bims-kimdis 2024-05-26 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–05–26
23 papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.
A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.
Take the bull by the horns and tackle the potential downsides of the ketogenic diet.
The interplay between glucose and ketone bodies in neural stem cell metabolism.
Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder.
Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.
Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats.
β-hydroxybutyrate alleviates neurological deficits by restoring glymphatic and inflammation after subarachnoid hemorrhage in mice.
Urolithin A suppresses NLRP3 inflammasome activation by inhibiting the generation of reactive oxygen species and prevents monosodium urate crystal-induced peritonitis.
Gut microbiota mediates the protective effects of β-hydroxybutyrate against cisplatin-induced acute kidney injury.
10 weeks low intensity treadmill exercise intervention ameliorates motor deficits and sustains muscle mass via decreasing oxidative damage and increasing mitochondria function in a rat model of Parkinson's disease.
Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling.
Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.
TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
Post-translational control of NLRP3 inflammasome signaling.
Mitochondria at the crossroads of health and disease.
Editorial: Role of nutrition in skeletal muscle atrophy and sarcopenia.
Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases.
DESIGN, SYNTHESIS AND ANTIBACTERIAL ASSESSMENT OF ACTIVE (4-ARYLAZO-3-METHYL-2-THIENYL) 4-ANTIPYRINE KETONES.
Ketoacidosis and SGLT2 Inhibitors: A Narrative Review.
SIRT1, resveratrol and aging.
Illuminating mitochondrial translation through mouse models.
Does photobiomodulation alter mitochondrial dynamics?

Am J Physiol Cell Physiol. 2024 May 20.

Exogenous Ketone Esters as a Potential Therapeutic for Treatment of Sarcopenic Obesity.

Sarah E Deemer, Brandon M Roberts, Daniel Larry Smith, Eric P Plaisance, Andy Philp.

  Identifying effective treatment(s) for sarcopenia and sarcopenic obesity are of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (> 80%), very low carbohydrate (< 5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in pre-clinical and clinical research has escalated within the past 10-15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R, S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans.

Keywords:  aging; ketone diester; ketone monoester; obesity; sarcopenia

DOI:  https://doi.org/10.1152/ajpcell.00471.2023
Sci Rep. 2024 May 24. 14(1): 11940

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.

Hester Meeusen, Alessia Romagnolo, Sophie A C Holsink, Thijs J M van den Broek, Ardy van Helvoort, Jan A Gorter, Erwin A van Vliet, J Martin Verkuyl, Jose P Silva, Eleonora Aronica.

  The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the β-hydroxybutyrate (βHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-βHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the βHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the βHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

Keywords:  Dietary fat; In vitro assay; Ketogenic diet; Lipids/oxidation; Liver; Nutrition; Omega-3 fatty acids; β-Hydroxybutyrate

DOI:  https://doi.org/10.1038/s41598-024-62723-7
Nutrition. 2024 May 02. pii: S0899-9007(24)00130-8. [Epub ahead of print]125 112480

Take the bull by the horns and tackle the potential downsides of the ketogenic diet.

Yiming Meng, Jing Sun, Guirong Zhang.

  The ketogenic diet (KD) is a distinctive dietary regimen known for its low-carbohydrate and high-fat composition. Recently, it has garnered considerable interest from the scientific community and the general population because of its claimed efficacy in facilitating weight reduction, improving the management of glucose levels, and raising overall energy levels. The core principle of the KD is the substantial decrease in carbohydrate consumption, which is subsequently substituted by ingesting nourishing fats. While the KD has promising advantages and is gaining popularity, it must be acknowledged that this dietary method may not be appropriate for all individuals. The dietary regimen may give rise to adverse effects, including constipation, halitosis, and imbalances in electrolyte levels, which may pose a potential risk if not adequately supervised. Hence, thorough and meticulous inquiry is needed to better comprehend the possible hazards and advantages linked to the KD over prolonged durations. By obtaining a more comprehensive perspective, we can enhance our ability to make well-informed judgments and suggestions as to implementation of this specific dietary regimen.

Keywords:  Dexamethasone; Ferroptosis; High-fat; Ketogenic diet; Low-carbohydrate

DOI:  https://doi.org/10.1016/j.nut.2024.112480
J Neurosci Res. 2024 May;102(5): e25342

The interplay between glucose and ketone bodies in neural stem cell metabolism.

Joseph W Molloy, Denis Barry.

  Glucose is the primary energy source for neural stem cells (NSCs), supporting their proliferation, differentiation, and quiescence. However, the high demand for glucose during brain development often exceeds its supply, leading to the utilization of alternative energy sources including ketone bodies. Ketone bodies, including β-hydroxybutyrate, are short-chain fatty acids produced through hepatic ketogenesis and play a crucial role in providing energy and the biosynthetic components for NSCs when required. The interplay between glucose and ketone metabolism influences NSC behavior and fate decisions, and disruptions in these metabolic pathways have been linked to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Additionally, ketone bodies exert neuroprotective effects on NSCs and modulate cellular responses to oxidative stress, energy maintenance, deacetylation, and inflammation. As such, understanding the interdependence of glucose and ketone metabolism in NSCs is crucial to understanding their roles in NSC function and their implications for neurological conditions. This article reviews the mechanisms of glucose and ketone utilization in NSCs, their impact on NSC function, and the therapeutic potential of targeting these metabolic pathways in neurological disorders.

Keywords:  glycolysis; ketone bodies; metabolism; neural stem cell; neurological conditions

DOI:  https://doi.org/10.1002/jnr.25342
Nutrients. 2024 May 07. pii: 1401. [Epub ahead of print]16(10):

Ketogenic Diet Induced Shifts in the Gut Microbiome Associate with Changes to Inflammatory Cytokines and Brain-Related miRNAs in Children with Autism Spectrum Disorder.

Nina P Allan, Brennan Y Yamamoto, Braden P Kunihiro, Chandler K L Nunokawa, Noelle C Rubas, Riley K Wells, Lesley Umeda, Krit Phankitnirundorn, Amada Torres, Rafael Peres, Emi Takahashi, Alika K Maunakea.

  In this interventional pilot study, we investigated the effects of a modified ketogenic diet (KD) on children with autism spectrum disorder (ASD). We previously observed improved behavioral symptoms in this cohort following the KD; this trial was registered with Clinicaltrials.gov (NCT02477904). This report details the alterations observed in the microbiota, inflammation markers, and microRNAs of seven children following a KD for a duration of 4 months. Our analysis included blood and stool samples, collected before and after the KD. After 4 months follow up, we found that the KD led to decreased plasma levels of proinflammatory cytokines (IL-12p70 and IL-1b) and brain-derived neurotrophic factor (BDNF). Additionally, we observed changes in the gut microbiome, increased expression of butyrate kinase in the gut, and altered levels of BDNF-associated miRNAs in the plasma. These cohort findings suggest that the KD may positively influence ASD sociability, as previously observed, by reducing inflammation, reversing gut microbial dysbiosis, and impacting the BDNF pathway related to brain activity.

Keywords:  BDNF; autism spectrum disorder; butyrate; inflammation; ketogenic diet; miRNA; microbiome

DOI:  https://doi.org/10.3390/nu16101401
Int J Mol Sci. 2024 May 17. pii: 5482. [Epub ahead of print]25(10):

Metabolic Contrasts: Fatty Acid Oxidation and Ketone Bodies in Healthy Brains vs. Glioblastoma Multiforme.

Corina Tamas, Flaviu Tamas, Attila Kovecsi, Alina Cehan, Adrian Balasa.

  The metabolism of glucose and lipids plays a crucial role in the normal homeostasis of the body. Although glucose is the main energy substrate, in its absence, lipid metabolism becomes the primary source of energy. The main means of fatty acid oxidation (FAO) takes place in the mitochondrial matrix through β-oxidation. Glioblastoma (GBM) is the most common form of primary malignant brain tumor (45.6%), with an incidence of 3.1 per 100,000. The metabolic changes found in GBM cells and in the surrounding microenvironment are associated with proliferation, migration, and resistance to treatment. Tumor cells show a remodeling of metabolism with the use of glycolysis at the expense of oxidative phosphorylation (OXPHOS), known as the Warburg effect. Specialized fatty acids (FAs) transporters such as FAT, FABP, or FATP from the tumor microenvironment are overexpressed in GBM and contribute to the absorption and storage of an increased amount of lipids that will provide sufficient energy used for tumor growth and invasion. This review provides an overview of the key enzymes, transporters, and main regulatory pathways of FAs and ketone bodies (KBs) in normal versus GBM cells, highlighting the need to develop new therapeutic strategies to improve treatment efficacy in patients with GBM.

Keywords:  carnitine; fatty acids; glioblastoma; ketone bodies; lipid metabolism; β-oxidation

DOI:  https://doi.org/10.3390/ijms25105482
Nutrients. 2024 May 14. pii: 1477. [Epub ahead of print]16(10):

Exogenous Ketone Supplement Administration Abrogated Isoflurane-Anesthesia-Induced Increase in Blood Glucose Level in Female WAG/Rij Rats.

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

  It has been demonstrated that isoflurane-induced anesthesia can increase the blood glucose level, leading to hyperglycemia and several adverse effects. The administration of a mix of ketone diester (KE) and medium-chain triglyceride (MCT) oil, named KEMCT, abolished the isoflurane-anesthesia-induced increase in blood glucose level and prolonged the recovery time from isoflurane anesthesia in a male preclinical rodent model, Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. While most preclinical studies use exclusively male animals, our previous study on blood glucose changes in response to KEMCT administration showed that the results can be sex-dependent. Thus, in this study, we investigated female WAG/Rij rats, whether KEMCT gavage (3 g/kg/day for 7 days) can change the isoflurane (3%)-anesthesia-induced increase in blood glucose level and the recovery time from isoflurane-evoked anesthesia using the righting reflex. Moreover, KEMCT-induced ketosis may enhance both the extracellular level of adenosine and the activity of adenosine A1 receptors (A1Rs). To obtain information on the putative A1R mechanism of action, the effects of an A1R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; intraperitoneal/i.p. 0.2 mg/kg), on KEMCT-generated influences were also investigated. Our results show that KEMCT supplementation abolished the isoflurane-anesthesia-induced increase in blood glucose level, and this was abrogated by the co-administration of DPCPX. Nevertheless, KEMCT gavage did not change the recovery time from isoflurane-induced anesthesia. We can conclude that intragastric gavage of exogenous ketone supplements (EKSs), such as KEMCT, can abolish the isoflurane-anesthesia-induced increase in blood glucose level in both sexes likely through A1Rs in WAG/Rij rats, while recovery time was not affected in females, unlike in males. These results suggest that the administration of EKSs as an adjuvant therapy may be effective in mitigating metabolic side effects of isoflurane, such as hyperglycemia, in both sexes.

Keywords:  adenosine receptor; female WAG/Rij rat; glucose level; isoflurane anesthesia; ketone supplement; recovery time

DOI:  https://doi.org/10.3390/nu16101477
Exp Neurol. 2024 May 17. pii: S0014-4886(24)00145-6. [Epub ahead of print]378 114819

β-hydroxybutyrate alleviates neurological deficits by restoring glymphatic and inflammation after subarachnoid hemorrhage in mice.

Xiaoli Tan, Xiaohong Li, Ruhua Li, Weiting Meng, Zhuoxi Xie, Jing Li, Yeyu Pang, Guilan Huang, Li Li, Hao Li.

   BACKGROUND: Both glymphatic system dysfunction and inflammatory response aggravate neurological dysfunction after subarachnoid hemorrhage (SAH). Studies have shown that β-hydroxybutyrate (BHB) may mitigate painful diabetic neuropathy (PDN) by upregulating SNTA1 expression and reinstating AQP4 polarity. However, the potential of BHB to ameliorate glymphatic system function and inflammatory response in SAH mice remains uncertain.
METHODS: The SAH models were constructed by injection of arterial blood into cisterna Magana. Three groups of C57 mice were randomly assigned: Sham, SAH, and BHB. All mice were subjected to neurological function assessment, western blot, immunofluorescence double staining, and RNA-seq. Glymphatic system function was examined with tracer and immunofluorescence double staining, and the differential genes were examined with RNA-seq. In addition, the expression of related inflammation was detected.
RESULTS: Compared with the SAH group, BHB reinstated AQP4 polarization by upregulating SNTA1 protein to enhance the glymphatic system. According to RNA-seq, the different genes were primarily connected to microglia activation, astrocytes, and inflammation. Western blot and immunofluorescence further confirmed that the related inflammatory protein expression levels were upregulated. BHB attenuated neuroinflammation after SAH. Ultimately, it can mitigate the neurological deficits in SAH mice.
CONCLUSION: The study reveals a novel mechanism that BHB treatment mitigates neurologic impairment in SAH mice. We propose that BHB may play a neuroprotective effect by enhancing glymphatic system function and attenuating neuroinflammatory subarachnoid hemorrhage.

Keywords:  AQP4; Astrocytes; Aβ; Glymphatic system; Inflammation; Microglia; RNA-seq; SNTA1; Subarachnoid hemorrhage (SAH); β-hydroxybutyrate (BHB)

DOI:  https://doi.org/10.1016/j.expneurol.2024.114819
Biosci Biotechnol Biochem. 2024 May 21. pii: zbae068. [Epub ahead of print]

Urolithin A suppresses NLRP3 inflammasome activation by inhibiting the generation of reactive oxygen species and prevents monosodium urate crystal-induced peritonitis.

Wataru Komatsu, Hisashi Kishi, Koji Uchiyama, Shuji Ohhira, Gen Kobashi.

  The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers the maturation of interleukin-1β (IL-1β) and is implicated in the pathogenesis of various inflammatory diseases. Urolithin A, a gut microbial metabolite of ellagic acid, reportedly exerts antiinflammatory effects in vitro and in vivo. However, whether urolithin A suppresses NLRP3 inflammasome activation is unclear. In this study, urolithin A inhibited the cleavage of NLRP3 inflammasome agonist-induced caspase-1, maturation of IL-1β, and activation of pyroptosis in lipopolysaccharide-primed mouse bone marrow-derived macrophages. Urolithin A reduced generation of intracellular and mitochondrial reactive oxygen species and restricted the interaction between thioredoxin-interacting protein and NLRP3, which attenuated NLRP3 inflammasome activation. Urolithin A administration prevented monosodium urate-induced peritonitis in mice. Collectively, these findings indicate that urolithin A suppresses NLRP3 inflammasome activation, at least partially, by repressing the generation of intracellular and mitochondrial reactive oxygen species.

Keywords:  NLRP3 inflammasome; TXNIP; macrophage; reactive oxygen species; urolithin A

DOI:  https://doi.org/10.1093/bbb/zbae068
Biomed Pharmacother. 2024 May 17. pii: S0753-3322(24)00636-X. [Epub ahead of print]175 116752

Gut microbiota mediates the protective effects of β-hydroxybutyrate against cisplatin-induced acute kidney injury.

Ruixue Tian, Xingru Wang, Shuqin Tang, Limei Zhao, Yajie Hao, Rongshan Li, Xiaoshuang Zhou.

  The gut microbiota has been reported to be perturbed by chemotherapeutic agents and to modulate side effects. However, the critical role of β-hydroxybutyrate (BHB) in the regulation of the gut microbiota and the pathogenesis of chemotherapeutic agents related nephrotoxicity remains unknown. We conducted a comparative analysis of the composition and function of gut microbiota in healthy, cisplatin-challenged, BHB-treated, and high-fat diet-treated mice using 16 S rDNA gene sequencing. To understand the crucial involvement of intestinal flora in BHB's regulation of cisplatin -induced nephrotoxicity, we administered antibiotics to deplete the gut microbiota and performed fecal microbiota transplantation (FMT) before cisplatin administration. 16 S rDNA gene sequencing analysis demonstrated that both endogenous and exogenous BHB restored gut microbiota dysbiosis and cisplatin-induced intestinal barrier disruption in mice. Additionally, our findings suggested that the LPS/TLR4/NF-κB pathway was responsible for triggering renal inflammation in the gut-kidney axis. Furthermore, the ablation of the gut microbiota ablation using antibiotics eliminated the renoprotective effects of BHB against cisplatin-induced acute kidney injury. FMT also confirmed that administration of BHB-treated gut microbiota provided protection against cisplatin-induced nephrotoxicity. This study elucidated the mechanism by which BHB affects the gut microbiota mediation of cisplatin-induced nephrotoxicity by inhibiting the inflammatory response, which may help develop novel therapeutic approaches that target the composition of the microbiota.

Keywords:  Acute kidney injury; Cisplatin; Gut microbiota; Inflammation; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.biopha.2024.116752
Life Sci. 2024 May 17. pii: S0024-3205(24)00323-0. [Epub ahead of print] 122733

10 weeks low intensity treadmill exercise intervention ameliorates motor deficits and sustains muscle mass via decreasing oxidative damage and increasing mitochondria function in a rat model of Parkinson's disease.

Yu-Tang Tung, Yi-Chi Liao, Tu-Hsueh Yeh, Shu-Ping Tsao, Chun-Chao Chang, Wei-Ting Shih, Hui-Yu Huang.

   AIMS: Parkinson's disease (PD) is characterized by loss of dopamine neurons in the brain, which leads to motor dysfunction; excessive inflammation induces neuronal death. This study aimed to determine the most effective exercise modality to improve motor dysfunction in PD by comparing three different exercise regimens (low-intensity treadmill, high-intensity treadmill, and swimming).
MATERIALS AND METHODS: The rat model for PD was established through stereotaxic surgery, inducing unilateral 6-OHDA (6-hydroxydopamine) lesions. The low-intensity treadmill regimen exerted better protective effects on neurological and motor functions in a rat model of unilateral 6-OHDA-induced PD compared to high-intensity treadmill and swimming. The most suitable exercise regimen and the optimal duration of daily exercise (15 or 30 min) on motor activity and oxidative stress parameters were evaluated.
KEY FINDINGS: Comparison of 15 and 30 min low-intensity treadmill regimens (10 m/min) revealed 30 min daily exercise was the optimal duration and had more favorable impacts on neurological and motor function. Furthermore, we assessed the neuroprotective effects of exercising for 15 and 30 min per day for either four or ten weeks; 30 min of daily exercise for ten weeks improved mitochondrial function, the antioxidant defense system, neurotrophic factors, and muscle mass, and thereby provided protection against dopaminergic neuron loss, and motor dysfunction in rats with 6-OHDA-induced PD.
SIGNIFICANCE: 30 min of daily low-intensity treadmill exercise over 10 weeks resulted in heightened mitochondrial function in both muscle and brain tissues, therefore, yielded a neuroprotective effect against the loss of dopaminergic neurons and motor dysfunction in PD rats.

Keywords:  Antioxidant defense system; Endurance exercise; Low-intensity treadmill running; Mitochondrial function; Parkinson's disease (PD)

DOI:  https://doi.org/10.1016/j.lfs.2024.122733
Mol Aspects Med. 2024 May 23. pii: S0098-2997(24)00036-0. [Epub ahead of print]97 101277

Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling.

Marcelo Flores-Opazo, Daniel Kopinke, Françoise Helmbacher, Rodrigo Fernández-Verdejo, Mauro Tuñón-Suárez, Gordon S Lynch, Osvaldo Contreras.

  Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions and can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, and unhealthy aging. Although IMAT results from fat accumulation in muscle, the mechanisms underlying its onset, development, cellular components, and functions remain unclear. IMAT levels are influenced by several factors, such as changes in the tissue environment, muscle type and origin, extent and duration of trauma, and persistent activation of fibro-adipogenic progenitors (FAPs). FAPs are a diverse and transcriptionally heterogeneous population of stromal cells essential for tissue maintenance, neuromuscular stability, and tissue regeneration. However, in cases of chronic inflammation and pathological conditions, FAPs expand and differentiate into adipocytes, resulting in the development of abnormal and ectopic IMAT. This review discusses the role of FAPs in adipogenesis and how they remodel IMAT. It highlights evidence supporting FAPs and FAP-derived adipocytes as constituents of IMAT, emphasizing their significance in adipose tissue maintenance and development, as well as their involvement in metabolic disorders, chronic pathologies and diseases. We also investigated the intricate molecular pathways and cell interactions governing FAP behavior, adipogenesis, and IMAT accumulation in chronic diseases and muscle deconditioning. Finally, we hypothesize that impaired cellular metabolic flexibility in dysfunctional muscles impacts FAPs, leading to IMAT. A deeper understanding of the biology of IMAT accumulation and the mechanisms regulating FAP behavior and fate are essential for the development of new therapeutic strategies for several debilitating conditions.

Keywords:  Adipocytes; Adipogenesis; FAPs; IMAT; Metabolism; Obesity; Skeletal muscle

DOI:  https://doi.org/10.1016/j.mam.2024.101277
Int J Mol Sci. 2024 May 08. pii: 5117. [Epub ahead of print]25(10):

Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.

Kylie Heitman, Matthew S Alexander, Christian Faul.

  Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

Keywords:  chronic kidney disease; fibroblast growth factor 23; klotho; parathyroid hormone; phosphate; sarcopenia; skeletal muscle atrophy; vitamin D

DOI:  https://doi.org/10.3390/ijms25105117
Nat Cell Biol. 2024 May 23.

TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.

Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.

When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

DOI: https://doi.org/10.1038/s41556-024-01419-6
J Biol Chem. 2024 May 17. pii: S0021-9258(24)01887-8. [Epub ahead of print] 107386

Post-translational control of NLRP3 inflammasome signaling.

Meghan E O'Keefe, George R Dubyak, Derek W Abbott.

  Inflammasomes serve as critical sensors for disruptions to cellular homeostasis, with inflammasome assembly leading to inflammatory caspase activation, gasdermin cleavage, and cytokine release. While the canonical pathways leading to priming, assembly, and pyroptosis are well characterized, recent work has begun to focus on the role of post-translational modifications (PTMs) in regulating inflammasome activity. A diverse array of PTMs, including phosphorylation, ubiquitination, SUMOylation, acetylation, and glycosylation, exert both activating and inhibitory influences on members of the inflammasome cascade through effects on protein-protein interactions, stability, and localization. Dysregulation of inflammasome activation is associated with a number of inflammatory diseases, and evidence is emerging that aberrant modification of inflammasome components contributes to this dysregulation. This review provides insight into PTMs within the NLRP3 inflammasome pathway and their functional consequences on the signaling cascade, and highlights outstanding questions that remain regarding the complex web of signals at play.

Keywords:  NLRP3; inflammasome; post-translational modification (PTM); signaling

DOI:  https://doi.org/10.1016/j.jbc.2024.107386
Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627

Mitochondria at the crossroads of health and disease.

Anu Suomalainen, Jodi Nunnari.

Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.

DOI: https://doi.org/10.1016/j.cell.2024.04.037
Front Nutr. 2024 ;11 1395491

Editorial: Role of nutrition in skeletal muscle atrophy and sarcopenia.

Tao Tong, Helong Quan, Chang Keun Kim, Weicai Zeng.



Keywords:  dietary intervention; nutrition; protein synthesis/proteolysis; sarcopenia; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fnut.2024.1395491
J Transl Med. 2024 May 24. 22(1): 491

Horizontal mitochondrial transfer as a novel bioenergetic tool for mesenchymal stromal/stem cells: molecular mechanisms and therapeutic potential in a variety of diseases.

Roberto Iorio, Sabrina Petricca, Vincenzo Mattei, Simona Delle Monache.

  Intercellular mitochondrial transfer (MT) is a newly discovered form of cell-to-cell signalling involving the active incorporation of healthy mitochondria into stressed/injured recipient cells, contributing to the restoration of bioenergetic profile and cell viability, reduction of inflammatory processes and normalisation of calcium dynamics. Recent evidence has shown that MT can occur through multiple cellular structures and mechanisms: tunneling nanotubes (TNTs), via gap junctions (GJs), mediated by extracellular vesicles (EVs) and other mechanisms (cell fusion, mitochondrial extrusion and migrasome-mediated mitocytosis) and in different contexts, such as under physiological (tissue homeostasis and stemness maintenance) and pathological conditions (hypoxia, inflammation and cancer). As Mesenchimal Stromal/ Stem Cells (MSC)-mediated MT has emerged as a critical regulatory and restorative mechanism for cell and tissue regeneration and damage repair in recent years, its potential in stem cell therapy has received increasing attention. In particular, the potential therapeutic role of MSCs has been reported in several articles, suggesting that MSCs can enhance tissue repair after injury via MT and membrane vesicle release. For these reasons, in this review, we will discuss the different mechanisms of MSCs-mediated MT and therapeutic effects on different diseases such as neuronal, ischaemic, vascular and pulmonary diseases. Therefore, understanding the molecular and cellular mechanisms of MT and demonstrating its efficacy could be an important milestone that lays the foundation for future clinical trials.

Keywords:  Extracellular vesicles; Horizontal mitochondrial transfer; Ischemic vascular diseases; Mesenchymal Stromal/Stem cells; Mitochondria; Neuronal diseases; Tunnelling nanotubes

DOI:  https://doi.org/10.1186/s12967-024-05047-4
Chem Biodivers. 2024 May 24. e202400894

DESIGN, SYNTHESIS AND ANTIBACTERIAL ASSESSMENT OF ACTIVE (4-ARYLAZO-3-METHYL-2-THIENYL) 4-ANTIPYRINE KETONES.

Khouloud M Baraka, Shymaa Adel Elsayed, Murat Yılmaz, Ehab Abdel-Latif, Hassan Ali Etman, Mohamed A Hamed, Ahmed El Nemr.

  The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing (4-arylazo-3-hydroxy-2-thienyl) 4-antipyrine ketones 1a, 1b and 1c and (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketones (2a, 2b and 2c) further replaced with six other coupling components, a broad spectrum of hybrid molecules have been created. Mass spectra, NMR, FTIR, and elemental analyses have all been used to confirm the structures of the synthesised compounds. The antimicrobial screening was investigated by agar well diffusion and diluting the broth technique against both Gram-negative and positive-tested bacterial strains. (3-methyl-5-(phenylamino)-4-(4-tolylazo)-2-thienyl) 4-antipyrine ketone (2a) was found to be superior to Ciprofloxacin against test strains: Acinetobacter sp (34.33 ±1.15 mm), Listeria monocytogenes (29.33 ±1.15 mm) and Streptococcus sp. (19.33 ±1.15 mm). Also, good to moderate activities were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) which were recorded at 9±1 to 59.67±4.51 µg/mL and 16±4 to > 512 µg/mL, respectively, using compounds 2a, 2b, and 2c. MBC/MIC ratio showed, that only, 2a and 2b have a bactericidal effect but other antipyrines with bacteriostatic strength. It was suggested that the use of these novel synthesized (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketone derivatives molecules as a new chemical class of antimicrobial agents.

Keywords:  4-Antipyrinyl ketone; Antimicrobial activity; Antipyrine derivative; Ciprofloxacin antibiotic; MIC

DOI:  https://doi.org/10.1002/cbdv.202400894
Metabolites. 2024 May 06. pii: 264. [Epub ahead of print]14(5):

Ketoacidosis and SGLT2 Inhibitors: A Narrative Review.

Carmela Morace, Giuseppe Lorello, Federica Bellone, Cristina Quartarone, Domenica Ruggeri, Annalisa Giandalia, Giuseppe Mandraffino, Letteria Minutoli, Giovanni Squadrito, Giuseppina T Russo, Herbert Ryan Marini.

  An acute metabolic complication of diabetes mellitus, especially type 1, is diabetic ketoacidosis (DKA), which is due to an increase in blood ketone concentrations. Sodium/glucose co-transporter-2 inhibitor (SGLT2-i) drugs have been associated with the occurrence of a particular type of DKA defined as euglycemic (euDKA), characterized by glycemic levels below 300 mg/dL. A fair number of euDKA cases in SGLT2-i-treated patients have been described, especially in the last few years when there has been a significant increased use of these drugs. This form of euDKA is particularly insidious because of its latent onset, associated with unspecific symptomatology, until it evolves (progressing) to severe systemic forms. In addition, its atypical presentation can delay diagnosis and treatment. However, the risk of euDKA associated with SGLT2-i drugs remains relatively low, but it is essential to promptly diagnose and manage it to prevent its serious life-threatening complications. In this narrative review, we intended to gather current research evidence on SGLT2i-associated euDKA from randomized controlled trials and real-world evidence studies, its diagnostic criteria and precipitating factors.

Keywords:  SGLT2-i; adverse drug reaction; diabetic ketoacidosis

DOI:  https://doi.org/10.3390/metabo14050264
Front Genet. 2024 ;15 1393181

SIRT1, resveratrol and aging.

Blanka Rogina, Heidi A Tissenbaum.

  Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD+) as co-substrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4'-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies.

Keywords:  SIRT1; aging; calorie restriction; dietary supplements; resveratrol; sirtuins

DOI:  https://doi.org/10.3389/fgene.2024.1393181
Hum Mol Genet. 2024 May 22. 33(R1): R61-R79

Illuminating mitochondrial translation through mouse models.

Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska.

  Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.

Keywords:  animal models; gene expression; mitochondria; protein synthesis

DOI:  https://doi.org/10.1093/hmg/ddae020
Photochem Photobiol. 2024 May 22.

Does photobiomodulation alter mitochondrial dynamics?

Larissa Alexsandra da Silva Neto Trajano, Priscyanne Barreto Siqueira, Mariana Moreno de Sousa Rodrigues, Bruno Ricardo Barreto Pires, Adenilson de Souza da Fonseca, Andre Luiz Mencalha.

  Mitochondrial dysfunction is one of the leading causes of disease development. Dysfunctional mitochondria limit energy production, increase reactive oxygen species generation, and trigger apoptotic signals. Photobiomodulation is a noninvasive, nonthermal technique involving the application of monochromatic light with low energy density, inducing non-thermal photochemical effects at the cellular level, and it has been used due to its therapeutic potential. This review focuses on the mitochondrial dynamic's role in various diseases, evaluating the possible therapeutic role of low-power lasers (LPL) and light-emitting diodes (LED). Studies increasingly support that mitochondrial dysfunction is correlated with severe neurodegenerative diseases such as Parkinson's, Huntington's, Alzheimer's, and Charcot-Marie-Tooth diseases. Furthermore, a disturbance in mitofusin activity is also associated with metabolic disorders, including obesity and type 2 diabetes. The effects of PBM on mitochondrial dynamics have been observed in cells using a human fibroblast cell line and in vivo models of brain injury, diabetes, spinal cord injury, Alzheimer's disease, and skin injury. Thus, new therapies aiming to improve mitochondrial dynamics are clinically relevant. Several studies have demonstrated that LPL and LED can be important therapies to improve health conditions when there is dysfunction in mitochondrial dynamics.

Keywords:  LED; fission; fusion; laser; mitochondrial dynamics; photobiomodulation

DOI:  https://doi.org/10.1111/php.13963