Estrogen-related receptor alpha (ERR?) is a key regulator of intestinal homeostasis and protects against colitis

The estrogen-related receptor alpha (ERR?) is a primary regulator of mitochondrial energy metabolism, function and dynamics, and has been implicated in autophagy and immune regulation. ERR? is abundantly expressed in the intestine and in cells of the immune system. However, its role in inflammatory bowel disease (IBD) remains unknown. Here, we report a protective role of ERR? in the intestine. We found that mice deficient in ERR? were susceptible to experimental colitis, exhibiting increased colon inflammation and tissue damage. This phenotype was mediated by impaired compensatory proliferation of intestinal epithelial cells (IEC) following injury, enhanced IEC apoptosis and necrosis and reduced mucus-producing goblet cell counts. Longitudinal analysis of the microbiota demonstrated that loss of ERR? lead to a reduction in microbiome ?-diversity and depletion of healthy gut bacterial constituents. Mechanistically, ERR? mediated its protective effects by acting within the radio-resistant compartment of the intestine. It promoted disease tolerance through transcriptional control of key genes involved in intestinal tissue homeostasis and repair. These findings provide new insights on the role of ERR? in the gut and extends our current knowledge of nuclear receptors implicated in IBD

ADRA1A-Gα_q signalling potentiates adipocyte thermogenesis through CKB and TNAP

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis(1). Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α(1)-adrenergic receptor (AR) and β(3)-AR signalling induces the expression of thermogenic genes of the futile creatine cycle(2,3), and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α(1)-AR subtype (ADRA1A) and Gα(q) to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gα(q) and Gα(s) signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A–Gα(q)–futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Study of links between actors of mitochondrial dynamics and apoptosis in dystrophin-dependent muscle degeneration in Caenorhabditis elegans

La forme des mitochondries change continuellement grâce aux actions combinées d'événements de fission et de fusion rendant le réseau mitochondrial très dynamique. Les processus mitochondriaux de fission et de fusion sont finement régulés par des GTPases de la famille des dynamines qui sont bien conservées entre les espèces. Chez C. elegans, la fission est régulée par DRP-1, la fusion de la membrane interne par EAT-3, homologue d’OPA1, et la fusion de la membrane externe par FZO-1, homologue de MFN1. Dans les cellules musculaires du nématode sauvage, les mitochondries tubulaires et circulaires sont dans des proportions égales et organisées le long du sarcomère. Cependant, durant la dégénérescence musculaire dystrophine-dépendante, une fragmentation du réseau mitochondrial dans les cellules musculaires apparaît. Or le rôle des acteurs de la dynamique mitochondriale dans les mécanismes moléculaires menant à la dégénérescence musculaire dystrophine-dépendante reste encore incompris. Nous avons trouvé que: (i) la dégénérescence musculaire dystrophine-dépendante s'accompagnait d'une augmentation drastique de la fragmentation mitochondriale qui peut être sauvée par des manipulations génétiques de la dynamique mitochondriale (ii) la perte de fonction du gène de fission drp-1 ou la surexpression des gènes de fusion eat-3 et fzo-1 provoquent une réduction de la dégénérescence musculaire et une mobilité améliorée des mutants dystrophiques (iii) les fonctions de DRP-1 dans l'apoptose et d’autres acteurs de l’apoptose sont importants pour la mort des cellules musculaires déficientes en dystrophine (iv) L’implication de DRP-1 dans l’apoptose est également importante pour la dégénérescence musculaire liée au vieillissement. En conclusion, nos résultats pointent vers un mécanisme impliquant la dynamique mitochondriale pour impacter la dégénérescence musculaire via l’apoptose chez Caenorhabditis elegansMitochondrial shape is continually changing thanks to the combined actions of fission and fusion events making the mitochondrial network very dynamic. The mitochondrial fission and fusion processes are finely regulated by GTPases of the family of dynamins that are well conserved between species. In C. elegans, fission is regulated by DRP-1, fusion of the inner membrane by EAT-3, homologue of OPA1, and fusion of the outer membrane by FZO-1, homologue of MFN1. In the muscle cells of wild nematode, tubular and circular mitochondria are in equal proportions and organized along the sarcomere. However, during dystrophin-dependent muscle degeneration, fragmentation of the mitochondrial network in muscle cells occurs. But the role of the actors of mitochondrial dynamics in the molecular mechanisms leading to dystrophin-dependent muscle degeneration is still misunderstood. We found that: (i) dystrophin-dependent muscle degeneration was accompanied by a drastic increase in mitochondrial fragmentation that can be saved by genetic manipulation of mitochondrial dynamics (ii) loss of function of the fission gene drp-1 or overexpression of the eat-3 and fzo-1 fusion genes causes a reduction in muscle degeneration and improved mobility of dystrophic mutants (iii) DRP-1 functions in apoptosis and other are important for the death of dystrophin-deficient muscle cells (iv) The involvement of DRP-1 in apoptosis is also important for age-dépendant muscle degeneration. In conclusion, our results point toward a mechanism involving mitochondrial dynamics to impact muscle degeneration via apoptosis in Caenorhabditis elegan

Transcriptional Regulation of ROS Homeostasis by the ERR Subfamily of Nuclear Receptors

Reactive oxygen species (ROS) such as superoxide anion (O2•−) and hydrogen peroxide (H2O2) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases. Transcriptional control of metabolic genes is a crucial mechanism to coordinate ROS homeostasis. Therefore, a better understanding of how ROS metabolism is regulated by specific transcription factors can contribute to uncovering new therapeutic strategies. A large body of work has positioned the estrogen-related receptors (ERRs), transcription factors belonging to the nuclear receptor superfamily, as not only master regulators of cellular energy metabolism but, most recently, of ROS metabolism. Herein, we will review the role played by the ERRs as transcriptional regulators of ROS generation and antioxidant mechanisms and also as ROS sensors. We will assess how the control of ROS homeostasis by the ERRs can be linked to physiology and disease and the possible contribution of manipulating ERR activity in redox medicine

ERRα fosters running endurance by driving myofiber aerobic transformation and fuel efficiency

Objective: Estrogen related receptor α (ERRα) occupies a central node in the transcriptional control of energy metabolism, including in skeletal muscle, but whether modulation of its activity can directly contribute to extend endurance to exercise remains to be investigated. The goal of this study was to characterize the benefit of mice engineered to express a physiologically relevant activated form of ERRα on skeletal muscle exercise metabolism and performance. Methods: We recently shown that mutational inactivation of three regulated phosphosites in the amino terminal domain of the nuclear receptor ERRα impedes its degradation, leading to an accumulation of ERRα proteins and perturbation of metabolic homeostasis in ERRα3SA mutant mice. Herein, we used a multi-omics approach in combination with physical endurance tests to ascertain the consequences of expressing the constitutively active phospho-deficient ERRα3SA form on muscle exercise performance and energy metabolism. Results: Genetic heightening of ERRα activity enhanced exercise capacity, fatigue-resistance, and endurance. This phenotype resulted from extensive reprogramming of ERRα global DNA occupancy and transcriptome in muscle leading to an increase in oxidative fibers, mitochondrial biogenesis, fatty acid oxidation, and lactate homeostasis. Conclusion: Our findings support the potential to enhance physical performance and exercise-induced health benefits by targeting molecular pathways regulating ERRα transcriptional activity

Quality of Life and Treatment Modalities in Patients with Interstitial Cystitis: The Patients’ Perspective

Background: Quality of life (QoL)-based outcomes are hardly incorporated into interstitial cystitis/bladder pain syndrome (IC/BPS) guidelines, because studies are limited and outdated. Therefore, guidelines might not reflect the current clinical situation accurately. Secondly, guidelines suggest using a multimodal approach for BPS/IC management, but data on the patient-perceived efficacy of these therapies are limited. The aim of this study is to investigate the perception of IC/BPS patients of their QoL, to determine which treatments they have received, and to examine how they evaluate the efficacy of these various (alternative) therapies. Methods: A quantitative retrospective database evaluation was performed, with data from an existing IC/BPS patient survey (n = 217) that was conducted in 2021. This survey contained QoL data based on validated questionnaires such as EQ-5D 5L. Results: The QoL of patients is affected significantly by IC/BPS. This is evident from the various affected domains on the EQ-5D 5L. The symptom severity was negatively affected by a delay in diagnosis, and there were clear differences in QoL domains between females and males. Secondly, coagulation therapy and intravesical glycosaminoglycan (GAG) therapy were most appreciated by patients. Other (alternative) treatments were commonly utilized, although some had doubtful results and high discontinuation rates. Conclusion: QoL is considerably impaired in IC/BPS patients. The diverse responses and adherence to various treatments warrant a personalized approach (phenotype-oriented therapy). To achieve QoL improvement, it is important to incorporate the patient’s perspective in treatment guidelines

Author Correction: DRP-1-mediated apoptosis induces muscle degeneration in dystrophin mutants

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Modulation of Protein Quality Control and Proteasome to Autophagy Switch in Immortalized Myoblasts from Duchenne Muscular Dystrophy Patients

The maintenance of proteome integrity is of primary importance in post-mitotic tissues such as muscle cells; thus, protein quality control mechanisms must be carefully regulated to ensure their optimal efficiency, a failure of these processes being associated with various muscular disorders. Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophies and is caused by mutations in the dystrophin gene. Protein quality control modulations have been diversely observed in degenerating muscles of patients suffering from DMD or in animal models of the disease. In this study, we investigated whether modulations of protein quality control mechanisms already pre-exist in undifferentiated myoblasts originating from DMD patients. We report for the first time that the absence of dystrophin in human myoblasts is associated with protein aggregation stress characterized by an increase of protein aggregates. This stress is combined with BAG1 to BAG3 switch, NFκB activation and up-regulation of BAG3/HSPB8 complexes that ensure preferential routing of misfolded/aggregated proteins to autophagy rather than to deficient 26S proteasome. In this context, restoration of pre-existing alterations of protein quality control processes might represent an alternative strategy for DMD therapies

Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice

Abstract Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics and pharmacological intervention showed that FBXW7 loss-of-function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression in male mice. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH