bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024–10–27
seventeen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.
  2. The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
  3. The dietary exposome: a brief history of diet, longevity, and age-related health in rodents.
  4. Females have better metabolic flexibility in different metabolically challenging stimuli.
  5. Inflammation and resolution in obesity.
  6. Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.
  7. Establishment of a dexamethasone-induced zebrafish skeletal muscle atrophy model and exploration of its mechanisms.
  8. Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
  9. Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
  10. HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.
  11. Circulating ketone bodies, genetic susceptibility, with left atrial structure, function and atrial fibrillation: A prospective study from UK Biobank.
  12. Mitochondrial Abundance and Function Differ Across Muscle Within Species.
  13. Ketone body oxidation and susceptibility to ethyl acetoacetate in a novel hemolytic multidrug-resistant strain Leptospira interrogans KeTo originated from sewage water.
  14. Mitochondrial pathways and sarcopenia in the geroscience era.
  15. Targeting MuRF1 to Combat Skeletal Muscle Wasting in Cardiac Cachexia: Mechanisms and Therapeutic Prospects.
  16. Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
  17. Effects of overnight-fasted versus fed-state exercise on the components of energy balance and interstitial glucose across four days in healthy adults.
  1. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    Metabolic Effects of Medium-Chain Triacylglycerol Consumption are Preserved in Obesity.
    Josephine M Kanta, Anne-Marie Lundsgaard, Jesper F Havelund, Sarah L Amour, Ole Bæk, Duc Ninh Nguyen, Erik A Richter, Jakob G Knudsen, Maximilian Kleinert, Nils Faergeman, Andreas M Fritzen, Bente Kiens.
      Several health beneficial effects are associated with intake of medium-chain triacylglycerol (MCT), however, the underlying mechanisms are unknown. Furthermore, it remains uncertain whether the acute metabolic effects of MCT differ between lean individuals and individuals with obesity - and whether these effects are sustained following chronic intake. This study aimed to elucidate the postprandial physiological and metabolic effects of MCT before and after eight days intake compared to intake of energy-matched triacylglycerol consisting of long-chain fatty acids (LCT) using a randomized cross-over design in lean individuals (n=8) and individuals with obesity (n=8). The study revealed that consumption of MCT increased ketogenesis and metabolic rate, while lowering blood glucose levels over five hours. The hypoglycemic action of MCT intake was accompanied by a concomitant transient increase in plasma insulin and glucagon levels. Interestingly, the effects on ketogenesis, metabolic rate, and glycemia were preserved in individuals with obesity and sustained after eight days of daily supplementation. Lipidomic plasma analysis in lean individuals (n=4) showed that a part of the ingested MCT bypasses the liver and entered the systemic circulation as medium-chain fatty acids (MCFA). The findings suggest that MCFA, along with ketone bodies from the liver, may act as signaling molecules and/or substrates in the peripheral tissues, thereby contributing to the effects of MCT intake. In summary, these findings underscore the health benefits of MCT in metabolically compromised individuals after daily supplementation. Moreover, we uncover novel aspects of MCFA biology, providing insights into how these fatty acids orchestrate physiological effects in humans.
    Keywords:  Medium-chain fatty acids; Metabolism; ketone bodies; lipid metabolism
    DOI:  https://doi.org/10.1152/ajpendo.00234.2024
  2. Am J Physiol Endocrinol Metab. 2024 Oct 23.
    The Acute and Chronic influence of Exercise on Mitochondrial Dynamics in Skeletal Muscle.
    Elya Janis Ritenis, Camila S Padilha, Matthew B Cooke, Christos George Stathis, Andrew Philp, Donny M Camera.
      Exercise and nutritional modulation are potent stimuli for eliciting increases in mitochondrial mass and function. Collectively, these beneficial adaptations are increasingly recognized to coincide with improvements to skeletal muscle health. Mitochondrial dynamics of fission and fusion are increasingly implicated as having a central role in mediating aspects of key organelle adaptions that are seen with exercise. Exercise-induced mitochondrial adaptations that dynamics have been implicated in are: 1) Increases to mitochondrial turnover, resulting from elevated rates of mitochondrial synthesis (biogenesis) and degradative (mitophagy) processes. 2) Morphological changes to the 3D tubular network, known as the mitochondrial reticulum, that mitochondria form in skeletal muscle. Notably, mitochondrial fission has also been implicated in coordinating increases in mitophagy, following acute exercise. Further, increased fusion following exercise training promotes increased connectivity of the mitochondrial reticulum and is associated with improved metabolism and mitochondrial function. However, the molecular basis and fashion in which exercise infers beneficial mitochondrial adaptations through mitochondrial dynamics remains poorly understood. This review attempts to highlight recent developments investigating the effects of exercise on mitochondrial dynamics, while attempting to offer a perspective of the methodological refinements and potential variables, such as substrate/glycogen availability, which should be considered going forward.
    Keywords:  Exercise; Mitochondrial Dynamics; Skeletal Muscle
    DOI:  https://doi.org/10.1152/ajpendo.00311.2024
  3. Clin Sci (Lond). 2024 Nov 06. 138(21): 1343-1356
    The dietary exposome: a brief history of diet, longevity, and age-related health in rodents.
    Colin Selman.
      It has been recognized for over a century that feeding animals less food than they would normally eat increases lifespan and leads to broad-spectrum improvements in age-related health. A significant number of studies have subsequently shown that restricting total protein, branched chain amino acids or individual amino acids in the diet, as well as ketogenic diets, can elicit similar effects. In addition, it is becoming clear that fasting protocols, such as time-restricted-feeding or every-other-day feeding, without changes in overall energy intake can also profoundly affect rodent longevity and late-life health. In this review, I will provide a historical perspective on various dietary interventions that modulate ageing in rodents and discuss how this understanding of the dietary exposome may help identify future strategies to maintain late-life health and wellbeing in humans.
    Keywords:  Ageing; Aging; Caloric restriction; Dietary restriction; Fasting; Lifespan
    DOI:  https://doi.org/10.1042/CS20241248
  4. Appl Physiol Nutr Metab. 2024 Oct 22.
    Females have better metabolic flexibility in different metabolically challenging stimuli.
    José Antonio Benitez-Muñoz, Isabel Guisado-Cuadrado, Miguel A Rojo-Tirado, María Alcocer-Ayuga, Nuria Romero-Parra, Ana Belén Peinado, Rocío Cupeiro.
      The first aim was to explore the difference in metabolic flexibility between sexes in response to changing exercise intensity under control conditions. The second aim was to evaluate metabolic flexibility between sexes in response to exercise intensity adding two different metabolically challenging stimuli (glycogen depletion and heat). Eleven males (22±3yrs, 176.2±4cm, 68.4±4.9kg and 60.2±4.1ml/kgFFM/min) and nine females (22±2yrs, 166.7±4.5cm, 61.9±2.9kg, 64.2±5.6 ml/kgFFM/min) performed a maximal incremental exercise test (30W every 3min) on a cycle ergometer under three conditions: control (24h high-carbohydrate diet followed by the incremental test), glycogen depletion (glycogen-depletion protocol followed by 24h low-carbohydrate diet and then the incremental test) and heat (24h high-carbohydrate diet followed by 30 min passive heating and then the incremental test in heat). In the last minute of each step, lactate was analysed, fat (FATox/FFM) and carbohydrate oxidation (CHox/FFM) and energy expenditure (EE/FFM) normalized to fat free mass was estimated by indirect calorimetry. Females presented a greater FATox/FFM as exercise intensity increases across conditions (control, glycogen depletion and heat) (p=0.006). In contrast, CHox/FFM was not significantly different between sexes at any specific intensity across conditions (p>0.05). Consequently, EE/FFM was higher in females throughout the different intensities across conditions (p=0.002). Finally, lactate concentration was not different between sexes at the same intensities across conditions (p=0.87). In conclusion, females present a greater metabolic flexibility, due to the higher FATox/FFM throughout the different intensities, regardless of whether the test is performed in a conditions emphasizing the oxidative pathway (glycogen depletion) or the glycolytic pathway (heat). Clinical trials:NCT05703100.
    DOI:  https://doi.org/10.1139/apnm-2024-0217
  5. Nat Rev Endocrinol. 2024 Oct 24.
    Inflammation and resolution in obesity.
    Matúš Soták, Madison Clark, Bianca E Suur, Emma Börgeson.
      Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.
    DOI:  https://doi.org/10.1038/s41574-024-01047-y
  6. Aging Cell. 2024 Oct 24. e14382
    Time-restricted feeding mediated modulation of microbiota leads to changes in muscle physiology in Drosophila obesity models.
    Christopher Livelo, Yiming Guo, Jagathnarayan Madhanagopal, Casey Morrow, Girish C Melkani.
      Recent research has highlighted the essential role of the microbiome in maintaining skeletal muscle physiology. The microbiota influences muscle health by regulating lipid metabolism, protein synthesis, and insulin sensitivity. However, metabolic disturbances such as obesity can lead to dysbiosis, impairing muscle function. Time-restricted feeding (TRF) has been shown to mitigate obesity-related muscle dysfunction, but its effects on restoring healthy microbiomes remain poorly understood. This study utilizes 16S microbiome analysis and bacterial supplementation to investigate the bacterial communities influenced by TRF that may benefit skeletal muscle physiology. In wild-type and obese Drosophila models (axenic models devoid of natural microbial communities), the absence of microbiota influence muscle performance and metabolism differently. Specifically, axenic wild-type Drosophila exhibited reduced muscle performance, higher glucose levels, insulin resistance, ectopic lipid accumulation, and decreased ATP levels. Interestingly, in obese Drosophila (induced by a high-fat diet or predisposed obesity mutant Sk2), the absence of microbiota improved muscle performance, lowered glucose levels, reduced insulin resistance, and increased ATP levels. TRF was found to modulate microbiota composition, notably increasing Acetobacter pasteurianus (AP) and decreasing Staphylococcus aureus (SA) in both obesity models. Supplementation with AP improved muscle performance and reduced glucose and insulin resistance, while SA supplementation had the opposite effect. This study provides novel insights into the complex interactions between TRF, microbiota, and skeletal muscle physiology in different Drosophila models.
    Keywords:  16S microbiome analysis; ATP; Drosophila obesity models; insulin sensitivity and resistance; metabolic homeostasis; muscle metabolism; skeletal muscle physiology; time‐restricted feeding
    DOI:  https://doi.org/10.1111/acel.14382
  7. Exp Gerontol. 2024 Oct 21. pii: S0531-5565(24)00261-4. [Epub ahead of print] 112615
    Establishment of a dexamethasone-induced zebrafish skeletal muscle atrophy model and exploration of its mechanisms.
    Chen-Chen Sun, Ye-Jun Li, Dan-Ting Zhu, Zhang-Lin Chen, Jiang-Ling Xiao, Xiang-Tao Chen, Lan Zheng, Xi-Yang Peng, Chang-Fa Tang.
       BACKGROUND: Skeletal muscle atrophy is one of the main side effects of high-dose or continuous use of glucocorticoids (such as dexamethasone). However, there are limited studies on dexamethasone-induced skeletal muscle atrophy in zebrafish and even fewer explorations of the underlying molecular mechanisms. This study aimed to construct a model of dexamethasone-induced skeletal muscle atrophy in zebrafish and to investigate the molecular mechanisms.
    METHODS: Zebrafish soaked in 0.01 % dexamethasone solution for 10 days. Loli Track (Denmark) and Loligo Swimming Respirometer were used to observe the effect of dexamethasone on swimming ability. The effects of dexamethasone on zebrafish skeletal muscle were observed by Transmission electron microscopy, H&E, and wheat germ agglutinin techniques. Enriched genes and signaling pathways were analyzed using Transcriptome sequencing. Further, the levels of mitochondrial and endoplasmic reticulum-related proteins were examined to investigate possible mechanisms.
    RESULTS: 0.01 % dexamethasone reduced zebrafish skeletal muscle mass (p < 0.05), myofibre size and cross-sectional area (p < 0.001), and increased protein degradation (ubiquitination and autophagy) (p < 0.05). In addition, 0.01 % dexamethasone reduced the swimming ability of zebrafish, as evidenced by the reluctance to move, fewer movement trajectories, decreased total distance traveled (p < 0.001), average velocity of movement (p < 0.001), oxygen consumption (p < 0.001), critical swimming speed (p < 0.01) and increased exhaustive swimming time (p < 0.001). Further, 0.01 % dexamethasone-induced mitochondrial dysfunction (decreased mitochondrial biogenesis, disturbs kinetic homeostasis, increased autophagy) and endoplasmic reticulum stress.
    CONCLUSIONS: 0.01 % dexamethasone induces skeletal muscle atrophy and impairs the swimming ability of zebrafish through mitochondrial dysfunction and endoplasmic reticulum stress.
    Keywords:  Dexamethasone; Endoplasmic reticulum stress; Mitochondrial dysfunction; Skeletal muscle atrophy; Zebrafish
    DOI:  https://doi.org/10.1016/j.exger.2024.112615
  8. J Vis Exp. 2024 Oct 04.
    Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry.
    Terri A Pietka, Rita T Brookheart.
      Mitochondrial function, a cornerstone of cellular energy production, is critical for maintaining metabolic homeostasis. Its dysfunction in skeletal muscle is linked to prevalent metabolic disorders (e.g., diabetes and obesity), muscular dystrophies, and sarcopenia. While there are many techniques to evaluate mitochondrial content and morphology, the hallmark method to assess mitochondrial function is the measurement of mitochondrial oxidative phosphorylation (OXPHOS) by respirometry. Quantification of mitochondrial OXPHOS provides insight into the efficiency of mitochondrial oxidative energy production and cellular bioenergetics. A high-resolution respirometer provides highly sensitive, robust measurements of mitochondrial OXPHOS in permeabilized muscle fibers by measuring real-time changes in mitochondrial oxygen consumption rate. The use of permeabilized muscle fibers, as opposed to isolated mitochondria, preserves mitochondrial networks, maintains mitochondrial membrane integrity, and ultimately allows for more physiologically relevant measurements. This system also allows for the measurement of fuel preference and metabolic flexibility - dynamic aspects of muscle energy metabolism. Here, we provide a comprehensive guide for mitochondrial OXPHOS measurements in human and mouse skeletal muscle fibers using a high-resolution respirometer. Skeletal muscle groups are composed of different fiber types that vary in their mitochondrial fuel preference and bioenergetics. Using a high-resolution respirometer, we describe methods for evaluating both aerobic glycolytic and fatty acid substrates to assess fuel preference and metabolic flexibility in a fiber-type-dependent manner. The protocol is versatile and applicable to both human and rodent muscle fibers. The goal is to enhance the reproducibility and accuracy of mitochondrial function assessments, which will improve our understanding of an organelle important to muscle health.
    DOI:  https://doi.org/10.3791/66834
  9. Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549
    Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
    Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.
      Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.
    Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.arr.2024.102549
  10. Circ Res. 2024 Oct 25. 135(10): 1018-1020
    HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.
    Xi Fang, Åsa B Gustafsson.
      
    Keywords:  Editorials; diet, high-fat; heart failure; metabolism; mitochondria, heart; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325501
  11. Heart Rhythm. 2024 Oct 19. pii: S1547-5271(24)03454-4. [Epub ahead of print]
    Circulating ketone bodies, genetic susceptibility, with left atrial structure, function and atrial fibrillation: A prospective study from UK Biobank.
    Nan Zhang, Daiqi Liu, Jinhua Zhao, Gary Tse, Jiandong Zhou, Qingpeng Zhang, Gregory Y H Lip, Tong Liu.
       BACKGROUND: Ketone bodies (KB) are important cardiac metabolic energy source. Metabolic remodeling has been recently pointed to play an important role in the pathological process of atrial fibrillation (AF).
    OBJECTIVE: To evaluate the associations between circulating KB levels with incident AF risk in the general population.
    METHODS: We studied 237,163 participants (mean age, 56.5 years; 55% women) from the UK Biobank who were free of AF at baseline and had data about circulating β-hydroxybutyrate (β-OHB), acetoacetate, and acetone. The associations between KB with new-onset AF were evaluated by Cox regression in the general population and across three genetic risk groups [low, moderate, and high polygenic risk score of AF].
    RESULTS: During a median follow-up of 14.8 years, 16,638 (7.0%) participants developed AF. There was a U-shaped association between total KB and β-OHB with incident AF, with nadirs at 60.6 and 40.8 μmol/L, respectively (P non-linear <0.05), whereas a positive association between acetoacetate and acetone with AF was observed (P overall <0.001, P non-linear >0.05). Consistently, a U-shaped association was observed between total KB and β-OHB with left atrial (LA) volume parameters, including LA maximum volume (LAVmax), LA minimum volume (LAVmin), and their body surface area-indexed counterparts, and an inverted U-shaped association was observed for LA ejection fraction (all P non-linear <0.05). The association between KB with AF was greater among individuals with low genetic risk (Pinteraction <0.05), while the highest AF risk was for those at high genetic risk with high KB levels. Significant mediation effects of inflammatory markers on the associations between KB and AF were identified.
    CONCLUSIONS: There was a U-shaped association between circulating total KB and β-OHB with incident AF, as well as a positive association between acetoacetate and acetone level with AF risk in the general population.
    Keywords:  Atrial fibrillation; UK Biobank; cardiac magnetic resonance; genetic risk; ketone bodies
    DOI:  https://doi.org/10.1016/j.hrthm.2024.10.028
  12. Metabolites. 2024 Oct 16. pii: 553. [Epub ahead of print]14(10):
    Mitochondrial Abundance and Function Differ Across Muscle Within Species.
    Con-Ning Yen, Jocelyn S Bodmer, Jordan C Wicks, Morgan D Zumbaugh, Michael E Persia, Tim H Shi, David E Gerrard.
      Background: Mitochondria are considered the powerhouse of cells, and skeletal muscle cells are no exception. However, information regarding muscle mitochondria from different species is limited. Methods: Different muscles from cattle, pigs and chickens were analyzed for mitochondrial DNA (mtDNA), protein and oxygen consumption. Results: Bovine oxidative muscle mitochondria contain greater mtDNA (p < 0.05), protein (succinate dehydrogenase, SDHA, p < 0.01; citrate synthase, CS, p < 0.01; complex I, CI, p < 0.05), and oxygen consumption (p < 0.01) than their glycolytic counterpart. Likewise, porcine oxidative muscle contains greater mtDNA (p < 0.01), mitochondrial proteins (SDHA, p < 0.05; CS, p < 0.001; CI, p < 0.01) and oxidative phosphorylation capacity (OXPHOS, p < 0.05) in comparison to glycolytic muscle. However, avian oxidative skeletal muscle showed no differences in absolute mtDNA, SDHA, CI, complex II, lactate dehydrogenase, or glyceraldehyde 3 phosphate dehydrogenase compared to their glycolytic counterpart. Even so, avian mitochondria isolated from oxidative muscles had greater OXPHOS capacity (p < 0.05) than glycolytic muscle. Conclusions: These data show avian mitochondria function is independent of absolute mtDNA content and protein abundance, and argue that multiple levels of inquiry are warranted to determine the wholistic role of mitochondria in skeletal muscle.
    Keywords:  metabolism; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo14100553
  13. Sci Rep. 2024 Oct 24. 14(1): 25198
    Ketone body oxidation and susceptibility to ethyl acetoacetate in a novel hemolytic multidrug-resistant strain Leptospira interrogans KeTo originated from sewage water.
    Amin Sonam, Asif Hameed, Punchappady Devasya Rekha, Paul Stothard, Rouchelle Charmaine Tellis, Ananthapadmanabha Bhagwath Arun.
      Terrestrial and aquatic environments contaminated with animal urine may contribute to the transmission of Leptospira, a causative agent of leptospirosis in humans and wild/domesticated animals. Although enormous amounts of work have been done decoding the ecophysiology, the factors governing the cell growth and virulence in Leptospires derived from environmental samples still remain elusive. Here, we show oxidation of a wide array of organic acids including acetoacetate by a new strain of Leptospira interrogans designated as KeTo, isolated from a sewage sample originating from a wildlife enclosure located at Mangalore, India. We further demonstrate the susceptibility of KeTo to ethyl ester of acetoacetate (ethyl acetoacetate, EA). A 4.7 Mbp genome of KeTo shared the highest relatedness to pathogenic L. interrogans RGAT (99.3%), followed by L. kirschneri 3522CT (91.3%) and other related species of Leptospira (80.8‒74.3%), and harbored genes encoding acetoacetyl-CoA synthetase and acetoacetate decarboxylase respectively involved in the acetoacetate utilization and acetone formation. In line with this, strain KeTo oxidized acetoacetate when supplied as a sole carbon. Aqueous EA suppressed biofilm formation (p < 0.0001) of KeTo in basal Ellinghausen-McCullough-Johnson-Harris (EMJH) medium. Similarly, significant inhibition in the growth/biofilm of Leptospira was recorded in semisolid EMJH with/without blood supplementation when exposed to volatile EA. The extent of ketone body oxidation and susceptibility to EA was found to vary with strain as evident through the analysis of L. interrogans serogroup Australis sv. Australis strain Ballico and L. interrogans serogroup Icterohaemorrhagiae sv. Lai Like strain AF61. In conclusion, our study demonstrated the ketone body metabolic ability and susceptibility to an esterified derivative of a major ketone body in the tested strains of L. interrogans. Molecular aspects governing EA-driven growth inhibition warrant further investigations to develop optimal therapeutics for leptospirosis.
    Keywords:  Acetoacetate; Antibiotic resistance; Leptospirosis; Succinyl-CoA:3 oxoacid CoA transferase; Virulence factor
    DOI:  https://doi.org/10.1038/s41598-024-76546-z
  14. J Nutr Health Aging. 2024 Oct 19. pii: S1279-7707(24)00485-8. [Epub ahead of print]28(12): 100397
    Mitochondrial pathways and sarcopenia in the geroscience era.
    Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Anna Picca.
      Sarcopenia is associated with structural, ultrastructural, and molecular abnormalities of skeletal muscle. Mitochondrial dysfunction is a pivotal factor involved in muscle aging and sarcopenia. Mitochondrial bioenergetics are significantly reduced in muscles of older adults which is associated with whole-body aerobic capacity, muscle strength, and physical performance. Transcriptional profiling of muscle samples from older adults also revealed inverse correlations between gene expression patterns of autophagy and mitophagy and muscle volume and physical performance. This is in line with the proposition that mitochondrial quality control (MQC) processes are key to organellar and tissue health. MQC encompasses mitochondrial biogenesis, dynamics, and mitophagy. The latter has recently been included among the hallmarks of aging and alterations in MQC have been associated with chronic sterile inflammation as well as muscle atrophy and dysfunction. Several biomarkers spanning MQC, inflammation, metabolism, intercellular communication, and gut microbiota have been linked to sarcopenia. Findings from these initial studies hold promise to inform geroscience-based research in the field of sarcopenia by offering a plausible biological framework for developing gerotherapeutics and monitoring their effects.
    Keywords:  Biology of aging; Extracellular vesicles; Inflammaging; Mitochondrial quality control; Multi-Marker; Omics
    DOI:  https://doi.org/10.1016/j.jnha.2024.100397
  15. Med Sci Monit. 2024 Oct 22. 30 e945211
    Targeting MuRF1 to Combat Skeletal Muscle Wasting in Cardiac Cachexia: Mechanisms and Therapeutic Prospects.
    Xiaotong Liu, Ya Wen, Yanmei Lu.
      Cardiac cachexia, the terminal stage of chronic heart failure, is characterized by severe systemic metabolic imbalances and significant weight loss, primarily resulting from skeletal muscle mass depletion. Despite the detrimental consequences, there is no standardized and clinically-approved intervention currently available for cardiac cachexia. In the context of cardiac cachexia, accelerated protein turnover, that is, inhibited protein synthesis and enhanced protein degradation, plays a crucial role in skeletal muscle wasting. This process is primarily mediated by various proteins encoded by atrogenes. Among them, the atrogene Trim63 (tripartite motif family 63) and its encoded protein MuRF1 have been extensively studied. This review article aims to elucidate the pathogenic mechanisms underlying skeletal muscle wasting in cardiac cachexia, describe the biochemical characteristics of MuRF1, and provide an overview of the investigation into MuRF1-targeting inhibitors. The ultimate goal is to offer novel strategies for the clinical treatment for skeletal muscle wasting associated with cardiac cachexia.
    DOI:  https://doi.org/10.12659/MSM.945211
  16. Physiol Rep. 2024 Oct;12(20): e70088
    Decreased mitochondrial-related gene expression in adipose tissue after acute sprint exercise in humans: A pilot study.
    Mona Esbjörnsson, Håkan C Rundqvist, Barbara Norman, Ted Österlund, Eric Rullman, Jens Bülow, Eva Jansson.
      The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30-s all-out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial-related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early-stage inhibition of the mitochondria, potentially as a protective mechanism against SIT-induced oxidative stress.
    Keywords:  biopsy; high intensity; microarray analysis; skeletal muscle; sprint interval exercise; subcutaneous white adipose tissue; transcriptome
    DOI:  https://doi.org/10.14814/phy2.70088
  17. Appetite. 2024 Oct 18. pii: S0195-6663(24)00520-8. [Epub ahead of print]203 107716
    Effects of overnight-fasted versus fed-state exercise on the components of energy balance and interstitial glucose across four days in healthy adults.
    I Podestá D, A K Blannin, G A Wallis.
      Exercise is an essential component of body mass management interventions. Overnight-fasted exercise (FASTex) acutely enhances fat oxidation compared with fed exercise (FEDex). However, consistent FASTex training does not typically further enhance body mass loss, suggesting the induction of energy compensation responses. The present study aimed to test the effects of FASTex or FEDex on the components of energy balance (i.e., energy intake (EI), energy expenditure (EE), and appetite) and interstitial glucose metrics across four days.
    METHODS: Twelve (10 men, 2 women) healthy, physically active participants (age 22.6 + 1.2 years (mean ± SD); BMI 22.5 ± 2.8 kg ⋅ m-2) were studied twice, across four days, after a 75-min run either FASTex or FEDex. Daily EI was obtained after subtracting leftovers from the provided food. Daily fasting appetite was measured by visual analogue scales. Activity- and total- EE (AEE & TEE, respectively) were estimated by combining heart rate and accelerometry. Continuous glucose monitoring was used to capture daily interstitial glucose metrics and Likert scales were utilised to quantify fatigue, stress, sleep quality, and muscle soreness levels.
    RESULTS: No differences between conditions were observed for EI (FASTex = 15.0 ± 0.1 vs FEDex = 15.0 ± 0.4 MJ⋅day-1; p = 0.865), AEE (FASTex = 7.6 ± 1.1 vs FEDex 7.8 ± 1.3 MJ⋅day-1; p = 0.223) and TEE (FASTex = 15.9 ± 3.4 vs 14.9 ± 4.5 MJ⋅day-1; p = 0.136). Additionally, no condition effects for appetite (p > 0.05) and interstitial glucose (p = 0.074) were observed.
    CONCLUSION: FASTex did not differ from FEDex in the response of components of energy balance or interstitial glucose across four days, suggesting that both exercise approaches could be used interchangeably.
    Keywords:  Appetite; Carbohydrate; Continuous glucose monitoring; Energy expenditure; Energy intake
    DOI:  https://doi.org/10.1016/j.appet.2024.107716
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