bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024–06–02
fourteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.
  2. Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells.
  3. Problems and Opportunities in the use of Bioelectrical Impedance Analysis for Assessing Body Composition During Ketogenic Diets: A Scoping Review.
  4. Analysis of dietary fats intake and lipid profile in Chilean patients with glucose transport type 1 deficiency syndrome: similarities and differences with the reviewed literature.
  5. Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.
  6. Intermittent fasting for the prevention of cardiovascular disease: implications for clinical practice.
  7. Emerging insights into the role of NLRP3 inflammasome and endoplasmic reticulum stress in renal diseases.
  8. Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.
  9. Mitochondrial quality control in human health and disease.
  10. Influence of intramuscular steroid receptor content and fiber capillarization on skeletal muscle hypertrophy.
  11. Intrinsic skeletal muscle function and contraction-stimulated glucose uptake do not vary by time-of-day in mice.
  12. Dietary protein and amino acid intakes for mitigating sarcopenia in humans.
  13. Skeletal Editing: A Novel Method for "Psychiatric Drug Flipping" to Produce New, Precise Ones with Fewer Side Effects.
  14. SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study.
  1. bioRxiv. 2024 May 18. pii: 2024.05.16.594369. [Epub ahead of print]
    Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.
    Cody M Cousineau, Detrick Snyder, JeAnna R Redd, Sophia Turner, Treyton Carr, Dave Bridges.
      The ketogenic diet (KD) has garnered considerable attention due to its potential benefits in weight loss, health improvement, and performance enhancement. However, the phenotypic responses to KD vary widely between individuals. Skeletal muscle is a major contributor to ketone body (KB) catabolism, however, the regulation of ketolysis is not well understood. In this study, we evaluated how mTORC1 activation and a ketogenic diet modify ketone body disposal in muscle Tsc1 knockout (KO) mice, inbred A/J mice, and Diversity Outbred (DO) mice. Muscle Tsc1 KO mice demonstrated enhanced ketone body clearance. Contrary to expectations, KD feeding in A/J mice did not improve KB disposal, and in most strains disposal was reduced. Transcriptional analysis revealed reduced expression of important ketolytic genes in KD-fed A/J mice, suggesting impaired KB catabolism. Diversity Outbred (DO) mice displayed variable responses to KD, with most mice showing worsened KB disposal. Exploratory analysis on these data suggest potential correlations between KB disposal and cholesterol levels as well as weight gain on a KD. Our findings suggest that ketone body disposal may be regulated by both nutritional and genetic factors and these relationships may help explain interindividual variability in responses to ketogenic diets.
    DOI:  https://doi.org/10.1101/2024.05.16.594369
  2. Cancer Metab. 2024 May 29. 12(1): 16
    Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells.
    Hadas Fulman-Levy, Raichel Cohen-Harazi, Bar Levi, Lital Argaev-Frenkel, Ifat Abramovich, Eyal Gottlieb, Sarah Hofmann, Igor Koman, Elimelech Nesher.
       BACKGROUND: The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro.
    METHODS: Using two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile.
    RESULTS: Significant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation.
    CONCLUSIONS: Based on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.
    Keywords:  Beta-hydroxybutyrate; Breast cancer; Ketone bodies; MCF7; βHb
    DOI:  https://doi.org/10.1186/s40170-024-00339-1
  3. Curr Obes Rep. 2024 May 27.
    Problems and Opportunities in the use of Bioelectrical Impedance Analysis for Assessing Body Composition During Ketogenic Diets: A Scoping Review.
    Antonio Paoli, Francesco Campa.
       PURPOSE OF THE REVIEW: The use of bioelectrical impedance analysis (BIA) for monitoring body composition during the ketogenic diet has experienced a rapid surge. This scoping review aimed to assess the validity of procedures applying BIA in the ketogenic diet and to suggest best practices for optimizing its utilization.
    RECENT FINDINGS: We conducted a systematic scoping review of peer-reviewed literature involving BIA for assessing body composition in individuals adhering to a ketogenic diet. Searches of international databases yielded 1609 unique records, 72 of which met the inclusion criteria and were reviewed. Thirty-five studies used foot-to-hand technology, 34 used standing position technology, while 3 did not declare the technology used. Raw bioelectrical parameters were reported in 21 studies. A total of 196 body mass components were estimated, but predictive equations were reported in only four cases. Most research on BIA during ketogenic diets did not report the equations used for predicting body composition, making it impossible to assess the validity of BIA outputs. Furthermore, the exceedingly low percentage of studies reporting and analyzing raw data makes it challenging to replicate methodologies in future studies, highlighting that BIA is not being utilized to its full potential. There is a need for more precise technology and device characteristics descriptions, full report of raw bioelectrical data, and predictive equations utilized. Moreover, evaluating raw data through vectorial analysis is strongly recommended. Eventually, we suggest best practices to enhance BIA outcomes during ketogenic diets.
    Keywords:  BIA; BIVA; Keto diet; Phase angle; Very low-carbohydrate ketogenic diet
    DOI:  https://doi.org/10.1007/s13679-024-00573-0
  4. Front Nutr. 2024 ;11 1390799
    Analysis of dietary fats intake and lipid profile in Chilean patients with glucose transport type 1 deficiency syndrome: similarities and differences with the reviewed literature.
    María Florencia Salazar, María Jesús Leal-Witt, Valentina Parga, Carolina Arias, Verónica Cornejo.
       Introduction: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a neurological disorder caused by mutations in the SLC2A1 gene. The main treatment is ketogenic diet therapy (KDT), which changes the brain's energy substrate from glucose to ketone bodies. The diet controls seizures, but there may be side effects such as dyslipidemia. This study aimed to describe the type of fats ingested by the Chilean cohort of patients with GLUT1-DS and analyze for alterations in the lipid profile.
    Methods: A GLUT1-DS group and a control group were formed, each with 13 subjects who were matched by age, gender, and nutritional status. Anthropometry, dietary intake, including types of fat, and blood tests were evaluated (lipid and liver profile, and 25-hydroxyvitamin D levels).
    Results: A high-fat diet, especially saturated fat, was identified in the GLUT1-DS group (38% of total calories), with the use of medium-chain triglycerides (17% of total calories). In addition, GLUT1-DS participants had a higher intake of monounsaturated (MUFA) and polyunsaturated (PUFA) fats and adequate consumption of omega-3 (2% of total calories). Despite the GLUT1-DS group receiving on average 80% of its total energy as fats, it is important to highlight that 50% are MUFA+PUFA fats, there were no significant differences in the lipid and liver profile compared to the control group.
    Conclusion: KDT did not negatively impact lipid profile, despite a high intake of fats. It is important to monitor lipid profiles, in a personalized and constant manner, to prevent future nutritional risks.
    Keywords:  dyslipidemia; fatty acid intake; ketogenic diet; lipids profile; transaminases; transporter type 1 deficiency syndrome
    DOI:  https://doi.org/10.3389/fnut.2024.1390799
  5. FEBS Lett. 2024 May 27.
    Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.
    Samantha Gallero, Kaspar W Persson, Carlos Henríquez-Olguín.
      Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.
    Keywords:  hydrogen peroxide; insulin action; insulin signaling; metabolism; reactive oxygen species; redox signaling; skeletal muscle
    DOI:  https://doi.org/10.1002/1873-3468.14937
  6. Br J Card Nurs. 2023 Sep 02. pii: 2023.0058. [Epub ahead of print]18(9):
    Intermittent fasting for the prevention of cardiovascular disease: implications for clinical practice.
    O Hamer, A Abouzaid, J Hill.
      Cardiovascular disease remains one of the most prevalent and preventable chronic conditions worldwide. Nutrition plays an important role in reducing several risk factors associated with cardiovascular disease. Intermittent fasting has been rapidly gaining interest among patients with cardiometabolic disease as a nutritional strategy for improving cardiovascular outcomes. However, research had yet to determine whether intermittent fasting provides greater cardiometabolic benefits compared to continuous daily caloric restriction. A recent Cochrane review has synthesised the benefits of intermittent fasting for the prevention of cardiovascular disease but is limited by its interpretation of the findings for clinical practice. This commentary aims to critically appraise the methods used within the review by Allaf et al, 2021 and expand upon the findings to determine its implications for clinical practice.
    Keywords:  Blood pressure; Cardiovascular diseases; Diet; Epidemiology; Intermittent fasting; Systematic review
    DOI:  https://doi.org/10.12968/bjca.2023.0058
  7. Int Immunopharmacol. 2024 May 30. pii: S1567-5769(24)00862-2. [Epub ahead of print]136 112342
    Emerging insights into the role of NLRP3 inflammasome and endoplasmic reticulum stress in renal diseases.
    Yanting Zhang, Shiyun Guo, Xiaodi Fu, Qi Zhang, Honggang Wang.
      NLRP3 inflammasome is a key component of the innate immune system, mediating the activation of caspase-1, and the maturity and secretion of the pro-inflammatory cytokine interleukin (IL)-1beta (IL-1β) and IL-18 to cope with microbial infections and cell injury. The NLRP3 inflammasome is activated by various endogenous danger signals, microorganisms and environmental stimuli, including urate, extracellular adenosine triphosphate (ATP) and cholesterol crystals. Increasing evidence indicates that the abnormal activation of NLRP3 is involved in multiple diseases including renal diseases. Hence, clarifying the mechanism of action of NLRP3 inflammasome in different diseases can help prevent and treat various diseases. Endoplasmic reticulum (ER) is an important organelle which participates in cell homeostasis maintenance and protein quality control. The unfolded protein response (UPR) and ER stress are caused by the excessive accumulation of unfolded or misfolded proteins in ER to recover ER homeostasis. Many factors can cause ER stress, including inflammation, hypoxia, environmental toxins, viral infections, glucose deficiency, changes in Ca2+ level and oxidative stress. The dysfunction of ER stress participates in multiple diseases, such as renal diseases. Many previous studies have shown that NLRP3 inflammasome and ER stress play an important role in renal diseases. However, the relevant mechanisms are not yet fully clear. Herein, we focus on the current understanding of the role and mechanism of ER stress and NLRP3 inflammasome in renal diseases, hoping to provide theoretical references for future related researches.
    Keywords:  Acute kidney injury; Apoptosis; Endoplasmic reticulum stress; NLRP3 inflammasome; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.intimp.2024.112342
  8. Mol Neurobiol. 2024 May 31.
    Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.
    Lilian Leite Fausto, Adriano Alberti, Gabriela Kades, Risoní Pereira Dias de Carvalho, Viviane Freiberger, Leticia Ventura, Paula Dias, Eliton Marcio Zanoni, Ben Hur Soares, Matheus Luchini Dutra, Daniel Fernandes Martins, Clarissa Martinelli Comim.
      Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.
    Keywords:  Central nervous system; Duchenne muscular dystrophy; Muscle; mdx
    DOI:  https://doi.org/10.1007/s12035-024-04258-6
  9. Mil Med Res. 2024 May 29. 11(1): 32
    Mitochondrial quality control in human health and disease.
    Bo-Hao Liu, Chen-Zhen Xu, Yi Liu, Zi-Long Lu, Ting-Lv Fu, Guo-Rui Li, Yu Deng, Guo-Qing Luo, Song Ding, Ning Li, Qing Geng.
      Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role in regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable in vital life processes such as cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, a sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key processes like mitochondrial biogenesis, mitochondrial dynamics, and mitophagy, which have garnered increasing attention from researchers to unveil their specific molecular mechanisms. In this review, we present a comprehensive summary of the primary mechanisms and functions of key regulators involved in major components of MQC. Furthermore, the critical physiological functions regulated by MQC and its diverse roles in the progression of various systemic diseases have been described in detail. We also discuss agonists or antagonists targeting MQC, aiming to explore potential therapeutic and research prospects by enhancing MQC to stabilize mitochondrial function.
    Keywords:  Cancer; Cardiovascular disease; Digestive system disease; Kidney disease; Metabolic disease; Metabolism; Mitochondrial quality control; Nervous disease; Programmed cell death; Pulmonary disease
    DOI:  https://doi.org/10.1186/s40779-024-00536-5
  10. Scand J Med Sci Sports. 2024 Jun;34(6): e14668
    Influence of intramuscular steroid receptor content and fiber capillarization on skeletal muscle hypertrophy.
    Kim Van Vossel, Julie Hardeel, Thibaux Van der Stede, Anneleen Weyns, Jan Boone, Silvia Salinas Blemker, Wim Derave, Eline Lievens.
      Multiple intramuscular variables have been proposed to explain the high variability in resistance training induced muscle hypertrophy across humans. This study investigated if muscular androgen receptor (AR), estrogen receptor α (ERα) and β (ERβ) content and fiber capillarization are associated with fiber and whole-muscle hypertrophy after chronic resistance training. Male (n = 11) and female (n = 10) resistance training novices (22.1 ± 2.2 years) trained their knee extensors 3×/week for 10 weeks. Vastus lateralis biopsies were taken at baseline and post the training period to determine changes in fiber type specific cross-sectional area (CSA) and fiber capillarization by immunohistochemistry and, intramuscular AR, ERα and ERβ content by Western blotting. Vastus lateralis volume was quantified by MRI-based 3D segmentation. Vastus lateralis muscle volume significantly increased over the training period (+7.22%; range: -1.82 to +18.8%, p < 0.0001) but no changes occurred in all fiber (+1.64%; range: -21 to +34%, p = 0.869), type I fiber (+1.33%; range: -24 to +41%, p = 0.952) and type II fiber CSA (+2.19%; range: -23 to +29%, p = 0.838). However, wide inter-individual ranges were found. Resistance training increased the protein expression of ERα but not ERβ and AR, and the increase in ERα content was positively related to changes in fiber CSA. Only for the type II fibers, the baseline capillary-to-fiber-perimeter index was positively related to type II fiber hypertrophy but not to whole muscle responsiveness. In conclusion, an upregulation of ERα content and an adequate initial fiber capillarization may be contributing factors implicated in muscle fiber hypertrophy responsiveness after chronic resistance training.
    Keywords:  androgen receptor; capillarization; estrogen receptor; muscle fiber hypertrophy; muscle hypertrophy
    DOI:  https://doi.org/10.1111/sms.14668
  11. bioRxiv. 2024 May 18. pii: 2024.05.15.594323. [Epub ahead of print]
    Intrinsic skeletal muscle function and contraction-stimulated glucose uptake do not vary by time-of-day in mice.
    Liam S Fitzgerald, Shannon N Bremner, Samuel R Ward, Yoshitake Cho, Simon Schenk.
      A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from female mice at four times-of-day (Zeitgeber Times 1, 7, 13, 19). Significantly, while both muscles demonstrated circadian-related changes in gene expression, intrinsic contractile function, endurance, and contraction-stimulated glucose uptake were not different between the four time points. Overall, these results demonstrate that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake.
    Impact statement: Ex vivo testing demonstrates that there is no time-of-day variation in the intrinsic contractile properties of skeletal muscle (including no effect on force production or endurance) or contraction-stimulated glucose uptake.
    DOI:  https://doi.org/10.1101/2024.05.15.594323
  12. Crit Rev Food Sci Nutr. 2024 May 27. 1-24
    Dietary protein and amino acid intakes for mitigating sarcopenia in humans.
    Wenliang He, Erin D Connolly, H Russell Cross, Guoyao Wu.
      Adult humans generally experience a 0.5-1%/year loss in whole-body skeletal muscle mass and a reduction of muscle strength by 1.5-5%/year beginning at the age of 50 years. This results in sarcopenia (aging-related progressive losses of skeletal muscle mass and strength) that affects 10-16% of adults aged ≥ 60 years worldwide. Concentrations of some amino acids (AAs) such as branched-chain AAs, arginine, glutamine, glycine, and serine are reduced in the plasma of older than young adults likely due to insufficient protein intake, reduced protein digestibility, and increased AA catabolism by the portal-drained viscera. Acute, short-term, or long-term administration of some of these AAs or a mixture of proteinogenic AAs can enhance blood flow to skeletal muscle, activate the mechanistic target of rapamycin cell signaling pathway for the initiation of muscle protein synthesis, and modulate the metabolic activity of the muscle. In addition, some AA metabolites such as taurine, β-alanine, carnosine, and creatine have similar physiological effects on improving muscle mass and function in older adults. Long-term adequate intakes of protein and the AA metabolites can aid in mitigating sarcopenia in elderly adults. Appropriate combinations of animal- and plant-sourced foods are most desirable to maintain proper dietary AA balance.
    Keywords:  amino acids; diet; health; nutrition; protein intake; skeletal muscle
    DOI:  https://doi.org/10.1080/10408398.2024.2348549
  13. Alpha Psychiatry. 2024 Jan;25(1): 111-112
    Skeletal Editing: A Novel Method for "Psychiatric Drug Flipping" to Produce New, Precise Ones with Fewer Side Effects.
    Muhammet Kartal, Murat Emul.
      
    DOI:  https://doi.org/10.5152/alphapsychiatry.2024.231488
  14. Sleep Med. 2024 May 17. pii: S1389-9457(24)00251-X. [Epub ahead of print]119 480-487
    SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study.
    Jinlan Luo, Ling Tu, Chenchen Zhou, Gen Li, Lili Shi, Shuiqing Hu.
       BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) initially emerged as oral antidiabetic medication but were subsequently discovered to exhibit pleiotropic actions. Insomnia is a prevalent and debilitating sleep disorder. To date, the causality between SGLT2 inhibitors and insomnia remains unclear. This study aims to evaluate the causality between SGLT2 inhibitors and insomnia and identify potential plasma protein mediators.
    METHODS: Using a two-sample Mendelian Randomization (MR) analysis, we estimated the causality of SGLT2 inhibition on insomnia and sleep duration. Additionally, employing a two-step and proteome-wide MR analysis, we evaluated the causal link of SGLT2 inhibition on 4907 circulating proteins and the causality of SGLT2 inhibition-driven plasma proteins on insomnia. We applied a false discovery rate (FDR) correction for multiple comparisons. Furthermore, mediation analyses were used to identify plasma proteins that mediate the effects of SGLT2 inhibition on insomnia.
    RESULTS: SGLT2 inhibition was negatively correlated with insomnia (odds ratio [OR] = 0.791, 95 % confidence interval [CI] [0.715, 0.876], P = 5.579*10^-6) and positively correlated with sleep duration (β = 0.186, 95 % CI [0.059, 0.314], P = 0.004). Among the 4907 circulating proteins, diadenosine tetraphosphatase (Ap4A) was identified as being linked to both SGLT2 inhibition and insomnia. Mediation analysis indicated that the effect of SGLT2 inhibition on insomnia partially operates through Ap4A (β = -0.018, 95 % CI [-0.036, -0.005], P = 0.023), with a mediation proportion of 7.7 %.
    CONCLUSION: The study indicated a causality between SGLT2 inhibition and insomnia, with plasma Ap4A potentially serving as a mediator.
    Keywords:  Ap4A; Insomnia; Mendelian randomization; Plasma protein; Sodium-glucose cotransporter 2
    DOI:  https://doi.org/10.1016/j.sleep.2024.05.036
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