bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–02–05
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Fasting: From Physiology to Pathology.
  2. Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.
  3. The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.
  4. β-hydroxybutyrate as a biomarker of β-cell function in new-onset type 2 diabetes and its association with treatment response at 6 months.
  5. β-hydroxybutyrate enhances bovine neutrophil adhesion by inhibiting autophagy.
  6. Link between emotional and external eating behaviors, peripheral neuropeptide Y, and β-hydroxybutyrate in participants with obesity on 12-week ketogenic diet.
  7. Dimethyl fumarate attenuates MSU-induced gouty arthritis by inhibiting NLRP3 inflammasome activation and oxidative stress.
  8. Use of Ketogenic Diet in Two Indian Children with a Rare Early-Onset Epileptic Encephalopathy.
  9. Metabolism and exercise: the skeletal muscle clock takes centre stage.
  10. Do statins blunt the beneficial effect of aerobic exercise on metabolic flexibility?
  11. Editorial: The NLRP3 inflammasome-mediated neuroinflammation and its related mitochondrial impairment in neurodegeneration.
  12. An update on the role of TRIM/NLRP3 signaling pathway in atherosclerosis.
  13. Effect of increased protein intake and exogenous ketosis on body composition, energy expenditure and exercise capacity during a hypocaloric diet in recreational female athletes.
  14. Controlling Inflammation Improves Aging Skeletal Muscle Health.
  15. A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.
  16. An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.
  17. Skeletal muscle fiber composition may modify the effect of nutrition on body composition in young females.
  18. Transcriptional reprogramming of skeletal muscle stem cells by the niche environment.
  19. Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.
  20. Predicting heart failure with preserved ejection fraction: revisiting an old friend with new knowledge.
  21. A Self-Selected 16:8 Time-Restricted Eating Protocol Improves Fat Oxidation Rates, Markers of Cardiometabolic Health, and 10-km Cycling Performance in Middle-Age Male Cyclists.
  22. Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions.
  23. Protein translation paradox: Implications in translational regulation of aging.
  24. Targeting negative energy balance with calorie restriction and mitochondrial uncoupling in db/db mice.
  25. Higher fasting fibroblast growth factor 21 was associated with a greater decline in postprandial blood pressure.
  1. Adv Sci (Weinh). 2023 Feb 03. e2204487
    Fasting: From Physiology to Pathology.
    Dongmei Tang, Qiuyan Tang, Huang Wei, Yuwei Zhang, Yan Tian, Xianghui Fu.
      Overnutrition is a risk factor for various human diseases, including neurodegenerative diseases, metabolic disorders, and cancers. Therefore, targeting overnutrition represents a simple but attractive strategy for the treatment of these increasing public health threats. Fasting as a dietary intervention for combating overnutrition has been extensively studied. Fasting has been practiced for millennia, but only recently have its roles in the molecular clock, gut microbiome, and tissue homeostasis and function emerged. Fasting can slow aging in most species and protect against various human diseases, including neurodegenerative diseases, metabolic disorders, and cancers. These centuried and unfading adventures and explorations suggest that fasting has the potential to delay aging and help prevent and treat diseases while minimizing side effects caused by chronic dietary interventions. In this review, recent animal and human studies concerning the role and underlying mechanism of fasting in physiology and pathology are summarized, the therapeutic potential of fasting is highlighted, and the combination of pharmacological intervention and fasting is discussed as a new treatment regimen for human diseases.
    Keywords:  aging; diseases; fasting-mimicking diet; intermittent fasting; time-restricted feeding
    DOI:  https://doi.org/10.1002/advs.202204487
  2. bioRxiv. 2023 Jan 13. pii: 2023.01.11.523492. [Epub ahead of print]
    Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System.
    Jonathan Enders, Jarrid Jack, Sarah Thomas, Paige Lynch, Sarah Lasnier, Xin Cao, M Taylor Swanson, Janelle M Ryals, John P Thyfault, Patrycja Puchalska, Peter A Crawford, Douglas E Wright.
      Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1 ), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated s ensory n euron-specific, A dvillin- C re k nockout of O xct1 (SNACKO) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and innervation of the skin and spinal dorsal horn. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. SNACKO mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet SNACKO mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.
    DOI:  https://doi.org/10.1101/2023.01.11.523492
  3. J Sleep Res. 2023 Feb 03. e13832
    The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.
    Lydia Rose Henderson, Margo van den Berg, David M Shaw.
      Extended wakefulness, or sleep deprivation, impairs cognitive performance and brain glucose metabolism. A ketogenic diet (KD) provides an alternative fuel source, ketone bodies, that could elicit a metabolic benefit during sleep deprivation. A randomised, cross-over trial was conducted with seven male military personnel. Participants ingested an iso-energetic ketogenic diet or carbohydrate-based diet for 14 days, immediately followed by 36 h of extended wakefulness and separated by a 12 day washout. Cognitive performance, mood, subjective sleepiness, capillary blood glucose, and D-β-hydroxybutyrate concentrations were measured every 2 h during extended wakefulness. Linear mixed models were used to analyse data. D-β-hydroxybutyrate was higher (p < 0.001) and glucose was lower (p < 0.01) on the KD compared with the carbohydrate-based diet. The KD improved psychomotor vigilance task performance (number of lapses, mean reciprocal response time, mean fastest 10% response time (RT), and mean slowest 10% RT; all p < 0.05), running memory continuous performance test performance (RT and number of correct responses per minute; both p < 0.01), and vigour, fatigue, and sleepiness (all, p ≤ 0.001) compared with the carbohydrate-based diet. In conclusion, a KD demonstrated beneficial effects on cognitive performance, mood, and sleepiness during 36 h of extended wakefulness compared with a carbohydrate-based diet.
    Keywords:  fatigue management; keto-adaptation; ketosis; psychomotor vigilance task; randomised controlled trial; sleep deprivation
    DOI:  https://doi.org/10.1111/jsr.13832
  4. Diabetes Metab. 2023 Jan 25. pii: S1262-3636(23)00009-5. [Epub ahead of print] 101427
    β-hydroxybutyrate as a biomarker of β-cell function in new-onset type 2 diabetes and its association with treatment response at 6 months.
    Minyoung Lee, Yongin Cho, Yong-Ho Lee, Eun Seok Kang, Bong-Soo Cha, Byung-Wan Lee.
       AIMS: Increasing attention has been paid to the potential metabolic benefits of ketone bodies, but the clinical relevance of ketone bodies in newly diagnosed type 2 diabetes mellitus (T2D) remains unclear. We investigated the clinical implications of ketone bodies at the time of diagnosis in patients with drug-naïve T2D.
    METHODS: Clinical data including serum β-hydroxybutyrate (βHB) levels, were collected from 369 patients with newly diagnosed drug-naïve T2D from 2017-2021. Subjects were categorized into four βHB groups based on the level of initial serum βHB. The associations of initial serum βHB and urinary ketone levels with glucometabolic indices were analyzed.
    RESULTS: Higher serum βHB group was associated with higher levels of glycemic parameters including glycated hemoglobin (HbA1c) with lower levels of indices for insulin secretory function at the point of initial diagnosis of T2D. Nevertheless, higher serum βHB group was an independent determinant of a greater relative improvement in HbA1c after 6 months of anti-diabetic treatment, regardless of the type of anti-diabetic drug. In addition, patients in higher serum βHB group were more likely to have well-controlled HbA1c levels (≤6.5%) after 6 months of anti-diabetic treatment.
    CONCLUSION: In patients with newly diagnosed T2D, a higher initial βHB level was a significant predictive marker of greater glycemic improvement after antidiabetic treatment, despite its associations with hyperglycemia and decreased insulin secretion at baseline.
    Keywords:  Biomarker; Ketone body; Type 2 diabetes; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.diabet.2023.101427
  5. Front Immunol. 2022 ;13 1096813
    β-hydroxybutyrate enhances bovine neutrophil adhesion by inhibiting autophagy.
    Jiyuan He, Kexin Wang, Mingchao Liu, Wen Zeng, Dong Li, Zolzaya Majigsuren, Tugsjargal Batbaatar, Yunfei Li, Siyuan Liu, Xiliang Du, Lin Lei, Yuxiang Song, Guowen Liu.
       Introduction: Subclinical ketosis (SCK) in dairy cows, a common metabolic disorder during the perinatal period, is accompanied by systemic inflammation and a high concentration of blood β-hydroxybutyrate (BHB). BHB induced adhesion of neutrophils may play a crucial role in the development of systemic inflammation in SCK cows. Autophagy, an intracellular degradation system, regulates the recycling of membrane adhesion molecules and may be involved in BHB regulating adhesion and pro-inflammatory activation of bovine neutrophils. Thus, the objective of this study was to determine the relationship between BHB, autophagy, and neutrophil adhesion.
    Results and discussion: Here, elevated abundance of serum amyloid A, haptoglobin, C-reactive protein, interleukin-1β, interleukin-6, and tumor necrosis factor-α were found in SCK cows, and all these pro-inflammatory factors had a strong positive correlation with serum BHB. After BHB treatment, the number of adherent neutrophils and the adhesion associated protein abundance of both total and membrane CD11a, CD11b, and CD18 was greater, confirming that BHB promoted the adhesion of bovine neutrophils. However, the mRNA abundance of ITGAL (CD11a), ITGAM (CD11b), and ITGB2 (CD18) did not show a significant difference, suggesting that the degradation of adhesion molecules may be impaired. Transmission electron microscopy revealed a decreased number of autophagosomes and a decrease in mRNA abundance of SQSTM1 (p62) and MAP1LC3B (LC3) after BHB treatment. In parallel, protein abundance of p62 increased while the ratio of protein LC3 II to LC3 I decreased after BHB treatment, indicating that BHB inhibits autophagy of bovine neutrophils. To confirm the regulatory role of autophagy in BHB promoting neutrophil adhesion, we used an autophagy activator rapamycin (RAPA). Data showed that RAPA relieved the inhibitory effect on autophagy and the promotive effect on cell adhesion induced by BHB. Importantly, BHB inhibited the colocalization of LC3 and CD11b, which was relieved by RAPA, further confirming the regulatory role of autophagy in the recycling of the above adhesion molecules. Furthermore, BHB treatment increased the mRNA abundance and the release of pro-inflammatory factors IL-1B, IL-6, and TNF of bovine neutrophils, and these effects were attenuated by RAPA. Overall, the present study revealed that BHB promotes the adhesion of bovine neutrophils by inhibiting autophagy.
    Keywords:  adhesion; dairy cows; ketosis; neutrophils; β-hydroxybutyrate
    DOI:  https://doi.org/10.3389/fimmu.2022.1096813
  6. Nutr Health. 2023 Feb 03. 2601060231154464
    Link between emotional and external eating behaviors, peripheral neuropeptide Y, and β-hydroxybutyrate in participants with obesity on 12-week ketogenic diet.
    Maša Černelič-Bizjak, Saša Kenig, Ana Petelin, Zala Jenko-Pražnikar, Nina Mohorko.
      Objective: Understanding the impact of stress on emotional and external eating behaviors and the psychological and the associated metabolic factors can help in designing subsequent interventions to protect health. In particular, psychological trait-like construct related to eating has been shown to be an important target for intervention. Methods and measures: This study aimed to investigate the biochemical variables associated with a decrease in emotional and external eating behaviors due to 12-week ketogenic diet (12KD) in 35 adult participants (12 males) with obesity. Results: Absolute changes in emotional and external eating were independent of changes in body mass, nutritional intake, and Δ cortisol, but were predicted with increases in serum β-hydroxybutyrate (BHB) and decreases in serum peripheral neuropeptide Y (pNPY) (all p's < 0.050). Decrease in pNPY was also associated with an increase in BHB but was independent of anthropometrical changes, Δ fasting glucose, and Δ insulin. Conclusion: The reductions in emotional and external eating behaviors in participants with obesity were uniquely predicted by an increase in BHB and a decrease in pNPY after 12KD. In ketosis, emotional and external eating dropped independently of body mass change. Change in pNPY predicted changes in emotional and external eating. The role of BHB in modulating eating behavior should be further explored.
    Keywords:  Emotional eating; external eating; ketogenic diet; peripheral neuropeptide y; stress-related obesity; β-hydroxybutyrate
    DOI:  https://doi.org/10.1177/02601060231154464
  7. Eur Rev Med Pharmacol Sci. 2023 Jan;pii: 31064. [Epub ahead of print]27(2): 628-641
    Dimethyl fumarate attenuates MSU-induced gouty arthritis by inhibiting NLRP3 inflammasome activation and oxidative stress.
    Y Cao, Y Hu, X-F Jin, Y Liu, J-M Zou.
       OBJECTIVE: Dimethyl fumarate (DMF) has shown anti-inflammatory and antioxidant activities. However, the effects of DMF on gouty arthritis remain elusive, and the underlying mechanism is not understood. In this study, we aim to investigate the role of DMF in gouty arthritis.
    MATERIALS AND METHODS: Mice were gavage with DMF for consecutive 7 days at two different doses (10 mg/kg/day or 30 mg/kg/day, once daily) in advance and then monosodium sodium urate (MSU) was injected into their joint to establish an acute gout mice model. The pain and swelling of the hind paw in mice were determined. The production of pro-inflammatory cytokine in the paw tissues was assessed by Elisa and the inflammatory infiltration of the joint was determined by hematoxylin and eosin (H&E) staining. The activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in the tissues were measured by commercial kits. In addition, the expression of nuclear factor kappa B (NF-κB) and NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome and downstream genes were detected by PCR and Western blot. Furthermore, LPS-primed murine macrophages Raw 264.7 cells were treated with different concentrations of DMF (2 μM, 5 μM, 10 μM) for 2 h, and then challenged with MSU (200 μg/mL) for other 12 h to observe the effect of DMF on cell viability via cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) levels in the supernatant of culture medium. Immunofluorescent staining was used to detect the NLRP3 inflammasome activation and reactive oxygen species (ROS) production in vitro. Caspase-1 activity was measured by corresponding assay kits both in vivo and in vitro.
    RESULTS: DMF attenuated pain and swelling in MSU-induced gout mice by decreasing pro-inflammatory cytokine production and inflammatory cell infiltration, as well as improved oxidative stress. Moreover, DMF inhibited the activation of NF-κB and NLRP3 inflammasome and subsequent expression of caspase-1, interleukin-1β (IL-1β), and IL-18 at both mRNA and protein levels. Meanwhile, DMF suppressed NLRP3 inflammasome expression and ROS production in LPS and MSU-stimulated Raw 264.7 cells, thereby protecting the cells from inflammatory injury.
    CONCLUSIONS: DMF serves as a new approach for the treatment of MSU-induced gouty arthritis by suppressing NLRP3 inflammasome activation and oxidative stress.
    DOI:  https://doi.org/10.26355/eurrev_202301_31064
  8. Indian J Pediatr. 2023 Feb 02.
    Use of Ketogenic Diet in Two Indian Children with a Rare Early-Onset Epileptic Encephalopathy.
    Pradeep Kumar Gunasekaran, Veena Laxmi, Asha Bilamge, Lokesh Saini.
      
    DOI:  https://doi.org/10.1007/s12098-023-04492-1
  9. Nat Rev Endocrinol. 2023 Feb 01.
    Metabolism and exercise: the skeletal muscle clock takes centre stage.
    Ryan A Martin, Mark R Viggars, Karyn A Esser.
      Circadian rhythms that influence mammalian homeostasis and overall health have received increasing interest over the past two decades. The molecular clock, which is present in almost every cell, drives circadian rhythms while being a cornerstone of physiological outcomes. The skeletal muscle clock has emerged as a primary contributor to metabolic health, as the coordinated expression of the core clock factors BMAL1 and CLOCK with the muscle-specific transcription factor MYOD1 facilitates the circadian and metabolic programme that supports skeletal muscle physiology. The phase of the skeletal muscle clock is sensitive to the time of exercise, which provides a rationale for exploring the interactions between the skeletal muscle clock, exercise and metabolic health. Here, we review the underlying mechanisms of the skeletal muscle clock that drive muscle physiology, with a particular focus on metabolic health. Additionally, we highlight the interaction between exercise and the skeletal muscle clock as a means of reinforcing metabolic health and discuss the possible implications of the time of exercise as a chronotherapeutic approach.
    DOI:  https://doi.org/10.1038/s41574-023-00805-8
  10. J Clin Endocrinol Metab. 2023 Jan 30. pii: dgad049. [Epub ahead of print]
    Do statins blunt the beneficial effect of aerobic exercise on metabolic flexibility?
    Tim Hollstein, Paolo Piaggi.
      
    Keywords:  aerobic exercise; fat oxidation; metabolic flexibility; metabolic syndrome; statins
    DOI:  https://doi.org/10.1210/clinem/dgad049
  11. Front Aging Neurosci. 2022 ;14 1118281
    Editorial: The NLRP3 inflammasome-mediated neuroinflammation and its related mitochondrial impairment in neurodegeneration.
    Chao Deng, Xiang Cai, Kunlin Jin, Qing Wang.
      
    Keywords:  NLRP3; aging; mitochondrial; neurodegeneration; neuroinflammation; δ-opioid receptors
    DOI:  https://doi.org/10.3389/fnagi.2022.1118281
  12. Biomed Pharmacother. 2023 Feb 01. pii: S0753-3322(23)00109-9. [Epub ahead of print]160 114321
    An update on the role of TRIM/NLRP3 signaling pathway in atherosclerosis.
    Sibo Liu, Hongfeng Bi, Meiling Jiang, Yuanli Chen, Meixiu Jiang.
      Atherosclerosis (AS) is a chronic inflammatory disease of large and medium arteries that includes lipid metabolism disorder and recruitment of immune cells to the artery wall. An increasing number of studies have confirmed that inflammasome over-activation is associated with the onset and progression of atherosclerosis. The NLRP3 inflammasome, in particular, has been proven to increase the incidence rate of cardiovascular diseases (CVD) by promoting pro-inflammatory cytokine release and reducing plaque stability. The strict control of inflammasome and prevention of excessive inflammatory reactions have been the research focus of inflammatory diseases. Tripartite motif (TRIM) is a protein family with a conservative structure and rapid evolution. Several studies have demonstrated the TRIM family's regulatory role in mediating inflammation. This review aims to clarify the relationship between TRIMs and NLRP3 inflammasome and provide insights for future research and treatment discovery.
    Keywords:  Atherosclerosis; NLRP3 inflammasome; TRIM family
    DOI:  https://doi.org/10.1016/j.biopha.2023.114321
  13. Front Physiol. 2022 ;13 1063956
    Effect of increased protein intake and exogenous ketosis on body composition, energy expenditure and exercise capacity during a hypocaloric diet in recreational female athletes.
    Charlotte Hiroux, Moniek Schouten, Isabelle de Glisezinski, Chantal Simon, François Crampes, Peter Hespel, Katrien Koppo.
      Introduction: Since low body weight is an important determinant of success in many sports such as gymnastics, martial arts and figure skating, athletes can benefit from effective weight loss strategies that preserve muscle mass and athletic performance. The present study investigates the effects of increased protein intake and exogenous ketosis on body composition, energy expenditure, exercise capacity, and perceptions of appetite and well-being during a hypocaloric diet in females. Methods: Thirty-two female recreational athletes (age: 22.2 ± .5 years; body weight: 58.3 ± .8 kg; BMI: 20.8 ± .2 kg·m-2) underwent 4 weeks of 30% caloric restriction and were randomized to receive either an increased daily amount of dietary protein (PROT, ∼2.0-2.2 g protein·kg-1·day-1), 3 × 20 g·day-1 of a ketone ester (KE), or an isocaloric placebo (PLA). Body composition was measured by DXA, resting energy expenditure (REE) by indirect calorimetry, exercise capacity during a VO2max test, appetite hormones were measured in serum, and perceptions of general well-being were evaluated via questionnaires. Results: The hypocaloric diet reduced body weight by 3.8 ± .3 kg in PLA, 3.2 ± .3 kg in KE and 2.4 ± .2 kg in PROT (Ptime<.0001). The drop in fat mass was similar between treatments (average: 2.6 ± .1 kg, Ptime<.0001), while muscle mass was only reduced in PLA and KE (average: .8 ± .2 kg, Ptime<.05), and remained preserved in PROT (Pinteraction<.01). REE [adjusted for lean mass] was reduced after caloric restriction in PLA (pre: 32.7 ± .5, post: 28.5 ± .6 kcal·day-1·kg-1) and PROT (pre: 32.9 ± 1.0, post: 28.4 ± 1.0 kcal·day-1·kg-1), but not in KE (pre: 31.8 ± .9, post: 30.4 ± .8 kcal·day-1·kg-1) (Pinteraction<.005). Furthermore, time to exhaustion during the VO2max test decreased in PLA (by 2.5 ± .7%, p < .05) but not in KE and PROT (Pinteraction<.05). Lastly, the perception of overall stress increased in PLA and PROT (p < .05), but not in KE (Pinteraction<.05). Conclusion: Increased protein intake effectively prevented muscle wasting and maintained exercise capacity during a period of caloric restriction in female recreational athletes. Furthermore, exogenous ketosis did not affect body composition, but showed its potential in weight management by preserving a drop in exercise capacity and REE and by improving overall stress parameters during a period of caloric restriction.
    Keywords:  VO2max; appetite; ketones; performance; resting metabolic rate
    DOI:  https://doi.org/10.3389/fphys.2022.1063956
  14. Exerc Sport Sci Rev. 2023 Feb 01.
    Controlling Inflammation Improves Aging Skeletal Muscle Health.
    William A Fountain, Masatoshi Naruse, Alex Claiborne, Scott Trappe, Todd A Trappe.
       SUMMARY FOR TABLE OF CONTENTS: Controlling cyclooxygenase pathway regulated inflammation may help protect the health and plasticity of aging skeletal muscle.
    DOI:  https://doi.org/10.1249/JES.0000000000000313
  15. Acta Physiol (Oxf). 2023 Feb 01. e13943
    A single dose of exercise stimulates skeletal muscle mitochondrial plasticity in myotonic dystrophy type 1.
    Andrew I Mikhail, Alexander Manta, Sean Y Ng, Aislin K Osborne, Stephanie R Mattina, Mark R Mackie, Vladimir Ljubicic.
       AIM: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1-specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking.
    METHODS: Skeletal muscle tissue were sampled from healthy and DM1 mice under sedentary conditions and at several recovery time-points following an exhaustive treadmill run.
    RESULTS: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy- and lysosome-related machinery responsible for the clearance of dysfunctional organelles.
    CONCLUSION: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients.
    Keywords:  AMP-activated protein kinase; autophagy; biogenesis; dynamics; mitophagy
    DOI:  https://doi.org/10.1111/apha.13943
  16. PNAS Nexus. 2022 Sep;1(4): pgac192
    An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.
    Axel Kowald, Felix P Kemeth, Tom B L Kirkwood.
      Mitochondria are cellular organelles of crucial relevance for the survival of metazoan organisms. Damage to the mitochondrial DNA can give rise to a variety of mitochondrial diseases and is thought also to be involved in the aging process. The fate of mtDNA mutants is controlled by their synthesis as well as degradation and mathematical models can help to better understand this complex interplay. We present here a model that combines a replicative advantage for mtDNA mutants with selective degradation enabled by mitochondrial fission and fusion processes. The model not only shows that the cell has efficient means to deal with (many) types of mutants but, surprisingly, also predicts that under certain conditions a stable co-existence of mutant and wild-type mtDNAs is possible. We discuss how this new finding might explain how mitochondria can be at the heart of processes with such different phenotypes as mitochondrial diseases and aging.
    Keywords:  aging; mathematical model; mitochondrial disease
    DOI:  https://doi.org/10.1093/pnasnexus/pgac192
  17. Nutr Metab Cardiovasc Dis. 2023 Jan 05. pii: S0939-4753(23)00004-2. [Epub ahead of print]
    Skeletal muscle fiber composition may modify the effect of nutrition on body composition in young females.
    Spyridon Methenitis, Tzortzis Nomikos, Eleni Kontou, Kleio-Maria Kiourelli, George Papadimas, Constantinos Papadopoulos, Gerasimos Terzis.
       BACKGROUND AND AIM: The aim of this study was to investigate the hypothesis that healthy, normal-weight females with greater proportions and sizes of the oxidative muscle fibers would also be characterized by a healthier body composition compared with individuals with increased glycolytic fibers, even if both follow similar nutritional plans.
    METHODS AND RESULTS: Vastus lateralis muscle fiber-type composition, body composition through dual-energy X-ray absorptiometry, and dietary intakes through questionnaire were evaluated in twenty-two young, healthy, non-obese females (age: 21.3±1.8yrs, body mass: 67.5±6.2 kg, body height: 1.66±0.05m, body mass index (BMI): 24.2±2.6  kg m-2). The participants were allocated into two groups according to their type I muscle fibers percentage [high (HI) and low (LI)]. The participants of the LI group were characterized by significantly higher body mass, fat mass, BMI, and cross-sectional and percentage cross-sectional area (%CSA) of type IIx muscle fibers compared with participants of the HI group (p < 0.021). In contrast, the HI group was characterized by higher cross-sectional and %CSA of type I muscle fibers compared with the LI group (p < 0.038). Significant correlations were observed between body fat mass, lean body mass, total energy intake, fat energy intake, and %CSAs of type I and IIx muscle fibers (r: -0.505 to 0.685; p < 0.05).
    CONCLUSION: In conclusion, this study suggests that muscle fiber composition is an important factor that at least partly could explain the observed differential inter-individual responses of the body composition to nutrition in female individuals. Increased %CSAs of type I muscle fibers seem to act as a protective mechanism against obesity and favor a healthier body composition, neutralizing the negative effect of increased caloric fats intake on body composition, probably because of their greater oxidative metabolic properties and fat utilization capacities. In contrast, female individuals with low type I and high type IIx %CSAs of type I seem to be more metabolically inflexible and dietinduced obesity prone, even if they consume fewer total daily calories and fats.
    Keywords:  Body fat; Dietary intake; Glycolytic muscle fibers; Lean body mass; Oxidative muscle fibers; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.numecd.2022.12.027
  18. Nat Commun. 2023 Feb 01. 14(1): 535
    Transcriptional reprogramming of skeletal muscle stem cells by the niche environment.
    Felicia Lazure, Rick Farouni, Korin Sahinyan, Darren M Blackburn, Aldo Hernández-Corchado, Gabrielle Perron, Tianyuan Lu, Adrien Osakwe, Jiannis Ragoussis, Colin Crist, Theodore J Perkins, Arezu Jahani-Asl, Hamed S Najafabadi, Vahab D Soleimani.
      Adult stem cells are indispensable for tissue regeneration, but their function declines with age. The niche environment in which the stem cells reside plays a critical role in their function. However, quantification of the niche effect on stem cell function is lacking. Using muscle stem cells (MuSC) as a model, we show that aging leads to a significant transcriptomic shift in their subpopulations accompanied by locus-specific gain and loss of chromatin accessibility and DNA methylation. By combining in vivo MuSC transplantation and computational methods, we show that the expression of approximately half of all age-altered genes in MuSCs from aged male mice can be restored by exposure to a young niche environment. While there is a correlation between gene reversibility and epigenetic alterations, restoration of gene expression occurs primarily at the level of transcription. The stem cell niche environment therefore represents an important therapeutic target to enhance tissue regeneration in aging.
    DOI:  https://doi.org/10.1038/s41467-023-36265-x
  19. Int J Biochem Cell Biol. 2023 Jan 27. pii: S1357-2725(23)00014-6. [Epub ahead of print] 106375
    Metformin induces mitochondrial fission and reduces energy metabolism by targeting respiratory chain complex I in hepatic stellate cells to reverse liver fibrosis.
    Ying Su, Chenjian Hou, Meili Wang, Kehan Ren, Danmei Zhou, Xiaoli Liu, Shanyu Zhao, Xiuping Liu.
      The activation and proliferation of hepatic stellate cells (HSCs) are critical processes for the treatment of liver fibrosis. It is necessary to identify effective drugs for the treatment of liver fibrosis and elucidate their mechanisms of action. Metformin can inhibit HSCs; however, no systematic studies demonstrating the effects of metformin on mitochondria in HSCs have been reported. This study demonstrated that metformin induces mitochondrial fission by phosphorylating AMPK/DRP1 (S616) in HSCs to decrease the expression of α-SMA and collagen. Additionally, metformin repressed the total ATP production rate, especially the production rate of ATP produced through mitochondrial oxidative phosphorylation, by inhibiting the enzymatic activity of complex I. Further analysis revealed that metformin strongly constrained the transcription of mitochondrial genes (ND1-ND6 and ND4L) that encode the core subunits of respiratory chain I. Upregulation of the mRNA expression of HK2 and GLUT1 slightly enhanced glycolysis. Additionally, metformin increased mitochondrial DNA (mtDNA) copy number to suppress the proliferation and activation of HSCs, indicating that mtDNA copy number can alter the fate of HSCs. In conclusion, metformin can induce mitochondrial fragmentation and low-level energy metabolism in HSCs, thereby suppressing HSCs activation and proliferation to reverse liver fibrosis.
    Keywords:  Hepatic stellate cells (HSCs); Liver fibrosis; Metformin; Mitochondrial dynamics; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.biocel.2023.106375
  20. Eur Heart J Digit Health. 2021 Mar;2(1): 104-105
    Predicting heart failure with preserved ejection fraction: revisiting an old friend with new knowledge.
    Robert M A van der Boon.
      
    DOI:  https://doi.org/10.1093/ehjdh/ztab017
  21. J Strength Cond Res. 2022 Nov 30.
    A Self-Selected 16:8 Time-Restricted Eating Protocol Improves Fat Oxidation Rates, Markers of Cardiometabolic Health, and 10-km Cycling Performance in Middle-Age Male Cyclists.
    Craig R Witt, Corey D Grozier, Lauren G Killen, Lee G Renfroe, Eric K O'Neal, Hunter S Waldman.
       ABSTRACT: Witt, CR, Grozier, CD, Killen, LG, Renfroe, LG, O'Neal, EK, and Waldman, HS. A self-selected 16:8 time-restricted eating protocol improves fat oxidation rates, markers of cardiometabolic health, and 10-km cycling performance in middle-age male cyclists. J Strength Cond Res XX(X): 000-000, 2022-The purpose of this study was to assess the impact of 4 weeks, 16:8 time restricted eating (TRE) on markers of metabolic health and 10-km time trial (TT) performance in middle-age male cyclists. Subjects (n = 12; age, 40-60 years; V̇o2peak, 41.8 ± 5.6 ml·kg-1·min-1) consisting of individuals following a habitual Western diet completed a familiarization and 2 experimental trials [PRE] and [POST]. Following habitual Western diet without TRE, anthropometric measures were assessed, followed by completion of a graded exercise test and 10-km TT. Subjects then adhered to a 4-week TRE protocol where all calories had to be consumed within a self-selected 8-hour window and then returned for repeat testing. Although self-reported caloric intake did not statistically change PRE to POST, body mass (PRE, 83.2 ± 13.4 vs. POST, 80.7 ± 12.6 kg), fat mass (∼2.5 kg), and blood pressure (systolic, 8 mm Hg; diastolic, 4 mm Hg) were all significantly lower POST (all p < 0.05), with no changes in fat-free mass. Furthermore, fat oxidation significantly increased (PRE, 0.36 ± 0.03 vs. POST, 0.42 ± 0.03 g·min-1; p = 0.04) following the TRE intervention and 10-km TT performance improved by ∼2 minutes POST (PRE, 29.7 ± 7.3 vs. POST, 27.4 ± 5.5 minutes; p = 0.02). Overall, our data demonstrated that middle-age male cyclists adhering to a 4-week TRE protocol can improve their body composition profile and 10-km TT performance without detriments to fat-free mass.
    DOI:  https://doi.org/10.1519/JSC.0000000000004353
  22. Exp Gerontol. 2023 Jan 30. pii: S0531-5565(23)00026-8. [Epub ahead of print]173 112105
    Aging, aerobic exercise, and cardiovascular health: Barriers, alternative strategies and future directions.
    Kevin O Murray, Sophia A Mahoney, Ravinandan Venkatasubramanian, Douglas R Seals, Zachary S Clayton.
      Age-associated cardiovascular (CV) dysfunction, namely arterial dysfunction, is a key antecedent to the development of CV disease (CVD). Arterial dysfunction with aging is characterized by impaired vascular endothelial function and stiffening of the large elastic arteries, each of which is an independent predictor of CVD. These processes are largely mediated by an excess production of reactive oxygen species (ROS) and an increase in chronic, low-grade inflammation that ultimately leads to a reduction in bioavailability of the vasodilatory molecule nitric oxide. Additionally, there are other fundamental aging mechanisms that may contribute to excessive ROS and inflammation termed the "hallmarks of aging"; these additional mechanisms of arterial dysfunction may represent therapeutic targets for improving CV health with aging. Aerobic exercise is the most well-known and effective intervention to prevent and treat the effects of aging on CV dysfunction. However, the majority of mid-life and older (ML/O) adults do not meet recommended exercise guidelines due to traditional barriers to aerobic exercise, such as reduced leisure time, motivation, or access to fitness facilities. Therefore, it is a biomedical research priority to develop and implement time- and resource-efficient alternative strategies to aerobic exercise to reduce the burden of CVD in ML/O adults. Alternative strategies that mimic or are inspired by aerobic exercise, that target pathways specific to the fundamental mechanisms of aging, represent a promising approach to accomplish this goal.
    Keywords:  Arterial function; Barriers to aerobic exercise; Cardiovascular function; Older adults; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.exger.2023.112105
  23. Front Cell Dev Biol. 2023 ;11 1129281
    Protein translation paradox: Implications in translational regulation of aging.
    Harper S Kim, Andrew M Pickering.
      Protein translation is an essential cellular process playing key roles in growth and development. Protein translation declines over the course of age in multiple animal species, including nematodes, fruit flies, mice, rats, and even humans. In all these species, protein translation transiently peaks in early adulthood with a subsequent drop over the course of age. Conversely, lifelong reductions in protein translation have been found to extend lifespan and healthspan in multiple animal models. These findings raise the protein synthesis paradox: age-related declines in protein synthesis should be detrimental, but life-long reductions in protein translation paradoxically slow down aging and prolong lifespan. This article discusses the nature of this paradox and complies an extensive body of work demonstrating protein translation as a modulator of lifespan and healthspan.
    Keywords:  ageing; aging; eIF; hallmarks of aging; lifespan; protein translation; sk6; theories of aging
    DOI:  https://doi.org/10.3389/fcell.2023.1129281
  24. Mol Metab. 2023 Jan 30. pii: S2212-8778(23)00018-2. [Epub ahead of print] 101684
    Targeting negative energy balance with calorie restriction and mitochondrial uncoupling in db/db mice.
    Sing-Young Chen, Martina Beretta, Ellen M Olzomer, Divya P Shah, Derek Y H Wong, Stephanie J Alexopoulos, Isabella Aleksovska, Joseph M Salamoun, Christopher J Garcia, Blake J Cochran, Kerry-Anne Rye, Greg C Smith, Frances L Byrne, Margaret J Morris, Webster L Santos, James Cantley, Kyle L Hoehn.
       OBJECTIVE: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver.
    METHODS: Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR.
    RESULTS: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis.
    CONCLUSIONS: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease.
    Keywords:  Calorie restriction; Diabetes; Mitochondrial uncoupling; Obesity
    DOI:  https://doi.org/10.1016/j.molmet.2023.101684
  25. Diabetes Metab Syndr. 2023 Jan 25. pii: S1871-4021(23)00016-4. [Epub ahead of print]17(2): 102720
    Higher fasting fibroblast growth factor 21 was associated with a greater decline in postprandial blood pressure.
    Jane Yu Ying Ong, Kaveri Pathak, Yun Zhao, Emily Calton, Christopher M Reid, Mario J Soares.
       BACKGROUND: A fall in blood pressure (BP) following a meal is well known and is usually a transient phenomenon, due to appropriate cardiovascular adjustments. Older individuals and those with high BP experience a greater postprandial fall that can manifest as postprandial hypotension (PPH). Fibroblast growth factor 21 (FGF21) is positively associated with BP, and is known to increase after meal ingestion. We explored whether fasting FGF21 or its postprandial change would be associated with meal induced BP change, after accounting for several covariates.
    METHODS: Eighty-three Western Australian adults were studied. Supine resting BP was recorded and an oral glucose test was administered. Serial measurements of systolic BP (SBP) and diastolic BP (DBP) were then made in duplicate every 30 min up to 120 min. Fasting and 120 min blood samples were analysed for FGF21 and clinical chemistry. Multiple linear regression analyses of the incremental area under curve of postprandial SBP and DBP was conducted on 12 known determinants.
    RESULTS: The final parsimonious model based on backward regression of postprandial SBP included fasting SBP, gender, fasting insulin and fasting FGF21 (β = -0.009 (95% confidence interval (CI): 0.017, -0.002, P = 0.015)). For postprandial DBP these included fasting DBP, gender, fasting glucose, fasting insulin and fasting FGF21 (β = -0.005; 95% CI: 0.010, -0.001, P = 0.021).
    CONCLUSIONS: A higher fasting FGF21, independent of glucose and insulin, was associated with a greater postprandial decline in SBP and in DBP.
    Keywords:  Blood pressure; Cardiovascular disease; Fibroblast growth factor 21; Oral glucose tolerance test; Postprandial hypotension
    DOI:  https://doi.org/10.1016/j.dsx.2023.102720
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