bims-kimdis 2023-03-19 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023–03–19
28 papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins

Ketogenic diets initiated in late mid-life improved measures of spatial memory in male mice.
Metabolic and ruck performance effects of a novel, light-weight, energy-dense ketogenic bar.
Impact of two ketogenic diet types in refractory childhood epilepsy.
Effects of very low-carbohydrate ketogenic diets on lipid profiles in normal-weight (body mass index < 25 kg/m2) adults: a meta-analysis.
Aldehyde dehydrogenase 2 and NOD-like receptor thermal protein domain associated protein 3 inflammasome in atherosclerotic cardiovascular diseases: A systematic review of the current evidence.
Pre-habilitation with high whey-protein-based meal replacement therapy and exercise promote weight loss and preserve muscle mass before bariatric surgery.
The role of skeletal muscle mass on cardiovascular disease risk: an emerging role on modulating lipid profile.
Palmitoylation promotes chaperone-mediated autophagic degradation of NLRP3 to modulate inflammation.
Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.
Mitochondrial pores at the crossroad between cell death and inflammatory signaling.
Short-chain fatty acids as a link between diet and cardiometabolic risk: a narrative review.
Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway.
The multifaceted roles of mitochondria.
Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.
β-Hydroxybutyrate alleviates cartilage senescence through hnRNP A1-mediated up-regulation of PTEN.
UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.
There's no one 'best' diet for promoting health.
Establishing Pragmatic Analytical Performance Specifications for Blood Beta-Hydroxybutyrate Testing.
The role of dietary strategies in the modulation of hallmarks of aging.
Cut Calories, Lengthen Life Span? Randomized Trial Uncovers Evidence That Calorie Restriction Might Slow Aging, but Questions Remain.
Myonuclear alterations after training: Train your muscles, train your nuclei.
Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver.
Fiber type and metabolic characteristics of skeletal muscle in 16 breeds of domestic dogs.
The association of circulating fibroblast growth factor 21 levels with incident heart failure: The Multi-Ethnic Study of Atherosclerosis.
Revisiting IL-1β: Linking Metainflammation to Diastolic Dysfunction.
Lean vs. obese NAFLD, two phenotypes of NAFLD: look the same but different or vice versa?
The crucial role of muscle glucocorticoid signaling in accelerating obesity and glucose intolerance via hyperinsulinemia.
Metabolic sensing and control in mitochondria.

Geroscience. 2023 Mar 18.

Ketogenic diets initiated in late mid-life improved measures of spatial memory in male mice.

Zeyu Zhou, Kyoungmi Kim, Jon J Ramsey, Jennifer M Rutkowsky.

  Studies have shown ketogenic diets (KD) started from early middle-age improved health span and longevity in mice. KDs started later in life or administered intermittently may be more feasible and promote compliance. Therefore, this study sought to test if continuous or intermittent KDs started in late-middle-aged mice would improve cognition and motor function at advanced age. Eighteen-month-old male C57BL/6JN mice were assigned to an isocaloric control (CD), KD, or intermittent ketogenic (IKD, 3-day KD/week) diet. A panel of behavior tests were performed to assess cognitive and motor functions with aging. Y-maze alternation rate was higher for both IKD and KD mice at 23 months of age and for KD mice at 26 months indicating an improved spatial working memory. Twenty-six-month-old KD mice also showed better spatial learning memory in Barnes maze when compared to the CD. Improved grid wire hang performance was observed in aged IKD and KD versus CD mice indicating better muscle endurance under isometric contraction. A reduced level of circulating proinflammatory cytokines in aged KD (IL-6 and TNF-α) and IKD (IL-6) mice may contribute to the phenotypic improvements observed with these interventions. This study demonstrates that when initiated at late-middle age, the KD improved measures of spatial memory and grid wire hang performance in aged male mice, with IKD showing results intermediate to the CD and KD groups.

Keywords:  Aging; Health span; Ketogenic diet

DOI:  https://doi.org/10.1007/s11357-023-00769-7
Exp Physiol. 2023 Mar 13.

Metabolic and ruck performance effects of a novel, light-weight, energy-dense ketogenic bar.

Alex Buga, Chris D Crabtree, Justen T Stoner, Drew D Decker, Bradley T Robinson, Madison L Kackley, Teryn N Sapper, Jeffrey D Buxton, Dominic P D'Agostino, Tyler S McClure, Anthony Berardi, Shawn Cline, Trevor Fleck, Jared Krout, Doran Newby, Andrew P Koutnik, Jeff S Volek, Philip J Prins.

   NEW FINDINGS: What is the central question of the study? Can a novel, energy-dense and lightweight ketogenic bar (1000 kcal) consumed 3 h before exercise modulate steady-state incline rucksack march ('ruck') performance compared to isocaloric carbohydrate bars in recreationally active, college-aged men? What is the main finding and its importance? Acute ingestion of either nutritional bar sustained ∼1 h of exhaustive rucking with a 30% of body weight rucksack. This proof-of-concept study is the first to demonstrate that carbohydrate bars and lipid bars are equally feasible for preserving ruck performance. Novel ketogenic nutrition bars may have military-relevant applications to lessen carry load without compromising exercise capacity.
ABSTRACT: Rucksack marches ('rucks') are strenuous, military-relevant exercises that may benefit from pre-event fuelling. The purpose of this investigation was to explore whether acute ingestion of carbohydrate- or lipid-based nutritional bars before rucking can elicit unique advantages that augment exercise performance. Recreationally active and healthy males (n = 29) were randomized and counterbalanced to consume 1000 kcal derived from a novel, energy-dense (percentage energy from carbohydrate/fat/protein: 5/83/12) ketogenic bar (KB), or isocaloric high-carbohydrate bars (CB; 61/23/16) 3 h before a time-to-exhaustion (TTE) ruck. Conditions were separated by a 1-week washout. The rucksack weight was standardized to 30% of bodyweight. Steady-state treadmill pace was set at 3.2 km/h (0.89 m/s) and 14% grade. TTE was the primary outcome; respiratory exchange ratio (RER), capillary ketones (R-β-hydroxybutyrate), glucose and lactate, plus subjective thirst/hunger were the secondary outcomes. Mean TTE was similar between conditions (KB: 55 ± 25 vs. CB: 54 ± 22 min; P = 0.687). The RER and substrate oxidation rates revealed greater fat and carbohydrate oxidation after the KB and CB, respectively (all P < 0.0001). Capillary R-βHB increased modestly after the KB ingestion (P < 0.0001). Neither bar influenced glycaemia. Lactate increased during the ruck independent of the condition (P < 0.0001). Thirst/fullness perceptions changed independent of the nutritional bar consumed. A novel KB nutritional bar produced equivalent TTE ruck results to the isocaloric CBs. The KB's energy density relative to CB (6.6 vs. 3.8 kcal/g) may provide a lightweight (-42% weight), pre-event fuelling alternative that does not compromise ruck physical performance.

Keywords:  carbohydrate; exercise; ketogenic; ruck; supplementation; time-to-exhaustion

DOI:  https://doi.org/10.1113/EP091029
Pediatr Res. 2023 Mar 11.

Impact of two ketogenic diet types in refractory childhood epilepsy.

Ali M El-Shafie, Wael A Bahbah, Sameh A Abd El Naby, Zein A Omar, Elsayedamr M Basma, Aya A A Hegazy, Heba M S El Zefzaf.

BACKGROUND: Ketogenic diet (KD) refers to any diet in which food composition induces a ketogenic state of human metabolism.
OBJECTIVE: To assess short- and long-term efficacy, safety, and tolerability of KD [classic KD and modified Atkins diet (MAD)] in childhood drug-resistant epilepsy (DRE) and to investigate the effect of KD on electroencephalographic (EEG) features of children with DRE.
METHODS: Forty patients diagnosed with DRE according to International League Against Epilepsy were included and randomly assigned into classic KD or MAD groups. KD was initiated after clinical, lipid profile and EEG documentation, and regular follow-up was done for 24 months.
RESULTS: Out of 40 patients with DRE, 30 completed this study. Both classic KD and MAD were effective in seizure control as 60% in classic KD group and 53.33% in MAD group became seizure free, and the remaining showed ≥50% seizure reduction. Lipid profile remained within acceptable levels throughout the study period in both groups. Adverse effects were mild and managed medically with an improvement of growth parameters and EEG during the study period.
CONCLUSIONS: KD is an effective and safe non-pharmacologic, non-surgical therapy for the management of DRE with a positive impact on growth and EEG.
IMPACT: Both common types of KD (classic KD and MAD) are effective for DRE, but unfortunately, nonadherence and dropout rates are frequent. High serum lipid profile (cardiovascular AE) is often suspected in children following a high-fat diet, but lipid profile remained in the acceptable level up to 24 months. Therefore, KD constitutes a safe treatment. KD had a positive impact on growth, despite inconsistent results of the KD's effect on growth. In addition to showing strong clinical effectiveness, KD also considerably decreased the frequency of interictal epileptiform discharges and enhanced the EEG background rhythm.

DOI: https://doi.org/10.1038/s41390-023-02554-w
Nutr Rev. 2023 Mar 17. pii: nuad017. [Epub ahead of print]

Effects of very low-carbohydrate ketogenic diets on lipid profiles in normal-weight (body mass index < 25 kg/m2) adults: a meta-analysis.

Minjin Joo, Sumin Moon, Young Seo Lee, Myeong Gyu Kim.

   CONTEXT: Very low-carbohydrate diets or ketogenic diets (KDs) have garnered attention for weight loss in patients with overweight or obesity as well as for normal-weight adults, yet the adverse effects of KDs, such as dyslipidemia in normal-weight adults, have not been studied extensively.
OBJECTIVE: This meta-analysis aimed to identify the effects of KDs on the lipid profile in normal-weight (body mass index [BMI] < 25 kg/m2) adults from randomized controlled trials.
DATA SOURCES: PubMed and Embase databases were searched on November 21, 2021, using search terms representing KDs and lipid profiles. Two researchers independently screened articles according to PICOS inclusion criteria.
DATA EXTRACTION: General study information, dietary data, and lipid profiles were extracted from eligible studies. Risk of bias was assessed using the Cochrane risk of bias 2 tool.
DATA ANALYSIS: Fixed- or random-effects meta-analysis was performed to estimate the effects of KDs on total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides, apolipoprotein A (apoA), and apolipoprotein B (apoB), considering heterogeneity across studies. The certainty of evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.
RESULTS: Three studies were selected for meta-analysis. A KD significantly increased TC by 1.47 mmol/L (95%CI, 0.72-2.22 mmol/L), LDL-C by 1.08 mmol/L (95%CI, 0.37-1.79 mmol/L), and apoB by 0.35 g/L (95%CI, 0.06-0.65 g/L). In addition, a KD significantly increased HDL-C by 0.35 mmol/L (95%CI, 0.27-0.42 mmol/L) and apoA by 0.34 g/L (95%CI, 0.28-0.41 g/L) compared with control diets. Triglyceride levels were not significantly different between KDs and control diets (P = 0.63).
CONCLUSION: This study suggests unfavorable effects of KDs on TC and LDL-C in normal-weight adults. Although an increase in HDL-C can compensate for unfavorable changes in lipids, normal-weight individuals should consider the risk of hypercholesterolemia when consuming a KD. Results for triglycerides were inconsistent.

Keywords:  carbohydrate-restricted; diet; ketogenic; lipid; meta-analysis; normal-weight

DOI:  https://doi.org/10.1093/nutrit/nuad017
Front Cardiovasc Med. 2023 ;10 1062502

Aldehyde dehydrogenase 2 and NOD-like receptor thermal protein domain associated protein 3 inflammasome in atherosclerotic cardiovascular diseases: A systematic review of the current evidence.

Xue-Yun Shi, Xiao-Lin Yue, You-Shun Xu, Mei Jiang, Rui-Jian Li.

  Inflammation and dyslipidemia underlie the pathological basis of atherosclerosis (AS). Clinical studies have confirmed that there is still residual risk of atherosclerotic cardiovascular diseases (ASCVD) even after intense reduction of LDL. Some of this residual risk can be explained by inflammation as anti-inflammatory therapy is effective in improving outcomes in subjects treated with LDL-lowering agents. NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation is closely related to early-stage inflammation in AS. Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme of toxic aldehyde metabolism located in mitochondria and works in the metabolism of toxic aldehydes such as 4-HNE and MDA. Despite studies confirming that ALDH2 can negatively regulate NLRP3 inflammasome and delay the development of atherosclerosis, the mechanisms involved are still poorly understood. Reactive Oxygen Species (ROS) is a common downstream pathway activated for NLRP3 inflammasome. ALDH2 can reduce the multiple sources of ROS, such as oxidative stress, inflammation, and mitochondrial damage, thereby reducing the activation of NLRP3 inflammasome. Further, according to the downstream of ALDH2 and the upstream of NLRP3, the molecules and related mechanisms of ALDH2 on NLRP3 inflammasome are comprehensively expounded as possible. The potential mechanism may provide potential inroads for treating ASCVD.

Keywords:  ALDH2; CD36; NLRP3 inflammasome; Nrf2; atherosclerosis; inflammatory response; mitochondrial damage; oxidative stress

DOI:  https://doi.org/10.3389/fcvm.2023.1062502
Asian J Surg. 2023 Mar 16. pii: S1015-9584(23)00300-7. [Epub ahead of print]

Pre-habilitation with high whey-protein-based meal replacement therapy and exercise promote weight loss and preserve muscle mass before bariatric surgery.

ChiouYi Ho, Siti Nuraini Mohd Samwil, Zuliehaiza Kahairudin, Norshariza Jamhuri, Adibah Abd Aziz.

   BACKGROUND: Bariatric surgery is considered as an effective therapy for those with morbid obesity. Preoperative weight loss with a very low-calorie diet is commonly used to ease the bariatric surgery. Pre-habilitation increases functional and physiological capacity. The study demonstrated the changes of body composition and functional status following short term pre-habilitation before bariatric surgery.
METHOD: This prospective study targeted those admitted for bariatric surgery. Participants underwent the biweekly pre-habilitation program included an individualized high whey-based protein very low-calorie (VLCHP) enteral regime (600-900 kcal/day) and moderate intensive exercise before bariatric surgery. Body composition and waist circumference were assessed after fortnight. Participants were segregated into morbid obese (MOG) (BMI <49 kg/m2) and super morbid obese group (SMOG) (BMI ≥50 kg/m2) for analysis.
RESULT: Majority of participants were female (71%) with median age 36.0 years old (MOG) and 34.3 years old (SMOG) respectively. SMOG achieved significant greater loss in weight (-7.4 kg vs -4.0 kg), fat percentage (-4.4% vs -1.7%) and fat mass (-9.9 kg vs -3.8 kg); but MOG had a significant increment in muscle mass (3.2 kg vs 2.8 kg) as compared to SOG (p < 0.001).
DISCUSSION: Body composition measurement and changes remain critical in nutritional assessment to achieve successful surgery and minimize nutritional complication. Whey-based VLCHP attenuates muscle loss and preserves myofibrillar protein synthesis; promotes a better muscle strength and mass growth during periods of negative energy balance combined with moderately intense aerobic activity.
CONCLUSION: Individualized whey-based VLCHP enteral regime and moderate intensive exercise encourage weight loss; increases muscle mass and strength; improve function status prior to bariatric surgery.

Keywords:  Bariatric; Exercise; High protein low calories

DOI:  https://doi.org/10.1016/j.asjsur.2023.03.026
Curr Opin Cardiol. 2023 Mar 15.

The role of skeletal muscle mass on cardiovascular disease risk: an emerging role on modulating lipid profile.

Evangelia Damigou, Matina Kouvari, Demosthenes Panagiotakos.

PURPOSE OF REVIEW: The purpose of this review was to present updated evidence on the role of skeletal muscle mass on cardiometabolic health.
RECENT FINDINGS: Increased lean, and especially skeletal, muscle mass has been associated with better cardiometabolic health in various epidemiological studies, even in younger age groups. In addition, the link between skeletal muscle mass and adult lipid profile is of interest. A preliminary analysis using the data from the ATTICA prospective cohort study (2002-2022) supports this association.
SUMMARY: Skeletal muscle mass has many metabolic functions (i.e., glucose, insulin and protein metabolism, mitochondrial function, arterial stiffness, inflammation, oxidative stress, brain function, hormone status). Given its associations with the lipid profile and overall cardiometabolic risk, skeletal muscle mass stands among the emerging risk factors for cardiovascular diseases. In addition to only using body mass index or fat distribution, more studies should evaluate lean mass and its prognostic and predictive ability regarding chronic diseases.

DOI: https://doi.org/10.1097/HCO.0000000000001047
Autophagy. 2023 Mar 16.

Palmitoylation promotes chaperone-mediated autophagic degradation of NLRP3 to modulate inflammation.

Liqiu Wang, Jun Cui.

  The critical intracellular pattern recognition receptor NLRP3 senses pathogenic organisms and endogenous danger signals via forming inflammasomes to orchestrate innate immune responses. Dysfunction of NLRP3 inflammasomes is implicated in several inflammatory disorders. Hence, it is important to uncover the mechanisms preventing sustained NLRP3 inflammasome activation. Recently, we revealed that ZDHHC12-mediated palmitoylation enhances NLRP3 degradation through the chaperone-mediated autophagy pathway, and identified gain-of-function variants of NLRP3 in autoinflammatory disease, which induce excessive NLRP3 inflammasome activation through decreased palmitoylation level and impaired chaperone-mediated autophagic degradation.

Keywords:  NLRP3; chaperone-mediated autophagy; inflammasome; inflammation; palmitoylation

DOI:  https://doi.org/10.1080/15548627.2023.2187957
Scand J Med Sci Sports. 2023 Mar 17.

Lowered muscle glycogen reduces body mass with no effect on short-term exercise performance in men.

Camilla Tvede Schytz, Niels Ørtenblad, Thor Andersen Birkholm, Peter Plomgaard, Lars Nybo, Kristoffer Jensen Kolnes, Ole Emil Andersen, Carsten Lundby, Joachim Nielsen, Kasper Degn Gejl.

  Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on muscle glycogen content, body mass and short-term exercise performance. In a cross-over design twenty-two men completed two maximal cycle tests of either 1-min (n = 10) or 15-min (n = 12) duration with different pre-exercise muscle glycogen levels. Glycogen manipulation was initiated three days prior to the tests by exercise-induced glycogen-depletion followed by ingestion of a moderate (M-CHO) or high (H-CHO) CHO-diet. Subjects were weighed before each test, and muscle glycogen content was determined in biopsies from m. vastus lateralis before and after each test. Pre-exercise muscle glycogen content was lower following M-CHO than H-CHO (367 mmol · kg-1 DW vs. 525 mmol · kg-1 DW, P < 0.00001), accompanied by a 0.7 kg lower body mass (P < 0.00001). No differences were observed in performance between diets in neither the 1-min (P = 0.33) nor the 15-min (P = 0.99) test. In conclusion, pre-exercise muscle glycogen content and body mass was lower after ingesting moderate compared with high amounts of CHO, while short-term exercise performance was unaffected. This demonstrates that adjusting pre-exercise glycogen levels to the requirements of competition may provide an attractive weight management strategy in weight-bearing sports, particularly in athletes with high resting glycogen levels.

Keywords:  Diet Manipulation; Fatigue; Skeletal Muscle; Taper; Weight Management

DOI:  https://doi.org/10.1111/sms.14354
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00124-7. [Epub ahead of print]83(6): 843-856

Mitochondrial pores at the crossroad between cell death and inflammatory signaling.

Hector Flores-Romero, Shashank Dadsena, Ana J García-Sáez.

  Mitochondria are cellular organelles with a major role in many cellular processes, including not only energy production, metabolism, and calcium homeostasis but also regulated cell death and innate immunity. Their proteobacterial origin makes them a rich source of potent immune agonists, normally hidden within the mitochondrial membrane barriers. Alteration of mitochondrial permeability through mitochondrial pores thus provides efficient mechanisms not only to communicate mitochondrial stress to the cell but also as a key event in the integration of cellular responses. In this regard, eukaryotic cells have developed diverse signaling networks that sense and respond to the release of mitochondrial components into the cytosol and play a key role in controlling cell death and inflammatory pathways. Modulating pore formation at mitochondria through direct or indirect mechanisms may thus open new opportunities for therapy. In this review, we discuss the current understanding of the structure and molecular mechanisms of mitochondrial pores and how they function at the interface between cell death and inflammatory signaling to regulate cellular outcomes.

Keywords:  BAK; BAX; VDAC; apoptosis; gasdermin; inflammation; mPTP; membrane pore

DOI:  https://doi.org/10.1016/j.molcel.2023.02.021
Lipids Health Dis. 2023 Mar 14. 22(1): 40

Short-chain fatty acids as a link between diet and cardiometabolic risk: a narrative review.

Eline Birkeland, Sedegheh Gharagozlian, Jørgen Valeur, Anne-Marie Aas.

   AIM: Diet has a profound impact on cardiometabolic health outcomes such as obesity, blood glucose, blood lipids and blood pressure. In recent years, the gut microbiota has emerged as one of several potential key players explaining dietary effects on these outcomes. In this review we aim to summarise current knowledge of interaction between diet and gut microbiota focusing on the gut-derived microbial metabolites short-chain fatty acids and their role in modulating cardiometabolic risk.
FINDINGS: Many observational and interventional studies in humans have found that diets rich in fibre or supplemented with prebiotic fibres have a favourable effect on the gut microbiota composition, with increased diversity accompanied by enhancement in short-chain fatty acids and bacteria producing them. High-fat diets, particularly diets high in saturated fatty acids, have shown the opposite effect. Several recent studies indicate that the gut microbiota modulates metabolic responses to diet in, e.g., postprandial blood glucose and blood lipid levels. However, the metabolic responses to dietary interventions, seem to vary depending on individual traits such as age, sex, ethnicity, and existing gut microbiota, as well as genetics. Studies mainly in animal models and cell lines have shown possible pathways through which short-chain fatty acids may mediate these dietary effects on metabolic regulation. Human intervention studies appear to support the favourable effect of short-chain fatty acid in animal studies, but the effects may be modest and vary depending on which cofactors were taken into consideration.
CONCLUSION: This is an expanding and active field of research that in the near future is likely to broaden our understanding of the role of the gut microbiota and short-chain fatty acids in modulating metabolic responses to diet. Nevertheless, the findings so far seem to support current dietary guidelines encouraging the intake of fibre rich plant-based foods and discouraging the intake of animal foods rich in saturated fatty acids.

Keywords:  Diet; Gut microbiota; Human studies; Metabolic effects; Short-chain fatty acids

DOI:  https://doi.org/10.1186/s12944-023-01803-5
Front Endocrinol (Lausanne). 2023 ;14 1059020

Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway.

Manuel Arias-Calderón, Mariana Casas, Julián Balanta-Melo, Camilo Morales-Jiménez, Nadia Hernández, Paola Llanos, Enrique Jaimovich, Sonja Buvinic.

  Fibroblast growth factor 21 (FGF21) is a hormone involved in the regulation of lipid, glucose, and energy metabolism. Although it is released mainly from the liver, in recent years it has been shown that it is a "myokine", synthesized in skeletal muscles after exercise and stress conditions through an Akt-dependent pathway and secreted for mediating autocrine and endocrine roles. To date, the molecular mechanism for the pathophysiological regulation of FGF21 production in skeletal muscle is not totally understood. We have previously demonstrated that muscle membrane depolarization controls gene expression through extracellular ATP (eATP) signaling, by a mechanism defined as "Excitation-Transcription coupling". eATP signaling regulates the expression and secretion of interleukin 6, a well-defined myokine, and activates the Akt/mTOR signaling pathway. This work aimed to study the effect of electrical stimulation in the regulation of both production and secretion of skeletal muscle FGF21, through eATP signaling and PI3K/Akt pathway. Our results show that electrical stimulation increases both mRNA and protein (intracellular and secreted) levels of FGF21, dependent on an extracellular ATP signaling mechanism in skeletal muscle. Using pharmacological inhibitors, we demonstrated that FGF21 production and secretion from muscle requires the activation of the P2YR/PI3K/Akt/mTOR signaling pathway. These results confirm skeletal muscle as a source of FGF21 in physiological conditions and unveil a new molecular mechanism for regulating FGF21 production in this tissue. Our results will allow to identify new molecular targets to understand the regulation of FGF21 both in physiological and pathological conditions, such as exercise, aging, insulin resistance, and Duchenne muscular dystrophy, all characterized by an alteration in both FGF21 levels and ATP signaling components. These data reinforce that eATP signaling is a relevant mechanism for myokine expression in skeletal muscle.

Keywords:  Akt signaling; excitation-transcription coupling; extracellular nucleotides; fibroblast growth factor 21; membrane depolarization; muscle activity; myokines

DOI:  https://doi.org/10.3389/fendo.2023.1059020
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00157-0. [Epub ahead of print]83(6): 819-823

The multifaceted roles of mitochondria.

Thomas J Pucadyil, Jerry Edward Chipuk, Ying Liu, Luke O'Neill, Quan Chen.

Much more than the "powerhouse" of the cell, mitochondria have emerged as critical hubs involved in metabolism, cell death, inflammation, signaling, and stress responses. To open our mitochondria focus issue, we asked several scientists to share the unanswered questions, emerging themes, and topics of investigation that excite them.

DOI: https://doi.org/10.1016/j.molcel.2023.02.030
EMBO J. 2023 Mar 14. e111901

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.

Jennifer Ngo, Dong Wook Choi, Illana A Stanley, Linsey Stiles, Anthony J A Molina, Pei-Hsuan Chen, Ana Lako, Isabelle Chiao Han Sung, Rishov Goswami, Min-Young Kim, Nathanael Miller, Siyouneh Baghdasarian, Doyeon Kim-Vasquez, Anthony E Jones, Brett Roach, Vincent Gutierrez, Karel Erion, Ajit S Divakaruni, Marc Liesa, Nika N Danial, Orian S Shirihai.

  Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet β-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

Keywords:  CPT1; fatty acid oxidation; fission; fusion; mitochondrial dynamics

DOI:  https://doi.org/10.15252/embj.2022111901
Exp Gerontol. 2023 Mar 15. pii: S0531-5565(23)00061-X. [Epub ahead of print]175 112140

β-Hydroxybutyrate alleviates cartilage senescence through hnRNP A1-mediated up-regulation of PTEN.

Guang Xia, Zi Wen, Lina Zhang, Junjie Huang, Xinxing Wang, Chi Liang, Xiaoyu Cui, Xu Cao, Song Wu.

  Senescence chondrocytes play an important role in Osteoarthritis (OA) progression. However, alleviating OA progression through senescent chondrocyte intervention still faces great challenges. β-Hydroxybutyrate (BHB) exhibits anti-senescence effects in a variety of age-related dis-eases, but its role in osteoarthritis remains poorly understood. To explore the molecular mechanisms, gene sequencing was used to identify critical genes and potential cellular signaling pathways and male SD rats were used to generate an osteoarthritis model. Results showed that BHB attenuated the senescence of Osteoarthritis chondrocytes (OA-Chos) and alleviated OA progression. Gene ontology (GO) enrichment analysis revealed significant changes in cell cycle genes, with PTEN being the most significant differentially expressed gene. BHB up-regulated the expression of PTEN in OA-Chos, thereby alleviating chondrocyte senescence. Furthermore, BHB facilitated the expression of PTEN by binding to hnRNP A1 and inhibiting the phosphorylation of Akt. This study provided evidence that BHB mitigated chondrocyte senescence and delayed OA, and could thus be used as a novel therapeutic approach for osteoarthritis treatment.

Keywords:  Osteoarthritis; Phosphatase and tensin homolog; Senescent; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.exger.2023.112140
J Clin Invest. 2023 Mar 15. pii: e169986. [Epub ahead of print]133(6):

UCP2-induced fatty acid synthase promotes NLRP3 inflammasome activation during sepsis.

Jong-Seok Moon, Seonmin Lee, Mi-Ae Park, Ilias I Siempos, Maria Haslip, Patty J Lee, Mijin Yun, Chun K Kim, Judie Howrylak, Stefan W Ryter, Kiichi Nakahira, Augustine Mk Choi.

DOI: https://doi.org/10.1172/JCI169986
Nature. 2023 Mar 14.

There's no one 'best' diet for promoting health.



Keywords:  Nutrition

DOI:  https://doi.org/10.1038/d41586-023-00752-4
Clin Chem. 2023 Mar 15. pii: hvad020. [Epub ahead of print]

Establishing Pragmatic Analytical Performance Specifications for Blood Beta-Hydroxybutyrate Testing.

Eric S Kilpatrick, Alexandra E Butler, Stephen L Atkin, David B Sacks.

BACKGROUND: Currently, no authoritative guidelines exist recommending the analytical performance specification (APS) of blood beta-hydroxybutyrate (BOHB) testing in order to meet the clinical needs of patients. This study has applied existing diabetic ketoacidosis (DKA) BOHB diagnostic thresholds and the recommended rates of fall in BOHB concentrations during DKA treatment to establish pragmatic APSs for BOHB testing.
METHODS: Required analytical performance was based on 2 clinical requirements: (a) to reliably distinguish between non-adjacent DKA BOHB diagnostic categories of <0.6, 0.6 to 1.5, 1.6 to 2.9, and ≥3 mmol/L, and (b) to be assured that a measured 0.5 mmol/L reduction in BOHB indicates the true concentration is at least falling (meaning >0 mmol/L decline).
RESULTS: An analytical coefficient of variation (CV) of <21.5% could reliably distinguish all non-adjacent diagnostic categories with >99% certainty, assuming zero bias. In contrast, within-day CVs of 4.9%, 7.0%, and 9.1% at 3 mmol/L BOHB were required to assure truly falling ketone concentrations with 99% (optimal), 95% (desirable), and 90% (minimal) probability, respectively. These CVs are larger at lower BOHB concentrations and smaller at higher concentrations.
CONCLUSIONS: Reliable tracking of changes in BOHB during DKA treatment largely drives the requirement for analytical performance. These data can be used to guide minimal, desirable, and optimal performance targets for BOHB meters and laboratory assays.

DOI: https://doi.org/10.1093/clinchem/hvad020
Ageing Res Rev. 2023 Mar 09. pii: S1568-1637(23)00067-3. [Epub ahead of print] 101908

The role of dietary strategies in the modulation of hallmarks of aging.

Natasha A Grande de França, Yves Rolland, Sophie Guyonnet, Philipe de Souto Barreto.

  The hallmarks of aging constitute an interconnected network of basic mechanisms that modulate aging and can be modulated by lifestyle factors, including dietary strategies. This narrative review aimed to summarize the evidence on promoting dietary restriction or adherence to specific dietary patterns on cellular hallmarks of aging. Studies with preclinical models or humans were considered. Dietary restriction (DR), usually operationalized as a reduction in caloric intake, is the main strategy applied to study the axis diet-hallmarks of aging. DR has been shown to modulate mainly genomic instability, loss of proteostasis, deregulating nutrient sensing, cellular senescence, and altered intercellular communication. Much less evidence exists on the role of dietary patterns, with most of the studies evaluating the Mediterranean Diet and other similar plant-based diets, and the ketogenic diet. Potential benefits are described in genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, and altered intercellular communication. Given the predominant place of food in human life, it is imperative to determine the impact of nutritional strategies on the modulation of lifespan and health span, considering applicability, long-term adherence, and side effects.

Keywords:  caloric restriction; dietary patterns; fasting; food intake; hallmarks of aging

DOI:  https://doi.org/10.1016/j.arr.2023.101908
JAMA. 2023 Mar 15.

Cut Calories, Lengthen Life Span? Randomized Trial Uncovers Evidence That Calorie Restriction Might Slow Aging, but Questions Remain.

Rita Rubin.

DOI: https://doi.org/10.1001/jama.2023.2437
J Physiol. 2023 Mar 17.

Myonuclear alterations after training: Train your muscles, train your nuclei.

Zakarias Kefil Jensen Ogueboule.



Keywords:  Ageing; Exercise; Mechanotransduction; Nuclear lamina; Nuclear shape; Rho GTPases; Sarcopenia

DOI:  https://doi.org/10.1113/JP284476
J Clin Invest. 2023 Mar 16. pii: e167442. [Epub ahead of print]

Persistent fasting lipogenesis links impaired ketogenesis with citrate synthesis in humans with non-alcoholic fatty liver.

Xiaorong Fu, Justin A Fletcher, Stanisław Deja, Melissa Inigo-Vollmer, Shawn C Burgess, Jeffrey D Browning.

   BACKGROUND: Hepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of non-alcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.
METHODS: Forty consecutive non-diabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24-hr, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry.
RESULTS: Within a subset of subjects, DNL was detectable after a 24-hr fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, NEFA, and ketones. Additionally, they sustained glycogenolysis and spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis.
CONCLUSION: Metabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL.
TRIAL REGISTRATION: Data obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease; ClinicalTrials.gov NCT02690792.

Keywords:  Endocrinology; Fatty acid oxidation; Hepatology; Intermediary metabolism

DOI:  https://doi.org/10.1172/JCI167442
Anat Rec (Hoboken). 2023 Mar 17.

Fiber type and metabolic characteristics of skeletal muscle in 16 breeds of domestic dogs.

Kathryn M van Boom, Johan P Schoeman, Johan C A Steyl, Tertius A Kohn.

  The domestic dog (Canis lupus familiaris) species comprises hundreds of breeds, each differing in physical characteristics, behavior, strength, and running capability. Very little is known about the skeletal muscle composition and metabolism between the different breeds, which may explain disease susceptibility. Muscle samples from the triceps brachii (TB) and vastus lateralis (VL) were collected post mortem from 35 adult dogs, encompassing 16 breeds of varying ages and sex. Samples were analyzed for fiber type composition, fiber size, oxidative, and glycolytic metabolic capacity (citrate synthase [CS], 3-hydroxyacetyl-coA dehydrogenase [3HAD], creatine kinase [CK], and lactate dehydrogenase [LDH] enzyme activities). There was no significant difference between the TB and VL in any of the measurements. However, there were large intra species variation, with some variables confirming the physical attributes of a specific breed. Collectively, type IIA was the predominant fiber type followed by type I and type IIX. The cross-sectional areas (CSA) of the fibers were all smaller when compared to humans and similar to other wild animals. There was no difference in the CSA between the fiber types and muscle groups. Metabolically, the muscle of the dog displayed high oxidative capacity with high activities for CS and 3HAD. Lower CK and higher LDH activities than humans indicate a lower and higher flux through the high energy phosphate and glycolytic pathways, respectively. The high variability found across the different breeds may be attributed to genetics, function or lifestyle which have largely been driven through human intervention. This data may provide a foundation for future research into the role of these parameters in disease susceptibility, such as insulin resistance and diabetes, across breeds.

Keywords:  canine; domestic animal; metabolism; myosin heavy chain

DOI:  https://doi.org/10.1002/ar.25207
Metabolism. 2023 Mar 15. pii: S0026-0495(23)00138-5. [Epub ahead of print] 155535

The association of circulating fibroblast growth factor 21 levels with incident heart failure: The Multi-Ethnic Study of Atherosclerosis.

William Tucker, Robyn L McClelland, Matthew A Allison, Moyses Szklo, Kerry-Anne Rye, Kwok Leung Ong.

   BACKGROUND: Fibroblast growth factor 21 (FGF21) levels are often elevated in heart failure (HF), although this has not been assessed using a longitudinal study design. Therefore, we investigated the association between baseline plasma FGF21 levels and incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA).
METHODS: A total of 5408 participants, free of clinically apparent cardiovascular disease, were included in the analysis, of which 342 developed HF over a median follow-up period of 16.7 years. Multivariable Cox regression analysis was performed and the additive value of FGF21 in the performance of risk prediction over other well-established cardiovascular biomarkers was assessed.
RESULTS: The mean age of the participants was 62.6 years with 47.6 % male. Regression spline analysis demonstrated a significant association of FGF21 levels with incident HF among participants with FGF21 levels ≥239.0 pg/mL (hazard ratio = 1.84 [95 % confidence interval 1.21, 2.80] per SD increase in ln-transformed levels) after adjustment for traditional cardiovascular risk factors and biomarkers, but not in participants with FGF21 levels <239.0 pg/mL (p for heterogeneity = 0.004). Among participants with FGF21 levels ≥239.0 pg/mL, FGF21 levels were associated with HF with preserved ejection fraction (HR [95 % CI] = 2.57 [1.51, 4.37]), but not HF with reduced ejection fraction.
CONCLUSIONS: The present study suggests baseline FGF21 levels could predict the development of incident HF with preserved ejection fraction, among participants with elevated FGF21 levels at baseline. This study may suggest a pathophysiological role of FGF21 resistance in HF with preserved ejection fraction.

Keywords:  Biomarker; Fibroblast growth factor 21; Heart failure; Heart failure with preserved ejection fraction; Multi-Ethnic Study of Atherosclerosis

DOI:  https://doi.org/10.1016/j.metabol.2023.155535
JACC Basic Transl Sci. 2023 Feb;8(2): 186-188

Revisiting IL-1β: Linking Metainflammation to Diastolic Dysfunction.

Mallory Filipp, Edward B Thorp.



Keywords:  diabetes; diastolic dysfunction; heart failure with preserved ejection fraction; inflammation; macrophages

DOI:  https://doi.org/10.1016/j.jacbts.2022.10.006
Clin Mol Hepatol. 2023 Mar 09.

Lean vs. obese NAFLD, two phenotypes of NAFLD: look the same but different or vice versa?

Ho Soo Chun, Minjong Lee.



Keywords:   metabolic dysfunction; mortality; nonalcoholic steatohepatitis; obesity; Nonalcoholic fatty liver disease

DOI:  https://doi.org/10.3350/cmh.2023.0061
JCI Insight. 2023 Mar 14. pii: e162382. [Epub ahead of print]

The crucial role of muscle glucocorticoid signaling in accelerating obesity and glucose intolerance via hyperinsulinemia.

Hiroki Yamazaki, Masaaki Uehara, Noritada Yoshikawa, Akiko Kuribara-Souta, Motohisa Yamamoto, Yasuko Hirakawa, Yasuaki Kabe, Makoto Suematsu, Hirotoshi Tanaka.

  Metabolic crosstalk from skeletal muscle to multiple organs is important for maintaining homeostasis, and its dysregulation can lead to various diseases. Chronic glucocorticoid administration often induces muscle atrophy and metabolic disorders such as diabetes and central obesity; however, the detailed underlying mechanism remains unclear. We previously reported that the deletion of glucocorticoid receptor (GR) in skeletal muscle increases muscle mass and reduces fat mass through muscle-liver-fat communication under physiological conditions. In this study, we show that muscle GR signaling plays a crucial role in accelerating obesity through the induction of hyperinsulinemia. Fat accumulation in liver and adipose tissue, muscle atrophy, hyperglycemia, and hyperinsulinemia induced by chronic corticosterone (CORT) treatment improved in muscle-specific GR knockout (GRmKO) mice. Such CORT-induced fat accumulation was alleviated by suppressing insulin production (streptozotocin injection), indicating that hyperinsulinemia enhanced by muscle GR signaling promotes obesity. Strikingly, glucose intolerance and obesity in ob/ob mice without CORT treatment were also improved in GRmKO mice, indicating that muscle GR signaling contributes to obesity-related metabolic changes, regardless of systemic glucocorticoid levels. Thus, this study provides new insight for the treatment of obesity and diabetes by targeting muscle GR signaling.

Keywords:  Endocrinology; Insulin; Muscle Biology; Obesity

DOI:  https://doi.org/10.1172/jci.insight.162382
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00119-3. [Epub ahead of print]83(6): 877-889

Metabolic sensing and control in mitochondria.

Yuyang Liu, Kıvanç Birsoy.

Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.

DOI: https://doi.org/10.1016/j.molcel.2023.02.016