bims-kimdis 2024-09-15 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–09–15
25 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate.
Starvation Ketoacidosis on the Acute Medical Take: An Easily Missed Complication of the Keto Diet.
Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers.
Effects of Ketogenic Diet on Increased Ethanol Consumption Induced by Social Stress in Female Mice.
Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.
Ketogenic Diet and Its Potential Role in Preventing Type 2 Diabetes Mellitus and Its Complications: A Narrative Review of Randomized Controlled Trials.
Effect of ketogenic diets on lipid metabolism in adults: protocol for a systematic review.
Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.
The Effectiveness of Modified Atkins Ketogenic Diet on Children with Intractable Epilepsy: A Pilot Study from Indonesia.
Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
Fat burning capacity in a mixed macronutrient meal protocol does not reflect metabolic flexibility in women who are overweight or obese.
Clinical Application of Skeletal Muscle Quantity and Quality Assessment Using Bioelectrical Impedance and Ultrasound Images.
Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.
Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in Mice.
Comparison of weight loss effects among overweight/obese adults: A network meta-analysis of mediterranean, low carbohydrate, and low-fat diets.
Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses.
Lifelong dietary protein restriction induces denervation and skeletal muscle atrophy in mice.
Effects of Different Caloric Restriction Patterns on Blood Pressure and Other Cardiovascular Risk Factors: A Systematic Review and Network Meta-Analysis of Randomized Trials.
Aerobic Exercise Attenuates Doxorubicin-Induced Cardiomyopathy by Suppressing NLRP3 Inflammasome Activation in a Rat Model.
PCPE-2 (procollagen C-proteinase enhancer-2): the NON-IDENTICAL twin of PCPE-1.
Visualizing mitochondrial dynamics at the nanoscale.
DRP1 Association in Inflammation and Metastasis: A Review.
Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.
Fat body glycolysis defects inhibit mTOR and promote distant muscle disorganization through TNF-α/egr and ImpL2 signaling in Drosophila larvae.

Front Nutr. 2024 ;11 1443483

Ketogenic diet with aerobic exercise can induce fat browning: potential roles of β-hydroxybutyrate.

Sujin Kim, Dong-Ho Park, Sohee Moon, Bonsang Gu, Keren Esther Kristina Mantik, Hyo-Bum Kwak, Ji-Kan Ryu, Ju-Hee Kang.

   Introduction: Despite evidence suggesting that metabolic intermediates like β-HB influence white adipose tissue (WAT) metabolism, the precise molecular mechanisms remain unclear. The aim of this study was to investigate the impact of beta-hydroxybutyrate (β-HB) on the fat browning program and to explore the underlying molecular mechanisms using both in vitro and in vivo models. We assessed the effects of β-HB on fat browning in adipocytes using 3T3-L1 cells and rat models.
Methods: We evaluated the effects of β-HB on fat browning, thermogenesis, lipid accumulation, adipokine expression, and mitochondrial biogenesis by treating mature 3T3-L1 adipocytes with sodium β-HB for 24 h or by continuously exposing preadipocytes to β-HB during the 8-day differentiation process. Male Sprague Dawley rats were divided into control, exercise only (EX), ketogenic diet only (KD), and combined exercise and ketogenic diet (KE) groups for an 8-week intervention involving diet and/or exercise. After intervention, we evaluated WAT histology, plasma lipids and adipokines, and the expression of markers related to fat browning, thermogenesis and mitochondrial biogenesis in WAT of rats.
Results: In our adipocyte culture experiments, β-HB reduced intracellular lipid accumulation by enhancing lipolysis and stimulated the expression of thermogenic and fat browning genes like uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), and adipokines such as fibroblast growth factor 21 (FGF21) and Fibronectin type III domain-containing protein 5 (FDNC5). Additionally, β-HB activated the AMPK-SIRT1-PGC-1α pathway, with UCP1 and PRDM16 upregulation mediated by β-HB intracellular action and SIRT1 activity. In animal experiments, KE group raised β-HB levels, decreasing body weight and blood lipids. KD with EX promoted WAT browning possibly via AMPK-SIRT1-PGC-1α, augmenting PRDM16, UCP1, FGF21, and FNDC5 expression.
Conclusion: β-HB induction via KD and/or EX shows potential in promoting WAT browning by activating mitochondrial biogenesis, lipolysis, and thermogenesis, suggesting that dietary and physical intervention inducing β-HB may benefit metabolic health.

Keywords:  adipokine; beta-hydroxybutyrate; exercise; fat browning; ketogenic diet; mitochondrial biogenesis

DOI:  https://doi.org/10.3389/fnut.2024.1443483
Eur J Case Rep Intern Med. 2024 ;11(9): 004830

Starvation Ketoacidosis on the Acute Medical Take: An Easily Missed Complication of the Keto Diet.

Ayesha Shaikh, David M Williams, Jeffrey W Stephens, Rhodri Edwards.

  Starvation ketoacidosis represents one of the three forms of metabolic acidosis caused by the accumulation of ketone bodies within the blood stream. It can be easily missed in patients who present acutely and are found to have an unexplained or profound metabolic acidosis. Here, we present a life-threatening case of severe ketoacidosis in a breast-feeding mother without diabetes who was on a strict ketogenic diet. Although a ketogenic diet has been previously considered to be safe in non-pregnant individuals, its safety in breast-feeding mothers in the post-partum period is less known and may be associated with greater harm. Health professionals and mothers should be aware of the potential risks associated with a strict ketogenic diet when combined with breast-feeding, especially in the earlier stages of the post-partum period. Prompt investigation, diagnosis and immediate management is vital to avoid life-threatening complications. We report a case admitted on the acute medical take with starvation ketoacidosis associated with ketogenic diet and adequate calorie consumption who was breast-feeding at the time of admission.
LEARNING POINTS: Always check ketones in patients with an unexplained metabolic acidosis; there can be overlap between starvation, alcohol-related and lactic acidosis.Management of starvation ketoacidosis is often empirical, involving close monitoring of fluid status and electrolytes.Clinicians should discuss the risk of ketoacidosis associated with the ketogenic diet in women who plan to breast-feed and lose weight following pregnancy.

Keywords:  Ketoacidosis; keto diet; weight-loss diet

DOI:  https://doi.org/10.12890/2024_004830
Curr Heart Fail Rep. 2024 Sep 07.

Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers.

Michael W Foster, Joshua M Riley, Praneet C Kaki, Amine Al Soueidy, Ehson Aligholiazadeh, J Eduardo Rame.

   PURPOSE OF REVIEW: The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression.
RECENT FINDINGS: Recent insights into myocardial metabolism shed light on the heart's response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure. Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure.

Keywords:  Biomarkers; Cardiomyopathy; Heart failure; Ketone bodies; Myocardial metabolism

DOI:  https://doi.org/10.1007/s11897-024-00678-6
Nutrients. 2024 Aug 23. pii: 2814. [Epub ahead of print]16(17):

Effects of Ketogenic Diet on Increased Ethanol Consumption Induced by Social Stress in Female Mice.

Laura Torres-Rubio, Marina D Reguilón, Susana Mellado, María Pascual, Marta Rodríguez-Arias.

  Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD's effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (n = 32) and KD (n = 32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (n = 16), VSD-STD (n = 16), EXP-KD (n = 16), and VSD-KD (n = 16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 h after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that the KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, the KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results point to the KD as a useful tool to increase resilience to social stress in female mice.

Keywords:  ethanol; female; ketogenic diet; mice; social stress

DOI:  https://doi.org/10.3390/nu16172814
Physiol Rep. 2024 Sep;12(17): e70048

Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.

Tatsuya Miyaji, Ryuichi Kasuya, Atsushi Sawada, Daisuke Sawamura, Yu Kitaoka, Mitsunori Miyazaki.

  Insulin-like growth factor-1-induced activation of ATP citrate lyase (ACLY) improves muscle mitochondrial function through an Akt-dependent mechanism. In this study, we examined whether Akt1 deficiency alters skeletal muscle fiber type and mitochondrial function by regulating ACLY-dependent signaling in male Akt1 knockout (KO) mice (12-16 weeks old). Akt1 KO mice exhibited decreased body weight and muscle wet weight, with reduced cross-sectional areas of slow- and fast-type muscle fibers. Loss of Akt1 did not affect the phosphorylation status of ACLY in skeletal muscle. The skeletal muscle fiber type and expression of mitochondrial oxidative phosphorylation complex proteins were unchanged in Akt1 KO mice compared with the wild-type control. These observations indicate that Akt1 is important for the regulation of skeletal muscle fiber size, whereas the regulation of muscle fiber type and muscle mitochondrial content occurs independently of Akt1 activity.

Keywords:  Akt1; glycolysis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70048
Cureus. 2024 Aug;16(8): e66419

Ketogenic Diet and Its Potential Role in Preventing Type 2 Diabetes Mellitus and Its Complications: A Narrative Review of Randomized Controlled Trials.

Ali H Alluwyam, Edric D Estrella.

  Diabetes mellitus is a global health crisis affecting millions. Nutrition plays a vital role in its management and prevention. While carbohydrate reduction is beneficial for glycemic control, various dietary approaches exist. The ketogenic diet, characterized by very low carbohydrate intake, has shown promise in weight management and blood sugar control. However, its potential for preventing type 2 diabetes mellitus (T2DM) remains largely unexplored. To evaluate the ketogenic diet's potential in preventing T2DM, this review searched the PubMed database for studies published between 2013 and 2023. Findings suggest that the diet can effectively aid weight loss and improve blood glucose levels. Some evidence indicates reduced reliance on diabetes medications. However, effects on cholesterol levels are inconsistent, and long-term adherence challenges exist. Additionally, potential micronutrient deficiencies and safety concerns require careful consideration. While the ketogenic diet offers potential benefits, further research is needed to establish its efficacy and safety as a long-term prevention strategy for T2DM. However, the results of the present study indicate the need for further research in this area, utilizing rigorous methodology.

Keywords:  complication; diabetes type 2; ketogenic diet; prevention; rct

DOI:  https://doi.org/10.7759/cureus.66419
BMJ Open. 2024 Sep 10. 14(9): e076938

Effect of ketogenic diets on lipid metabolism in adults: protocol for a systematic review.

Serene Hilary, Linda Östlundh, Carine Platat, Rami H Al-Rifai, Osha Almehairbi, Fayeza Alshamsi, Habiba I Ali, Ayesha S Al Dhaheri, Leila Cheikh Ismail, Lily Stojanovska.

   INTRODUCTION: The ketogenic diet is a very low carbohydrate diet known for its ability to reduce weight and counteract hyperglycaemia. However, ketogenic diets recommend an increased intake of fats, raising concerns about cardiometabolic risk in adults. Due to the higher intake of fats in the ketogenic diet, there is significant variability in outcomes of lipid metabolism in the population. Interventions have reported improvements in lipid profile while other studies did not find changes, and there are reports of increased low density lipoprotein (LDL) and triglyceride values. Hence, this is a protocol for a systematic review of the published literature and a summary of the effect of ketogenic diets on lipid metabolism in adults.
METHODS AND ANALYSIS: Five databases (PubMed, Embase, Scopus, Cochrane Library and Web of Science) will be searched for studies on ketogenic diets in adult populations. Studies will be included if they report results from ketogenic diet interventions among adults. Exclusion is populations with diagnosed neurological disorders. Two reviewers will independently screen retrieved citations, extract data and appraise the risk of bias. Quantitative estimates (eg, standardised mean difference) measuring the change in the total cholesterol, LDL and triglyceride concentration will be pooled using random effects meta-analysis to produce one summarised weighted estimate. Sources of heterogeneity will be explored using subgroup analysis. This protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis for Protocols (PRISMA), and the final review will be reported following the PRISMA 2020 guidelines.
ETHICS AND DISSEMINATION: The present protocol and the systematic review to be carried out do not require ethics clearance. The data source will be published studies. This review will provide estimates to inform the public about the effect of ketogenic diets on lipid metabolism and the possible peril of increasing cardiometabolic risk. The results will be published in a peer-reviewed journal.
PROSPERO REGISTRATION NUMBER: CRD42022309665.

Keywords:  NUTRITION & DIETETICS; Obesity; Systematic Review

DOI:  https://doi.org/10.1136/bmjopen-2023-076938
Sci Rep. 2024 09 10. 14(1): 21154

Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.

Jialin Li, Sheng Zhang, Can Li, Xiaoxia Zhang, Yuhui Shan, Ziyi Zhang, Hai Bo, Yong Zhang.

  Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Keywords:  AMPK; Endurance exercise; Histone methylation; Mitochondrial biogenesis; ROS; Skeletal muscle fiber type

DOI:  https://doi.org/10.1038/s41598-024-72088-6
J Nutr Metab. 2023 ;2023 9222632

The Effectiveness of Modified Atkins Ketogenic Diet on Children with Intractable Epilepsy: A Pilot Study from Indonesia.

Achmad Rafli, Setyo Handryastuti, Mulya Rahma Karyanti, Yoga Devaera, Cut Nurul Hafifah, Irawan Mangunatmadja, Muzal Kadim, Elisabeth Siti Herini, Lora Sri Nofi, Ariek Ratnawati, Suci Fitrianti.

Background: The ketogenic diet has recently been explored as a potential treatment approach for intractable epilepsy in children and has been applied in various parts of the world. The ketogenic diet is also effective for the treatment of mood disorders, especially for adolescent and young adults with epilepsy. The Modified Atkins Diet (MAD) is the less restrictive type of ketogenic diet with similar principles as the classic type. However, no study has been conducted to evaluate the use of MAD in children with severe epilepsy in Indonesia. This study aims to assess the effectiveness, tolerance, compliance, and the adverse effects of MAD in children with intractable epilepsy during a 6-month monitoring period.
Methods: This is a pilot experimental study involving children aged 2-18 years old with intractable epilepsy at the Pediatric Neurology and the Pediatric Nutrition & Metabolic Diseases Clinics at the Dr. Cipto Mangunkusumo Hospital Jakarta between November 2021 and June 2022.
Results: A total of 31 subjects met the inclusion criteria and received the MAD in the first month, followed by 13 (41.9%) subjects in the third month, and 9 (29%) subjects in the sixth month. The MAD reduced the seizure frequency by 50% (p = 0.144), 62% (p = 0.221), and 83.3% (p = 0.028) in the first, third, and sixth months, respectively. The most frequent adverse effects are vomiting and diarrhea. Noncompliance was observed in 18 (58.1%) subjects. A sample of the MAD food menu guidebook was developed to make it easier for parents to adhere to the diet.
Conclusions: The MAD reduces the mean seizure frequency in children with intractable epilepsy in the first, third, and sixth months, with a statistical significance in the sixth month. A further randomized, controlled, and multicenter clinical trial with a larger sample size and longer observation period is required. This trial is registered with Protocol ID 20-10-1323.

DOI: https://doi.org/10.1155/2023/9222632
EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.

  The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI:  https://doi.org/10.1038/s44318-024-00219-w
medRxiv. 2024 Aug 30. pii: 2024.08.29.24312791. [Epub ahead of print]

Fat burning capacity in a mixed macronutrient meal protocol does not reflect metabolic flexibility in women who are overweight or obese.

Mary M Ahern, Virginia M Artegoitia, Rémy Bosviel, John W Newman, Nancy L Keim, Sridevi Krishnan.

Introduction: Metabolic flexibility, the ability to switch from glucose to fat as a fuel source, is considered a marker of metabolic health. Higher fat oxidation is often associated with greater flexibility and insulin sensitivity, while lower fat oxidation is linked to metabolic inflexibility and insulin resistance. However, our study challenges the universal validity of this relationship, uncovering a more nuanced understanding of the complex interplay between fuel source switching and fat oxidation, especially in the presence of insulin resistance.
Methods: In an 8-week controlled feeding intervention, overweight to obese women with insulin resistance (as defined by McAuley's index) were randomized to consume either a diet based on the Dietary Guidelines for Americans 2010 (DGA) or a 'Typical' American Diet (TAD), n = 22 each. Participants were given a high-fat mixed macronutrient challenge test (MMCT) (60% fat, 28% carbohydrates, and 12% protein) at weeks 0, 2, and 8. Plasma lipids, metabolome, and lipidome were measured at 0, 0.5, 3, and 6h postprandial (PP); substrate oxidation measures were also recorded at 0,1 3, and 6h PP. Metabolic flexibility was evaluated as the change in fat oxidation from fasting to PP. Mixed model and multivariate analyses were used to evaluate the effect of diet on these outcomes, and to identify variables of interest to metabolic flexibility.
Results: Intervention diets (DGA and TAD) did not differentially affect substrate oxidation or metabolic flexibility, and equivalence tests indicated that groups could be combined for subsequent analyses. Participants were classified into three groups based on the % of consumed MMCT fat was oxidized in the 6h post meal period at weeks 0, 2 and 8. Low fat burners (LB, n = 6, burned <30% of fat in MMCT) and high fat burners (HB, n = 7, burned > 40% of fat in MMCT) at all weeks. Compared to LB, HB group had higher fat mass, total mass, lean mass, BMI, lower HDLc and lower RER (p < 0.05), but not different % body fat or % lean mass. During week 0, at 1h PP, LB had an increase in % fat oxidation change from 0h compared to HB (p<0.05), suggesting higher metabolic flexibility. This difference disappeared later in the PP phase, and we did not detect this beyond week 0. Partial least squares discriminant analysis (PLSDA (regular and repeated measures (sPLSDA)) models identified that LB group, in the late PP phase, was associated with higher rates of disappearance of acylcarnitines (AC) and lysophosphatidylcholines (LPC) from plasma (Q2: 0.20, R 2 X: 0.177, R 2 Y: 0.716).
Conclusion: In women with insulin resistance, a high fat burning capacity does not imply high metabolic flexibility, and not all women with insulin resistance are metabolically inflexible. LPCs and ACs are promising biomarkers of metabolic flexibility.

DOI: https://doi.org/10.1101/2024.08.29.24312791
Phys Ther Res. 2024 ;27(2): 49-57

Clinical Application of Skeletal Muscle Quantity and Quality Assessment Using Bioelectrical Impedance and Ultrasound Images.

Masashi Taniguchi.

  A decline in muscle strength is a key factor responsible for physical dysfunction in older individuals. Both loss of muscle quantity and quality are associated with muscle strength decline. While the gold standard method for evaluating muscle mass and quality is magnetic resonance imaging, it is not suitable for clinical settings because of the measurement and analysis costs. Bioelectrical impedance analysis (BIA) and B-mode ultrasonography are clinically useful alternatives for skeletal muscle assessment owing to their feasibility and noninvasiveness. The recent advancements in the techniques for BIA and ultrasonography have improved their accuracy in assessing skeletal muscle quantity and quality, making them useful in detecting age-related and disease-specific alterations. This review comprehensively analyzes the advantages of using BIA and ultrasound imaging for assessing skeletal muscle quantity and quality and detecting muscle degeneration. We summarize the recent findings regarding age-related changes in muscle characteristics and the associations of muscle degeneration with physical dysfunction in patients with knee osteoarthritis. Furthermore, we discuss the clinical application of skeletal muscle assessment using BIA and ultrasound for evaluating training effects and exercise prescription.

Keywords:  Echo intensity; Extracellular-to-intracellular water ratio; Intramuscular fat; Muscle degeneration; Muscle mass

DOI:  https://doi.org/10.1298/ptr.R0031
Cells. 2024 Aug 24. pii: 1413. [Epub ahead of print]13(17):

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging.

Gérald J Prud'homme, Qinghua Wang.

  The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer's disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.

Keywords:  Alzheimer; FGF23; Klotho; NF-κB; TGF-β; aging; atherosclerosis; fibrosis; inflammasome; sarcopenia

DOI:  https://doi.org/10.3390/cells13171413
Int J Mol Sci. 2024 Aug 28. pii: 9308. [Epub ahead of print]25(17):

Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in Mice.

Kylie Heitman, Seth Bollenbecker, Jordan Bradley, Brian Czaya, Abul Fajol, Sarah Madison Thomas, Qing Li, Svetlana Komarova, Stefanie Krick, Glenn C Rowe, Matthew S Alexander, Christian Faul.

  Chronic kidney disease (CKD) is associated with various pathologic changes, including elevations in serum phosphate levels (hyperphosphatemia), vascular calcification, and skeletal muscle atrophy. Elevated phosphate can damage vascular smooth muscle cells and cause vascular calcification. Here, we determined whether high phosphate can also affect skeletal muscle cells and whether hyperphosphatemia, in the context of CKD or by itself, is associated with skeletal muscle atrophy. As models of hyperphosphatemia with CKD, we studied mice receiving an adenine-rich diet for 14 weeks and mice with deletion of Collagen 4a3 (Col4a3-/-). As models of hyperphosphatemia without CKD, we analyzed mice receiving a high-phosphate diet for three and six months as well as a genetic model for klotho deficiency (kl/kl). We found that adenine, Col4a3-/-, and kl/kl mice have reduced skeletal muscle mass and function and develop atrophy. Mice on a high-phosphate diet for six months also had lower skeletal muscle mass and function but no significant signs of atrophy, indicating less severe damage compared with the other three models. To determine the potential direct actions of phosphate on skeletal muscle, we cultured primary mouse myotubes in high phosphate concentrations, and we detected the induction of atrophy. We conclude that in experimental mouse models, hyperphosphatemia is sufficient to induce skeletal muscle atrophy and that, among various other factors, elevated phosphate levels might contribute to skeletal muscle injury in CKD.

Keywords:  chronic kidney disease; hyperphosphatemia; phosphate; sarcopenia; skeletal muscle atrophy

DOI:  https://doi.org/10.3390/ijms25179308
Clin Nutr ESPEN. 2024 Sep 10. pii: S2405-4577(24)01295-6. [Epub ahead of print]64 7-15

Comparison of weight loss effects among overweight/obese adults: A network meta-analysis of mediterranean, low carbohydrate, and low-fat diets.

Maryam Akbari, Mohebat Vali, Shahla Rezaei, Sina Bazmi, Reza Tabrizi, Kamran B Lankarani.

   BACKGROUND & AIMS: Eating patterns significantly impact the weight loss process. This study aimed to investigate the influence of primary eating patterns on weight loss measures in overweight and obese adults using network meta-analysis.
METHODS: We systematically searched PubMed, Scopus, Web of Science (WOS), and Google Scholar until May 2, 2023. Our network meta-analysis followed the PRISMA extension guidelines for Comparing Mediterranean, low carbohydrate and low fat diet effects on weight loss among overweight/obese adults. We conducted a Frequentist random-effects network meta-analysis. Summary effects were presented as mean differences (MD) along with corresponding standard deviations (SD). P-scores were used for treatment ranking within the network.
RESULTS: Initial literature searches yielded 1574 citations. Ultimately, 1004 participants from 7 RCTs (or 9 trials) met inclusion criteria. All diets resulted in weight loss. Comparatively, the low-carbohydrate diet exhibited a significant decrease in weight loss compared to the Mediterranean diet (MD = -2.70 kg, 95% CI: -4.65, -0.75). Indirect evidence revealed that both the low-carbohydrate diet (MD = -6.31 kg, 95% CI: -11.23, -1.39) and the low-fat diet (MD = -5.61 kg, 95% CI: -10.61, -0.61) significantly reduced weight among overweight/obese adults compared to the standard hypolipemic diet. Rankings indicated the low-carbohydrate diet as the most effective dietary intervention for enhancing weight loss (P-score = 0.8994) and reducing body fat (P-score = 0.7060).
CONCLUSIONS: Overall, a low-carb diet appears to be among the most effective approaches for weight loss and body fat reduction. However, it's essential to consider that its efficacy may vary based on factors such as age, gender, genetics, and lifestyle habits.

Keywords:  Dietary patterns; Network meta-analysis; Overweight; Weight loss

DOI:  https://doi.org/10.1016/j.clnesp.2024.08.023
J Vis Exp. 2024 Aug 23.

Robust Mitochondrial Isolation from Rodent Cardiac Tissue.

Alyssa C Vadovsky, Melissa Quinn, Tianyi Xia, Yan Levitsky, Jason N Bazil.

Mitochondrial isolation has been practiced for decades, following procedures established by pioneers in the fields of molecular biology and biochemistry to study metabolic impairments and disease. Consistent mitochondrial quality is necessary to properly investigate mitochondrial physiology and bioenergetics; however, many different published isolation methods are available for researchers. Although different experimental strategies require different isolation methods, the basic principles and procedures are similar. This protocol details a method capable of extracting well-coupled mitochondria from a variety of tissue sources, including small animals and cells. The steps outlined include organ dissection, mitochondrial purification, protein quantification, and various quality control checks. The primary quality control metric used to identify high-quality mitochondria is the respiratory control ratio (RCR). The RCR is the ratio of the respiratory rate during oxidative phosphorylation to the rate in the absence of ADP. Alternative metrics are discussed. While high RCR values relative to their tissue source are obtained using this protocol, several steps can be optimized to suit the individual needs of researchers. This procedure is robust and has consistently resulted in isolated mitochondria with above-average RCR values across animal models and tissue sources.

DOI: https://doi.org/10.3791/67093
Acta Physiol (Oxf). 2024 Sep 12. e14215

Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses.

Javier Díaz-Lara, Elizabeth Reisman, Javier Botella, Bianka Probert, Louise M Burke, David J Bishop, Matthew J Lee.

   AIM: To investigate how delayed post-exercise carbohydrate intake affects muscle glycogen, metabolic- and mitochondrial-related molecular responses, and subsequent high-intensity interval exercise (HIIE) capacity.
METHODS: In a double-blind cross-over design, nine recreationally active men performed HIIE (10 × 2-min cycling, ~94% W˙peak) in the fed state, on two occasions. During 0-3 h post-HIIE, participants drank either carbohydrates ("Immediate Carbohydrate" [IC], providing 2.4 g/kg) or water ("Delayed Carbohydrate" [DC]); total carbohydrate intake over 24 h post-HIIE was matched (~7 g/kg/d). Skeletal muscle (sampled pre-HIIE, post-HIIE, +3 h, +8 h, +24 h) was analyzed for whole-muscle glycogen and mRNA content, plus signaling proteins in cytoplasmic- and nuclear-enriched fractions. After 24 h, participants repeated the HIIE protocol until failure, to test subsequent HIIE capacity; blood lactate, heart rate, and ratings of perceived effort (RPE) were measured throughout.
RESULTS: Muscle glycogen concentrations, and relative changes, were similar between conditions throughout (p > 0.05). Muscle glycogen was reduced from baseline (mean ± SD mmol/kg dm; IC: 409 ± 166; DC: 352 ± 76) at post-HIIE (IC: 253 ± 96; DC: 214 ± 82), +3 h (IC: 276 ± 62; DC: 269 ± 116) and + 8 h (IC: 321 ± 56; DC: 269 ± 116), returning to near-baseline by +24 h. Several genes (PGC-1ɑ, p53) and proteins (p-ACCSer79, p-P38 MAPKThr180/Tyr182) elicited typical exercise-induced changes irrespective of condition. Delaying carbohydrate intake reduced next-day HIIE capacity (5 ± 3 intervals) and increased RPE (~2 ratings), despite similar physiological responses between conditions.
CONCLUSION: Molecular responses to HIIE (performed in the fed state) were not enhanced by delayed post-exercise carbohydrate intake. Our findings support immediate post-exercise refueling if the goal is to maximize next-day HIIE capacity and recovery time is ≤24 h.

Keywords:  carbohydrates; exercise; mRNA; muscle glycogen; nutrition; signaling

DOI:  https://doi.org/10.1111/apha.14215
Free Radic Biol Med. 2024 Sep 06. pii: S0891-5849(24)00648-8. [Epub ahead of print]

Lifelong dietary protein restriction induces denervation and skeletal muscle atrophy in mice.

Ufuk Ersoy, Atilla Emre Altinpinar, Ioannis Kanakis, Moussira Alameddine, Anna Gioran, Niki Chondrogianni, Susan E Ozanne, Mandy Jayne Peffers, Malcolm J Jackson, Katarzyna Goljanek-Whysall, Aphrodite Vasilaki.

  As a widespread global issue, protein deficiency hinders development and optimal growth in offspring. Maternal low-protein diet influences the development of age-related diseases, including sarcopenia, by altering the epigenome and organ structure through potential increase in oxidative stress. However, the long-term effects of lactational protein restriction or postnatal lifelong protein restriction on the neuromuscular system have yet to be elucidated. Our results demonstrated that feeding a normal protein diet after lactational protein restriction did not have significant impacts on the neuromuscular system in later life. In contrast, a lifelong low-protein diet induced a denervation phenotype and led to demyelination in the sciatic nerve, along with an increase in the number of centralised nuclei and in the gene expression of atrogenes at 18 months of age, indicating an induced skeletal muscle atrophy. These changes were accompanied by an increase in proteasome activity in skeletal muscle, with no significant alterations in oxidative stress or mitochondrial dynamics markers in skeletal muscle later in life. Thus, lifelong protein restriction may induce skeletal muscle atrophy through changes in peripheral nerves and neuromuscular junctions, potentially contributing to the early onset or exaggeration of sarcopenia.

Keywords:  Skeletal muscle; atrophy; denervation; oxidative stress; protein restriction; proteostasis

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.005
Nutr Rev. 2024 Sep 10. pii: nuae114. [Epub ahead of print]

Effects of Different Caloric Restriction Patterns on Blood Pressure and Other Cardiovascular Risk Factors: A Systematic Review and Network Meta-Analysis of Randomized Trials.

Hui Zhang, Jinchao Du, Mingchen Zhang, Tingting Li, Pingping Zhang, Xiaowen Wang, Zhongguang Sun.

   CONTEXT: All types of caloric restriction are preventive against cardiovascular risk factors, but the best restriction method and most affected factors have not been identified.
OBJECTIVE: The objective of this study was to explore the effects of different caloric restriction methods on various cardiovascular risk factors by horizontally comparing program advantages and disadvantages via network meta-analysis.
DATA SOURCES: The PubMed, Web of Science, Cochrane Library, and Embase literature databases were searched (October 2013 to October 2023).
DATA EXTRACTION: Eligible randomized controlled trials involving participants who underwent caloric restriction and systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and high-density lipoprotein (HDL) cholesterol level measurements were included.
DATA ANALYSIS: Thirty-six of 13 208 records (0.27%) were included. Two researchers reviewed the articles, extracted data, and assessed article quality.
RESULTS: Alternate-day fasting (ADF) reduced SBP (4.88 mmHg; CI, 2.06-7.15) and DBP (5.10 mmHg; CI, 2.44-7.76). Time-restricted eating reduced SBP (2.46 mmHg; CI, 0.16-4.76) but not DBP. Continuous energy restriction (CER) significantly reduced BMI (1.11 kg/m2; CI = 0.16, 2.06) and waist circumference (3.28 cm; CI, 0.62-5.94).
CONCLUSIONS: This meta-analysis confirmed the preventive effect of CER and ADF on various cardiovascular risk factors. Additionally, CER is more likely to reduce obesity, and ADF is more likely to reduce blood pressure (BP). Based on this meta-analysis, CER is recommended to control obesity only for people who are obese and do not have elevated BP or other abnormal indicators. Additionally, ADF for early control or prevention is recommended for patients who have abnormal BP or other cardiovascular risk factors.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023455889.

Keywords:  5:2 diet; alternate-day fasting; blood pressure; calorie restriction; cardiovascular risk; network meta-analysis; time-restricted eating

DOI:  https://doi.org/10.1093/nutrit/nuae114
Int J Mol Sci. 2024 Sep 07. pii: 9692. [Epub ahead of print]25(17):

Aerobic Exercise Attenuates Doxorubicin-Induced Cardiomyopathy by Suppressing NLRP3 Inflammasome Activation in a Rat Model.

Phichaya Suthivanich, Worakan Boonhoh, Natticha Sumneang, Chuchard Punsawad, Zhaokang Cheng, Sukanya Phungphong.

  Doxorubicin (DOX) is a potent chemotherapeutic agent with well-documented dose-dependent cardiotoxicity. Regular exercise is recognized for its cardioprotective effects against DOX-induced cardiac inflammation, although the precise mechanisms remain incompletely understood. The activation of inflammasomes has been implicated in the pathogenesis and treatment of DOX-induced cardiotoxicity, with the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome emerging as a key mediator in cardiovascular inflammation. This study aimed to investigate the role of exercise in modulating the NLRP3 inflammasome to protect against DOX-induced cardiac inflammation. Male Sprague-Dawley rats were randomly assigned to receive a 10-day course of DOX or saline injections, with or without a preceding 10-week treadmill running regimen. Cardiovascular function and histological changes were subsequently evaluated. DOX-induced cardiotoxicity was characterized by cardiac atrophy, systolic dysfunction, and hypotension, alongside activation of the NLRP3 inflammasome. Our findings revealed that regular exercise preserved cardiac mass and hypertrophic indices and prevented DOX-induced cardiac dysfunction, although it did not fully preserve blood pressure. These results underscore the significant cardioprotective effects of exercise against DOX-induced cardiotoxicity. While regular exercise did not entirely prevent DOX-induced hypotension, our findings demonstrate that it confers protection against DOX-induced cardiotoxicity by suppressing NLRP3 inflammasome activation in the heart, underscoring its anti-inflammatory role. Further research should explore the temporal dynamics and interactions among exercise, pyroptosis, and other pathways in DOX-induced cardiotoxicity to enhance translational applications in cardiovascular medicine.

Keywords:  NLRP3 inflammasome; cardiomyopathy; doxorubicin; exercise; inflammation

DOI:  https://doi.org/10.3390/ijms25179692
Matrix Biol. 2024 Sep 07. pii: S0945-053X(24)00113-6. [Epub ahead of print]

PCPE-2 (procollagen C-proteinase enhancer-2): the NON-IDENTICAL twin of PCPE-1.

Manon Napoli, Julien Bauer, Christelle Bonod, Sandrine Vadon-Le Goff, Catherine Moali.

  PCPE-2 was discovered at the beginning of this century, and was soon identified as a close homolog of PCPE-1 (procollagen C-proteinase enhancer 1). After the demonstration that it could also stimulate the proteolytic maturation of fibrillar procollagens by BMP-1/tolloid-like proteinases (BTPs), PCPE-2 did not attract much attention as it was thought to fulfill the same functions as PCPE-1 which was already well-described. However, the tissue distribution of PCPE-2 shows both common points and significant differences with PCPE-1, suggesting that their activities are not fully overlapping. Also, the recently established connections between PCPE-2 (gene name PCOLCE2) and several important diseases such as atherosclerosis, inflammatory diseases and cancer have highlighted the need for a thorough reappraisal of the in vivo roles of this regulatory protein. In this context, the recent finding that, while retaining the ability to bind fibrillar procollagens and to activate their C-terminal maturation, PCPE-2 can also bind BTPs and inhibit their activity has substantially extended its potential functions. In this review, we describe the current knowledge about PCPE-2 with a focus on collagen fibrillogenesis, lipid metabolism and inflammation, and discuss how we could further advance our understanding of PCPE-2-dependent biological processes.

Keywords:  cancer; collagen; inflammation; inhibition; lipid metabolism; metalloprotease

DOI:  https://doi.org/10.1016/j.matbio.2024.09.001
Light Sci Appl. 2024 Sep 09. 13(1): 244

Visualizing mitochondrial dynamics at the nanoscale.

Till Stephan, Peter Ilgen, Stefan Jakobs.

The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.

DOI: https://doi.org/10.1038/s41377-024-01582-3
Curr Drug Targets. 2024 Sep 06.

DRP1 Association in Inflammation and Metastasis: A Review.

Parmar Keshri Nandan, Anica Tholath Job, Tamizhselvi Ramasamy.

  In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on aging, human health, and other advanced findings in metabolic functions. The latest finding shows that metabolic interventions are a leading cause of several diseases, which has sparked interest in finding new therapeutic treatments. Apart from this, the unique inheritance of genetic material from mother to offspring can help scientists find ways to prevent mitochondrial inherited diseases. Additionally, the anti-aging benefits of controlling mitochondrial functions are also being researched. The present study aims to provide a cohesive overview of the latest findings in mitochondrial research, focusing on the role of DRP1 (Dynamin- related protein 1), a member of the GTPase family, in mediating mitochondrial fission. The first section of this paper provides a concise explanation of how DRP1 controls processes such as mitophagy and mitochondrial fission. Subsequently, the paper delves into the topic of inflammation, discussing the current findings regarding the inflammatory response mediated by DRP1. Finally, the role of mitochondrial fission mediated by DRP1 in cancer is examined, reviewing ongoing research on various types of cancer and their recurrence. Moreover, this review also covers the epigenetic regulation of mitochondrial fission. The studies were selected, and evaluated, and the information was collected to present an overview of the key findings. By exploring various aspects of research and potential links, we hope to contribute to a deeper understanding of the intricate relationship between the fields of cancer research and inflammation studies with respect to mitochondrial- based research.

Keywords:  GTPase; cytokine.; inflammation; metastasis; mitochondrial fission; mitophagy

DOI:  https://doi.org/10.2174/0113894501304751240819111831
Mol Med. 2024 Sep 12. 30(1): 149

Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

Huaying Huang, Heye Chen, Yu Yao, Xueyong Lou.

   BACKGROUND: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes.
METHODS: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings.
RESULTS: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization.
CONCLUSIONS: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.

Keywords:  Adipose tissue inflammation; Branched-amino acids; INFGR1/JAK1/STAT1 pathway; Insulin resistance; Obesity; Pro-inflammatory macrophage polarization

DOI:  https://doi.org/10.1186/s10020-024-00894-9
EMBO Rep. 2024 Sep 09.

Fat body glycolysis defects inhibit mTOR and promote distant muscle disorganization through TNF-α/egr and ImpL2 signaling in Drosophila larvae.

Miriam Rodríguez-Vázquez, Jennifer Falconi, Lisa Heron-Milhavet, Patrice Lassus, Charles Géminard, Alexandre Djiane.

  The fat body in Drosophila larvae functions as a reserve tissue and participates in the regulation of organismal growth and homeostasis through its endocrine activity. To better understand its role in growth coordination, we induced fat body atrophy by knocking down several key enzymes of the glycolytic pathway in adipose cells. Our results show that impairing the last steps of glycolysis leads to a drastic drop in adipose cell size and lipid droplet content, and downregulation of the mTOR pathway and REPTOR transcriptional activity. Strikingly, fat body atrophy results in the distant disorganization of body wall muscles and the release of muscle-specific proteins in the hemolymph. Furthermore, we showed that REPTOR activity is required for fat body atrophy downstream of glycolysis inhibition, and that the effect of fat body atrophy on muscles depends on the production of TNF-α/egr and of the insulin pathway inhibitor ImpL2.

Keywords:   Drosophila ; Adipose Tissue; Glycolysis; Inter-Organ Communication; Muscle Wasting

DOI:  https://doi.org/10.1038/s44319-024-00241-3