host-microorganism interaction, playing a key role in morbidity and mortality due to the coronavirus disease 2019 (COVID-19) in subjects with chronic conditions and compromised immune system. The inflammasome consists of a multiprotein complex that finely regulates the activation of caspase-1 and the production and secretion of potent pro-inflammatory cytokines such as IL-1β and IL-18. The pyrin containing NOD (nucleotide-binding oligomerization domain) like receptor (NLRP) is a family of intracellular receptors, sensing patterns associated to pathogens or danger signals and NLRP3 inflammasome is the most deeply analyzed for its involvement in the innate and adaptive immune system as well as its contribution to several autoinflammatory and autoimmune diseases. It is highly expressed in leukocytes and up-regulated in sentinel cells upon inflammatory stimuli. NLRP3 expression has also been reported in B and T lymphocytes, in epithelial cells of oral and genital mucosa, in specific parenchymal cells as cardiomyocytes, and keratinocytes, and chondrocytes. It is well known that a dysregulated activation of the inflammasome is involved in the pathogenesis of different disorders that share the common red line of inflammation in their pathogenetic fingerprint. Here, we review the potential roles of the NLRP3 inflammasome in cardiovascular events, liver damage, pulmonary diseases, and in that wide range of systemic inflammatory syndromes named as a cytokine storm.
    Keywords:  DAMP; IL-1 β; IL-18; IL-6; NLRP3 inflammasome; PAMP; caspase-1; cytokines; heart; liver; lung; pyroptosis
    DOI:  https://doi.org/10.3390/ijms242316556
  21. Am J Physiol Renal Physiol. 2023 Dec 14.
    A Combination of ß-Hydroxybutyrate and Citrate Ameliorates Disease Progression in a Rat Model of Polycystic Kidney Disease.
    Jacob A Torres, Nickolas Holznecht, David A Asplund, Tselmeg Amarlkhagva, Bradley Kroes, Juliette Rebello, Shagun Agrawal, Thomas Weimbs.
      Our research has shown that interventions producing a state of ketosis are highly effective in rat, mouse, and cat models of polycystic kidney disease (PKD), preventing and partially reversing cyst growth and disease progression. The ketone ß-hydroxybutyrate (BHB) appears to underlie this effect. Additionally, we have demonstrated that naturally formed microcrystals within kidney tubules trigger a renoprotective response that facilitates tubular obstruction clearance in healthy animals but, alternatively, leads to cyst formation in PKD. The administration of citrate prevents microcrystal formation and slows PKD progression. Juvenile Cy/+ rats, a non-orthologous PKD model, were supplemented from 3 to 8 weeks of age with water containing titrated BHB, citrate, or in combination to find minimal effective and optimal dosages, respectively. Adult rats were given a reduced BHB/Citrate combination or equimolar control K/NaCl salts from 8 to 12 weeks of age. Additionally, adult rats were placed in metabolic cages following BHB, citrate, and BHB/Citrate administration to determine the impact on mineral, creatinine, and citrate excretion. BHB or citrate alone effectively ameliorates disease progression in juvenile rats, decreasing markers of cystic disease and, in combination, producing a synergistic effect. BHB/Citrate leads to partial disease regression in adult rats with established cystic disease, inhibiting cyst formation and kidney injury. BHB/Citrate confers benefits via multiple mechanisms, increases creatinine and citrate excretion, and normalizes mineral excretion. BHB and citrate are widely available and generally recognized as safe compounds and, in combination, exhibit high promise for supporting kidney health in polycystic kidney disease.
    Keywords:  beta-hydroxybutyrate; ketosis; kidney; nephrolithiasis; polycystic
    DOI:  https://doi.org/10.1152/ajprenal.00205.2023
  22. Commun Biol. 2023 Dec 08. 6(1): 1240
    Downregulation of mitochondrial metabolism is a driver for fast skeletal muscle loss during mouse aging.
    Raquel Fernando, Anastasia V Shindyapina, Mario Ost, Didac Santesmasses, Yan Hu, Alexander Tyshkovskiy, Sun Hee Yim, Jürgen Weiss, Vadim N Gladyshev, Tilman Grune, José Pedro Castro.
      Skeletal muscle aging is characterized by the loss of muscle mass, strength and function, mainly attributed to the atrophy of glycolytic fibers. Underlying mechanisms driving the skeletal muscle functional impairment are yet to be elucidated. To unbiasedly uncover its molecular mechanisms, we recurred to gene expression and metabolite profiling in a glycolytic muscle, Extensor digitorum longus (EDL), from young and aged C57BL/6JRj mice. Employing multi-omics approaches we found that the main age-related changes are connected to mitochondria, exhibiting a downregulation in mitochondrial processes. Consistent is the altered mitochondrial morphology. We further compared our mouse EDL aging signature with human data from the GTEx database, reinforcing the idea that our model may recapitulate muscle loss in humans. We are able to show that age-related mitochondrial downregulation is likely to be detrimental, as gene expression signatures from commonly used lifespan extending interventions displayed the opposite direction compared to our EDL aging signature.
    DOI:  https://doi.org/10.1038/s42003-023-05595-3
  23. Redox Biol. 2023 Dec 02. pii: S2213-2317(23)00381-6. [Epub ahead of print]69 102980
    Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis.
    Ufuk Ersoy, Ioannis Kanakis, Moussira Alameddine, Gibran Pedraza-Vazquez, Susan E Ozanne, Mandy Jayne Peffers, Malcolm J Jackson, Katarzyna Goljanek-Whysall, Aphrodite Vasilaki.
      The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.
    Keywords:  Maternal nutrition; Mitochondrial homeostasis; Protein restriction; Proteostasis; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2023.102980
  24. BMC Biol. 2023 Dec 08. 21(1): 287
    Geroprotector drugs and exercise: friends or foes on healthy longevity?
    Christian J Elliehausen, Rozalyn M Anderson, Gary M Diffee, Timothy W Rhoads, Dudley W Lamming, Troy A Hornberger, Adam R Konopka.
      Physical activity and several pharmacological approaches individually combat age-associated conditions and extend healthy longevity in model systems. It is tantalizing to extrapolate that combining geroprotector drugs with exercise could extend healthy longevity beyond any individual treatment. However, the current dogma suggests that taking leading geroprotector drugs on the same day as exercise may limit several health benefits. Here, we review leading candidate geroprotector drugs and their interactions with exercise and highlight salient gaps in knowledge that need to be addressed to identify if geroprotector drugs can have a harmonious relationship with exercise.
    Keywords:  Acarbose; Aging; Geroscience; Healthspan; Metformin; Physical activity; Rapamycin; SGLT2 inhibitors; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12915-023-01779-9
  25. Int J Mol Sci. 2023 Nov 24. pii: 16724. [Epub ahead of print]24(23):
    Mitochondrial Cation Signalling in the Control of Inflammatory Processes.
    Pampa Pain, Francesca Spinelli, Gaia Gherardi.
      Mitochondria are the bioenergetic organelles responsible for the maintenance of cellular homeostasis and have also been found to be associated with inflammation. They are necessary to induce and maintain innate and adaptive immune cell responses, acting as signalling platforms and mediators in effector responses. These organelles are also known to play a pivotal role in cation homeostasis as well, which regulates the inflammatory responses through the modulation of these cation channels. In particular, this review focuses on mitochondrial Ca2+ and K+ fluxes in the regulation of inflammatory response. Nevertheless, this review aims to understand the interplay of these inflammation inducers and pathophysiological conditions. In detail, we discuss some examples of chronic inflammation such as lung, bowel, and metabolic inflammatory diseases caused by a persistent activation of the innate immune response due to a dysregulation of mitochondrial cation homeostasis.
    Keywords:  inflammation; mitochondrial Ca2+ uptake; mitochondrial K+ flux
    DOI:  https://doi.org/10.3390/ijms242316724
  26. Biochim Biophys Acta Mol Basis Dis. 2023 Dec 06. pii: S0925-4439(23)00350-2. [Epub ahead of print]1870(2): 166984
    Butyrate ameliorated ferroptosis in ulcerative colitis through modulating Nrf2/GPX4 signal pathway and improving intestinal barrier.
    Hangping Chen, Yifan Qian, Chensheng Jiang, Leilei Tang, Jiawen Yu, Lingdi Zhang, Yiyang Dai, Guojun Jiang.
      Oxidative stress and intestinal inflammation are main pathological features of ulcerative colitis (UC). Ferroptosis, characterized by iron accumulation and lipid peroxidation, is closely related to the pathologic process of UC. 16S rRNA sequencing for intestinal microbiota analysis and gas chromatography-mass spectrometry (GC-MS) for short-chain fatty acid (SCFA) contents clearly demonstrated lower amounts of butyrate-producing bacteria and butyrate in colitis mice. However, the precise mechanisms of sodium butyrate (NaB) in treating UC remain largely unclear. We found that ferroptosis occurred in colitis models, as evidenced by the inflammatory response, intracellular iron level, mitochondria ultrastructural observations and associated protein expression. NaB inhibited ferroptosis in colitis, significantly rescued weight loss and colon shortening in mice and reduced inflammatory lesions and mitochondrial damage. Furthermore, NaB improved intestinal barrier integrity and markedly suppressed the expression of pro-ferroptosis proteins. Conversely, the protein expression of anti-ferroptosis markers including nuclear factor erythroid-related Factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4), was significantly upregulated with NaB treatment. Moreover, the knockdown of Nrf2 reversed the anti-colitis effect of NaB. Taken together, NaB exhibited a protective effect by ameliorating ferroptosis in experimental colitis through Nrf2/GPX4 signaling and improving intestinal barrier integrity, which provides a novel mechanism for NaB prevention of UC.
    Keywords:  Ferroptosis; Gut microbiota; Intestinal barrier integrity; Nrf2/GPX4 signaling; Sodium butyrate; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166984
  27. Int Immunopharmacol. 2023 Dec 12. pii: S1567-5769(23)01667-3. [Epub ahead of print]127 111340
    Arachidonic acid alleviates autoimmune diabetes in NOD mice.
    Yunjuan Zhao, Yimei Chen, Qiwen Xiao, Wangen Li.
      BACKGROUND: Arachidonic acid (AA) is considered to link nutrient metabolism, to inflammation and immunity, suggesting it may have a role in autoimmune diseases. Our previous study suggests that DPP-4 inhibitors (DPP-4i) might regulate AA - relative signaling in type 1 diabetes.AIMS: To examine the effect of AA on autoimmune diabetes and its cross-talk with DPP-4i in The Non-Obese Diabetic (NOD) mice.
    METHODS: The NOD mice were divided randomly and equally into three groups: AA group, AA plus DPP-4i group and control group. The incidence of diabetes, blood glucose, insulitis and cytokine profiles were monitored. At the end of the experiment, pancreatic tissues were stained by H&E. Serum cytokine profiles were examined using a Mesco Scale Discovery multiplexed-assay kit.
    RESULTS: Even though AA or AA plus DPP-4i treatment has no effect on incidence of diabetes and weight, AA treatment reduces blood glucose, preserves islet morphology and alleviates inflammatory cell infiltration into pancreatic islets in NOD mice, accompanying with increased serum levels of IL-10, IL-1 β, IL-6, IL-5, KC/GRO and TNF-α and decreased serum levels of IL-2.
    CONCLUSION: We observed that AA treatment alleviates autoimmune diabetes in NOD mice by reducing hyperglycemia, alleviating insulitis and improving cytokine profiles. DPP-4i might alleviate the effect of AA by cross-talk. We provide evidence of AA treatment to alleviate type 1 diabetes in NOD mice, which may provide a novel therapeutic option for type 1 diabetes.
    Keywords:  Arachidonic acid; Insulitis; NOD mice; Type 1 diabetes; β cell
    DOI:  https://doi.org/10.1016/j.intimp.2023.111340
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