bims-kimdis 2023-02-12 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–02–12
twenty papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Predictors of weight loss in patients with obesity treated with a Very Low-Calorie Ketogenic Diet.
Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.
Ketone supplementation abolished isoflurane anesthesia-induced elevation in blood glucose level and increased recovery time from anesthesia in Wistar Albino Glaxo Rijswijk rats.
The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy.
Ketogenic diet for epilepsy control and enhancement in adaptive behavior.
β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review.
The ketogenic diet: its impact on human gut microbiota and potential consequent health outcomes: a systematic literature review.
Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.
A prolonged fast improves overnight substrate oxidation without modulating hepatic glycogen in adults with and without nonalcoholic fatty liver: A randomized crossover trial.
Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation.
The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.
Butyrate: More Than a Short Chain Fatty Acid.
The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.
Exercise - the key to a forever unaged vasculature?
Increased Adiposity is Associated with Altered Skeletal Muscle Energetics.
Remission in Ketosis-Prone Diabetes.
Fiber-Type Shifting in Sarcopenia of Old Age: Proteomic Profiling of the Contractile Apparatus of Skeletal Muscles.
MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation.
Mitochondrial dysfunction in cardiovascular disease: Towards exercise regulation of mitochondrial function.
Role of the Circadian Clock and Effect of Time-Restricted Feeding in Adenine-Induced Chronic Kidney Disease.

Front Nutr. 2023 ;10 1058364

Predictors of weight loss in patients with obesity treated with a Very Low-Calorie Ketogenic Diet.

Ilaria Ernesti, Francesco Baratta, Mikiko Watanabe, Renata Risi, Elisabetta Camajani, Agnese Persichetti, Dario Tuccinardi, Stefania Mariani, Carla Lubrano, Alfredo Genco, Giovanni Spera, Lucio Gnessi, Sabrina Basciani.

   Introduction: The Very Low-Calorie Ketogenic Diet (VLCKD) has emerged as a safe and effective intervention for the management of metabolic disease. Studies examining weight loss predictors are scarce and none has investigated such factors upon VLCKD treatment. Among the molecules involved in energy homeostasis and, more specifically, in metabolic changes induced by ketogenic diets, Fibroblast Growth Factor 21 (FGF21) is a hepatokine with physiology that is still unclear.
Methods: We evaluated the impact of a VLCKD on weight loss and metabolic parameters and assessed weight loss predictors, including FGF21. VLCKD is a severely restricted diet (<800 Kcal/die), characterized by a very low carbohydrate intake (<50 g/day), 1.2-1.5 g protein/kg of ideal body weight and 15-30 g of fat/day. We treated 34 patients with obesity with a VLCKD for 45 days. Anthropometric parameters, body composition, and blood and urine chemistry were measured before and after treatment.
Results: We found a significant improvement in body weight and composition and most metabolic parameters. Circulating FGF21 decreased significantly after the VLCKD [194.0 (137.6-284.6) to 167.8 (90.9-281.5) p < 0.001] and greater weight loss was predicted by lower baseline FGF21 (Beta = -0.410; p = 0.012), male sex (Beta = 0.472; p = 0.011), and central obesity (Beta = 0.481; p = 0.005).
Discussion: VLCKD is a safe and effective treatment for obesity and obesity related metabolic derangements. Men with central obesity and lower circulating FGF21 may benefit more than others in terms of weight loss obtained following this diet. Further studies investigating whether this is specific to this diet or to any caloric restriction are warranted.

Keywords:  body composition; fibroblast growth factor 21; insulin resistance; low carbohydrate diet (LCD); protein sparing modified fasting; very low energy diet

DOI:  https://doi.org/10.3389/fnut.2023.1058364
Cells. 2023 Feb 02. pii: 486. [Epub ahead of print]12(3):

Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.

Juan Carlos Gómora-García, Teresa Montiel, Melanie Hüttenrauch, Ashley Salcido-Gómez, Lizbeth García-Velázquez, Yazmin Ramiro-Cortés, Juan Carlos Gomora, Susana Castro-Obregón, Lourdes Massieu.

  Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-β-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD+-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD+/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic-lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control.

Keywords:  autophagy; ketone bodies; lysosomal biogenesis; mitophagy; sirtuin2

DOI:  https://doi.org/10.3390/cells12030486
BMC Anesthesiol. 2023 Feb 07. 23(1): 43

Ketone supplementation abolished isoflurane anesthesia-induced elevation in blood glucose level and increased recovery time from anesthesia in Wistar Albino Glaxo Rijswijk rats.

Zsolt Kovács, Dominic P D'Agostino, Csilla Ari.

   BACKGROUND: It has been suggested that administration of exogenous ketone supplements (EKSs) not only increases blood ketone body levels but also decreases blood glucose level and modulates isoflurane-induced anesthesia in different rodents, such as Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. Thus, we investigated whether administration of EKSs can modulate the isoflurane anesthesia-generated increase in blood glucose level and the time required to recover from isoflurane-induced anesthesia.
METHODS: To investigate the effect of EKSs on isoflurane anesthesia-induced changes in blood glucose and R-β-hydroxybutyrate (R-βHB) level as well as recovery time from anesthesia, we used KEMCT (mix of ketone ester/KE and medium chain triglyceride/MCT oil in a 1:1 ratio) in WAG/Rij rats. First, to accustom the animals to the method, water gavage was carried out for 5 days (adaptation period). After adaptation period, rats of first group (group 1) were gavaged by water (3 g/kg), whereas, in the case of second group (group 2), the diet of animals was supplemented by KEMCT (3 g/kg, gavage) once per day for 7 days. One hour after the last gavage, isoflurane (3%) anesthesia was induced for 20 min (group 1 and group 2) and the time required for recovery from anesthesia was measured by using righting reflex. Subsequently, blood levels of both R-βHB and glucose were also evaluated. Changes in blood glucose and R-βHB levels were compared to control, which control glucose and R-βHB levels were measured on the last day of the adaptation period (group 1 and group 2). Time required for recovery from isoflurane anesthesia, which was detected after 7th KEMCT gavage (group 2), was compared to recovery time measured after 7th water gavage (group 1).
RESULTS: The KEMCT maintained the normal glucose level under isoflurane anesthesia-evoked circumstances preventing the glucose level elevating effect of isoflurane. Thus, we demonstrated that administration of KEMCT not only increased blood level of R-βHB but also abolished the isoflurane anesthesia-generated increase in blood glucose level. Moreover, the time required for recovery from isoflurane-evoked anesthesia increased significantly in KEMCT treated animals.
CONCLUSIONS: Putative influence of elevated blood ketone body level on isoflurane-evoked effects, such as modulation of blood glucose level and recovery time from anesthesia, should be considered by anesthesiologists.

Keywords:  Glucose; Isoflurane anesthesia; Ketone supplement; Ketosis; Recovery time; WAG/Rij rat

DOI:  https://doi.org/10.1186/s12871-023-02000-8
Epilepsy Behav. 2023 Feb 04. pii: S1525-5050(23)00024-0. [Epub ahead of print]140 109106

The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy.

Bita Poorshiri, Mohammad Barzegar, Mohammadreza Afghan, Siamak Shiva, Parviz Shahabi, Zahra Golchinfar, Hamid Reza Yousefi Nodeh, Sina Raeisi.

  The exact mechanism of a ketogenic diet (KD) as a suitable alternative therapeutic approach for drug-resistant epilepsy (DRE) in alleviating seizures is not yet fully understood. The present study aimed to evaluate the role of the KD in reducing oxidative stress (OS) by increasing the ketone body beta-hydroxybutyrate (BHB) and Arachidonic acid (ARA), an essential polyunsaturated fatty acid, as a possible mechanism in relieving seizure attacks in children with DRE. Forty children with refractory epilepsy were included in the present study. The serum levels of BHB, ARA, and OS markers, malondialdehyde (MDA), and 8-hydroxyl-deoxyguanosine (8-OHdG), were evaluated in children with DRE and compared before and after the three months of KD therapy. Thirty-four of 40 included children could complete the three-month KD therapy. Twenty-one (61.76%) patients had more than a 50% reduction in seizure frequency after the KD (responders). The remaining 13 children were considered non-responders to the diet. The serum levels of ARA and BHB significantly (p < 0.05) increased after the KD therapy. The serum levels of OS parameters MDA and 8-OHdG before the diet therapy were significantly (p < 0.05) higher than those after the administration. The serum levels of BHB and MDA after the KD therapy in the responders were respectively higher and lower than those in the non-responders (p < 0.001). Ketogenic diet might reduce brain OS by increasing BHB and ARA. The role of BHB in diminishing OS and seizure might be more remarkable than ARA.

Keywords:  Arachidonic acid; Beta-hydroxybutyrate; Drug-resistant epilepsy; Ketogenic diet; Oxidative stress

DOI:  https://doi.org/10.1016/j.yebeh.2023.109106
Sci Rep. 2023 Feb 06. 13(1): 2102

Ketogenic diet for epilepsy control and enhancement in adaptive behavior.

Omnia Fathy El-Rashidy, May Fouad Nassar, Wafaa Abdelwahab Shokair, Yasmin Gamal Abdou El Gendy.

The Ketogenic Diet (KD) is gaining attention as a management line in childhood drug resistant epilepsy (DRE). The objective of this study was to highlight KD benefits for Ain Shams University (ASU) Children's Hospital patients. This cross-sectional study included all patients at the Ketoclinic of ASU Children's Hospital since it started. Anthropometric measurements and laboratory data were recorded. Chalfont severity score and daily frequency of epileptic attacks were used to evaluate KD efficacy. Vineland test was used to demonstrate the adaptive behavior of a selected group of patients. ASU Children's Hospital Ketoclinic records included 143 patients. During KD therapy, the weight and height/length assessment showed significant increase with significant decrease in the severity of seizures and its frequency. There were no significant changes in the lipid profile of the patients. Vineland test showed significant improvement in the adaptive behavior in 65% of patients. The Ketoclinic data proves that KD is a tolerable, safe, and effective line of therapy for DRE in children without significant negative impact on their anthropometric measurements or lipid profile. Furthermore, the enhancement in adaptive behavior is a promising finding. It is prudent to recommend wider scale studies for longer duration to demonstrate additional cognitive benefits of KD in pediatric age group.

DOI: https://doi.org/10.1038/s41598-023-27373-1
Nutrients. 2023 Jan 19. pii: 524. [Epub ahead of print]15(3):

β-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review.

Siva Shantini Jayashankar, Khaizurin Tajul Arifin, Muhammad Luqman Nasaruddin.

  This scoping review aimed to summarise the effects of the ketone body β-hydroxybutyrate. The review details the revealed pathways and functional properties following its intervention in the context of neurodegenerative diseases. In this study, 5 research publications that met the inclusion and exclusion criteria were shortlisted. Following the intervention, we discovered a tendency of reduced inflammatory status in microglia, as evidenced by lower levels of pro-inflammatory mediators produced, reduced microgliosis in afflicted tissues, and enhanced cognitive functions in neurodegenerative models. We found that there is a significant overlap in the mechanism of action of β-hydroxybutyrate (BHB) via activation of the G-protein-Coupled Receptor 109A (GPR109a) receptor and deactivation of the inflammasome complex. Furthermore, although comparing outcomes can be challenging due to the heterogeneity in the study model, the results we have assembled here were consistent, giving us confidence in the intervention's efficacy. We also discussed new studies where BHB is involved in various roles in regulating inflammation in microglia, allowing for fresh therapeutic targets against neurodegeneration. This brief review provides evidence to support the huge potential of BHB in the treatment of neurodegenerative illnesses.

Keywords:  beta-hydroxybutyrate; inflammation; ketogenic diet; microglia; neurodegenerative disease

DOI:  https://doi.org/10.3390/nu15030524
Gastroenterol Hepatol Bed Bench. 2022 ;15(4): 326-342

The ketogenic diet: its impact on human gut microbiota and potential consequent health outcomes: a systematic literature review.

Leslyn Rew, Miranda D Harris, Joanna Goldie.

   Aim: This systematic review examined the diet's impact on the human gut microbiota to identify potential consequent health outcomes.
Background: The extreme macronutrient profile of the ketogenic diet (KD) instigates compositional shifts in the gut's microbial community.
Methods: In this systematic literature review, an evidence-based and methodical approach was undertaken, which involved systematic searches of the Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, generating a total of 263 relevant research papers. Following the application of inclusion and exclusion criteria, eight papers were deemed suitable for inclusion. These papers were critically appraised using a checklist tool adapted from the National Institute of Care and Excellence (NICE). The findings were analysed using a simplified thematic analysis.
Results: The results provide strong evidence for a persistent reduction in Bifidobacterium abundance following KD adherence. A reduced abundance of key Firmicutes butyrate-producing bacteria was found to be a likely impact, although two studies with extended intervention periods indicate this may be time-limited. Studies investigating short-chain fatty acids (SCFA's) indicate KD reduces total faecal SCFA's, acetate, and butyrate.
Conclusion: Changes to microbial communities resulting from KD adherence are potentially detrimental to colonic health. The persistent reduction in Bifidobacterium abundance was concerning, with obesity, type-2 diabetes, and depression highlighted as potential consequent risks. For nutrition and healthcare professionals, the findings emphasize the importance of considering KDs microbial effects and resulting health implications at an individual level.

Keywords:  Gut microbiota; Human; Ketogenic diet

DOI:  https://doi.org/10.22037/ghfbb.v15i4.2600
Eur J Neurosci. 2023 Feb 07.

Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.

Shiho Sato, Zhiqian Yu, Mai Sakai, Ikuko N Motoike, Daisuke Saigusa, Ryo Hirayama, Yoshie Kikuchi, Takaaki Abe, Kengo Kinoshita, Seizo Koshiba, Hiroaki Tomita.

  β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analyzed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5,722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the liver and prefrontal cortex at 2 h and 6 h, respectively. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly increased in the liver and PFC after acute SDS exposure and decreased after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.

Keywords:  Mitochondria; Monocarboxylic acid transporter 1; Social defeat stress; Voltage-dependent anion-selective channel 1; β-Hydroxybutyrate

DOI:  https://doi.org/10.1111/ejn.15931
Obesity (Silver Spring). 2023 Feb 09.

A prolonged fast improves overnight substrate oxidation without modulating hepatic glycogen in adults with and without nonalcoholic fatty liver: A randomized crossover trial.

Kay H M Roumans, Anna Veelen, Charlotte Andriessen, Julian Mevenkamp, Esther Kornips, Pandichelvam Veeraiah, Bas Havekes, Harry P F Peters, Lucas Lindeboom, Patrick Schrauwen, Vera B Schrauwen-Hinderling.

OBJECTIVE: Increasing overnight fasting time seems a promising strategy to improve metabolic health in individuals with nonalcoholic fatty liver (NAFL). Mechanisms underlying the beneficial effects of fasting may be related to larger fluctuations in hepatic glycogen and higher fat oxidation. This study investigated whether prolonging an overnight fast depletes hepatic glycogen stores and improves substrate metabolism in individuals with NAFL and healthy lean individuals.
METHODS: Eleven individuals with NAFL and ten control individuals participated in this randomized crossover trial. After a 9.5-hour or 16-hour fast, hepatic glycogen was measured by using carbon-13 magnetic resonance spectroscopy, and a meal test was performed. Nocturnal substrate oxidation was measured with indirect calorimetry.
RESULTS: Extending fasting time led to lower nocturnal carbohydrate oxidation and higher fat oxidation in both groups (intervention × time, p < 0.005 for carbohydrate and fat oxidation). In both arms, the respiratory exchange ratio measured during the night remained higher in the group with NAFL compared with the control group (population p < 0.001). No changes were observed in hepatic glycogen depletion with a prolonged overnight fast in the group with NAFL or the control group.
CONCLUSIONS: These results suggest that acutely prolonging the overnight fast can improve overnight substrate oxidation and that these alterations are not mediated by changes in hepatic glycogen depletion.

DOI: https://doi.org/10.1002/oby.23676
Annu Rev Immunol. 2022 Feb 07.

Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation.

Jianing Fu, Hao Wu.

As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cellular damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. The three major components of the NLRP3 inflammasome are NLRP3, which captures the danger signals and recruits downstream molecules; caspase-1, which elicits maturation of the cytokines IL-1β and IL-18 and processing of gasdermin D to mediate cytokine release and pyroptosis; and ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), which functions as a bridge connecting NLRP3 and caspase-1. In this article, we review the structural information that has been obtained on the NLRP3 inflammasome and its components or subcomplexes, with special focus on the inactive NLRP3 cage, NEK7 (NIMA-related kinase 7)-licensing of NLRP3 activation, and the PYD-PYD and CARD-CARD homotypic filamentous scaffolds of the inflammasome. We further implicate structure-derived mechanisms for the assembly and activation of the NLRP3 inflammasome. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-immunol-081022-021207
Front Immunol. 2022 ;13 1109938

The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.

Xiaoyan Zhan, Qiang Li, Guang Xu, Xiaohe Xiao, Zhaofang Bai.

  NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a cytosolic pattern recognition receptor (PRR) that recognizes multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once activated, NLRP3 initiates the inflammasome assembly together with the adaptor ASC and the effector caspase-1, leading to caspase-1 activation and subsequent cleavage of IL-1β and IL-18. Aberrant NLRP3 inflammasome activation is linked with the pathogenesis of multiple inflammatory diseases, such as cryopyrin-associated periodic syndromes, type 2 diabetes, non-alcoholic steatohepatitis, gout, and neurodegenerative diseases. Thus, NLRP3 is an important therapeutic target, and researchers are putting a lot of effort into developing its inhibitors. The review summarizes the latest advances in the mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.

Keywords:  NLRP3; inflammasome; inflammatory diseases; pattern recognition receptor; pharmacological inhibitors

DOI:  https://doi.org/10.3389/fimmu.2022.1109938
Curr Nutr Rep. 2023 Feb 10.

Butyrate: More Than a Short Chain Fatty Acid.

Osman Mohamed Elfadil, Manpreet S Mundi, Marwa G Abdelmagid, Ankitaben Patel, Nishant Patel, Robert Martindale.

   PURPOSE OF REVIEW: The mechanistic understanding of the importance and the potential benefits of the gut microbiome has exploded in potential roles in human health and disease. Short chain fatty acids (SCFAs), including butyrate, are one of the key metabolic end products that has been a major focus of microbiome understanding. This brief review aims to describe butyrate's relation to certain biological concepts and their clinical application.
RECENT FINDINGS: Butyrate has reportedly been described as a potent pro-resolution molecule that has a significant role in maintaining gut immunity, supporting gut barrier function, regulation of histone deacetylase (HDAC), and numerous systemic roles. Further research is needed to explore potential benefits of adding SCFAs for patients receiving total parenteral nutrition. Butyrate plays several biological roles in intestinal epithelium anti-inflammatory pathways with clear benefits in numerous acute and chronic disease states and overall human health helping to maintain homeostasis.

Keywords:  Butyrate; Gut microbiome; Parenteral nutrition; Short chain fatty acids

DOI:  https://doi.org/10.1007/s13668-023-00461-4
Mol Cells. 2023 Feb 09.

The Role of Pyruvate Metabolism in Mitochondrial Quality Control and Inflammation.

Min-Ji Kim, Hoyul Lee, Dipanjan Chanda, Themis Thoudam, Hyeon-Ji Kang, Robert A Harris, In-Kyu Lee.

  Pyruvate metabolism, a key pathway in glycolysis and oxidative phosphorylation, is crucial for energy homeostasis and mitochondrial quality control (MQC), including fusion/fission dynamics and mitophagy. Alterations in pyruvate flux and MQC are associated with reactive oxygen species accumulation and Ca2+ flux into the mitochondria, which can induce mitochondrial ultrastructural changes, mitochondrial dysfunction and metabolic dysregulation. Perturbations in MQC are emerging as a central mechanism for the pathogenesis of various metabolic diseases, such as neurodegenerative diseases, diabetes and insulin resistance-related diseases. Mitochondrial Ca2+ regulates the pyruvate dehydrogenase complex (PDC), which is central to pyruvate metabolism, by promoting its dephosphorylation. Increase of pyruvate dehydrogenase kinase (PDK) is associated with perturbation of mitochondria-associated membranes (MAMs) function and Ca2+ flux. Pyruvate metabolism also plays an important role in immune cell activation and function, dysregulation of which also leads to insulin resistance and inflammatory disease. Pyruvate metabolism affects macrophage polarization, mitochondrial dynamics and MAM formation, which are critical in determining macrophage function and immune response. MAMs and MQCs have also been intensively studied in macrophage and T cell immunity. Metabolic reprogramming connected with pyruvate metabolism, mitochondrial dynamics and MAM formation are important to macrophages polarization (M1/M2) and function. T cell differentiation is also directly linked to pyruvate metabolism, with inhibition of pyruvate oxidation by PDKs promoting proinflammatory T cell polarization. This article provides a brief review on the emerging role of pyruvate metabolism in MQC and MAM function, and how dysfunction in these processes leads to metabolic and inflammatory diseases.

Keywords:  T cell; macrophage; mitochondria quality control; mitochondria-associated membranes; pyruvate dehydrogenase complex; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.14348/molcells.2023.2128
J Physiol. 2023 Feb 09.

Exercise - the key to a forever unaged vasculature?

Camilla Collin Hansen, Sophie Møller.



Keywords:  ageing; lifelong exercise; oxidative stress; vascular dysfunction; vascular mitochondria

DOI:  https://doi.org/10.1113/JP284347
J Appl Physiol (1985). 2023 Feb 09.

Increased Adiposity is Associated with Altered Skeletal Muscle Energetics.

David A Reiter, Moriah P Bellissimo, Lei Zhou, Scott Boebinger, Greg D Wells, Dean P Jones, Thomas R Ziegler, Jessica A Alvarez, Candace C Fleischer.

  The objective of this pilot study was to characterize relationships between skeletal muscle energy metabolism and body composition in healthy adults with varied amounts and distribution of adipose tissue. In vivo muscle energetics were quantified using dynamic 31P magnetic resonance spectroscopy with knee extension exercise standardized to subject lean body mass. Spearman correlation analysis examined relationships between muscle metabolism indices and measures of adiposity including body mass index (BMI), total body fat, and quadriceps intermuscular adipose tissue (IMAT). Post-hoc partial correlations were examined controlling for additional body composition measures. Kruskal-Wallis tests with Dunn-Sidak post-hoc comparisons evaluated group differences in energy metabolism based on body composition profiles (i.e. lean, normal-weight obese, and overweight-obese) and IMAT tertiles. BMI negatively correlated with end-exercise muscle pH after correcting for IMAT and total body fat (r=-0.46, p=.034). Total adiposity negatively correlated with maximum oxidative capacity after correcting for IMAT (r=-0.54, p=.013). IMAT positively correlated with muscle proton buffering capacity after correcting for total body fat (r=0.53, p=.023). Body composition groups showed differences in end-exercise fall in [PCr] with normalized workload (p=.036; post-hoc: overweight-obese < lean, p=.029) and maximum oxidative capacity (p=.021; post-hoc: normal-weight obese < lean, p=.016). IMAT tertiles showed differences in end-exercise fall in [PCr] with normalized workload (p=.035; post-hoc: 3rd < 1st, p=.047). Taken together, these results support increased adiposity is associated with reduced muscle energetic efficiency with more reliance on glycolysis, and when accompanied with reduced lean mass, is associated with reduced maximum oxidative capacity.

Keywords:  Adiposity; Body composition; Energy Metabolism; MRS; Skeletal Muscle

DOI:  https://doi.org/10.1152/japplphysiol.00387.2022
Endocrinol Metab Clin North Am. 2023 Mar;pii: S0889-8529(22)00057-3. [Epub ahead of print]52(1): 165-174

Remission in Ketosis-Prone Diabetes.

Nupur Kikani, Ashok Balasubramanyam.

  Heterogeneous forms of Ketosis-prone diabetes (KPD) are characterized by patients who present with diabetic ketoacidosis (DKA) but lack the typical features and biomarkers of autoimmune T1D. The A-β+ subgroup of KPD provides unique insight into the concept of "remission" since these patients have substantial preservation of beta-cell function permitting the discontinuation of insulin therapy, despite initial presentation with DKA. Measurements of C-peptide levels are essential to predict remission and guide potential insulin withdrawal. Further studies into predictors of remission and relapse can help us guide patients with A-β+ KPD toward remission and develop targeted treatments for this form of atypical diabetes.

Keywords:  Atypical diabetes; Autoantibodies; Beta-cell; C-peptide; Diabetic ketoacidosis; Insulin; Ketosis-prone diabetes; Remission

DOI:  https://doi.org/10.1016/j.ecl.2022.06.005
Int J Mol Sci. 2023 Jan 26. pii: 2415. [Epub ahead of print]24(3):

Fiber-Type Shifting in Sarcopenia of Old Age: Proteomic Profiling of the Contractile Apparatus of Skeletal Muscles.

Paul Dowling, Stephen Gargan, Dieter Swandulla, Kay Ohlendieck.

  The progressive loss of skeletal muscle mass and concomitant reduction in contractile strength plays a central role in frailty syndrome. Age-related neuronal impairments are closely associated with sarcopenia in the elderly, which is characterized by severe muscular atrophy that can considerably lessen the overall quality of life at old age. Mass-spectrometry-based proteomic surveys of senescent human skeletal muscles, as well as animal models of sarcopenia, have decisively improved our understanding of the molecular and cellular consequences of muscular atrophy and associated fiber-type shifting during aging. This review outlines the mass spectrometric identification of proteome-wide changes in atrophying skeletal muscles, with a focus on contractile proteins as potential markers of changes in fiber-type distribution patterns. The observed trend of fast-to-slow transitions in individual human skeletal muscles during the aging process is most likely linked to a preferential susceptibility of fast-twitching muscle fibers to muscular atrophy. Studies with senescent animal models, including mostly aged rodent skeletal muscles, have confirmed fiber-type shifting. The proteomic analysis of fast versus slow isoforms of key contractile proteins, such as myosin heavy chains, myosin light chains, actins, troponins and tropomyosins, suggests them as suitable bioanalytical tools of fiber-type transitions during aging.

Keywords:  actin; aging; atrophy; frailty; myosin; sarcomere; sarcopenia; tropomyosin; troponin

DOI:  https://doi.org/10.3390/ijms24032415
Front Endocrinol (Lausanne). 2023 ;14 1120533

MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation.

Yuejun Zheng, Zilin Wei, Tianhui Wang.

  Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c) is a mitochondrial-derived peptide composed of 16 amino acids encoded by the 12S rRNA region of the mitochondrial genome. The MOTS-c protein is transferred to the nucleus during metabolic stress and directs the expression of nuclear genes to promote cell balance. Different tissues co-expressed the protein with mitochondria, and plasma also contained the protein, but its level decreased with age. In addition, MOTS-c has been shown to improve glucose metabolism in skeletal muscle, which indicates its benefits for diseases such as diabetes, obesity, and aging. Nevertheless, MOTS-c has been used less frequently in disease treatment, and no effective method of applying MOTS-c in the clinic has been developed. Throughout this paper, we discussed the discovery and physiological function of mitochondrial-derived polypeptide MOTS-c, and the application of MOTS-c in the treatment of various diseases, such as aging, cardiovascular disease, insulin resistance, and inflammation. To provide additional ideas for future research and development, we tapped into the molecular mechanisms and therapeutic potentials of MOTS-c to improve diseases and combined the technology with synthetic biology in order to offer a new approach to its development and application.

Keywords:  MOTS-c; endocrine; mitochondrial-derived peptide; synthetic biology; therapeutic exploitation

DOI:  https://doi.org/10.3389/fendo.2023.1120533
Front Physiol. 2023 ;14 1063556

Mitochondrial dysfunction in cardiovascular disease: Towards exercise regulation of mitochondrial function.

Kunzhe Li, Bingzhi Wan, Sujuan Li, Zhixin Chen, Hao Jia, Yinping Song, Jiamin Zhang, Wenyu Ju, Han Ma, Youhua Wang.

  The morbidity and mortality of cardiovascular diseases are exceedingly high worldwide. Pathological heart remodeling, which is developed as a result of mitochondrial dysfunction, could ultimately drive heart failure. More recent research target exercise modulation of mitochondrial dysfunction to improve heart failure. Therefore, finding practical treatment goals and exercise programs to improve cardiovascular disease is instrumental. Better treatment options are available with the recent development of exercise and drug therapy. This paper summarizes pathological states of abnormal mitochondrial function and intervention strategies for exercise therapy.

Keywords:  cardiovascular diseases; exercise; mitochondrial autophagy; mitochondrial dynamics; mitochondrial energy metabolism

DOI:  https://doi.org/10.3389/fphys.2023.1063556
Lab Invest. 2023 Jan;pii: S0023-6837(22)00008-3. [Epub ahead of print]103(1): 100008

Role of the Circadian Clock and Effect of Time-Restricted Feeding in Adenine-Induced Chronic Kidney Disease.

Yina Fang, Sang-Kyung Jo, Soo-Ji Park, Jihyun Yang, Yoon Sook Ko, Hee Young Lee, Se Won Oh, Won Yong Cho, Kyoungmi Kim, Gi Hoon Son, Myung-Gyu Kim.

  Most physiological functions exhibit circadian rhythmicity that is partly regulated by the molecular circadian clock. Herein, we investigated the relationship between the circadian clock and chronic kidney disease (CKD). The role of the clock gene in adenine-induced CKD and the mechanisms of interaction were investigated in mice in which Bmal1, the master regulator of the clock gene, was knocked out, and Bmal1 knockout (KO) tubule cells. We also determined whether the renoprotective effect of time-restricted feeding (TRF), a dietary strategy to enhance circadian rhythm, is clock gene-dependent. The mice with CKD showed altered expression of the core clock genes with a loss of diurnal variations in renal functions and key tubular transporter gene expression. Bmal1 KO mice developed more severe fibrosis, and transcriptome profiling followed by gene ontology analysis suggested that genes associated with the cell cycle, inflammation, and fatty acid oxidation pathways were significantly affected in the mutant mice. Tubule-specific deletion of BMAL1 in HK-2 cells by CRISPR/Cas9 led to upregulation of p21 and tumor necrosis α and exacerbated epithelial-mesenchymal transition-related gene expression upon transforming growth factor β stimulation. Finally, TRF in the mice with CKD partially restored the disrupted oscillation of the kidney clock genes, accompanied by improved cell cycle arrest and inflammation, leading to decreased fibrosis. However, the renoprotective effect of TRF was abolished in Bmal1 KO mice, suggesting that TRF is partially dependent on the clock gene. Our data demonstrate that the molecular clock system plays an important role in CKD via cell cycle regulation and inflammation. Understanding the role of the circadian clock in kidney diseases can be a new research field for developing novel therapeutic targets.

Keywords:  cell cycle; chronic kidney disease; circadian rhythm; inflammation; timed-restricted feeding

DOI:  https://doi.org/10.1016/j.labinv.2022.100008