Skeletal Muscle HIF-1α Expression Is Dependent on Muscle Fiber Type

Oxygen homeostasis is an essential regulation system for cell energy production and survival. The oxygen-sensitive subunit α of the hypoxia inducible factor-1 (HIF-1) complex is a key protein of this system. In this work, we analyzed mouse and rat HIF-1α protein and mRNA expression in parallel to energetic metabolism variations within skeletal muscle. Two physiological situations were studied using HIF-1α–specific Western blotting and semiquantitative RT-PCR. First, we compared HIF-1α expression between the predominantly oxidative soleus muscle and three predominantly glycolytic muscles. Second, HIF-1α expression was assessed in an energy metabolism switch model that was based on muscle disuse. These two in vivo situations were compared with the in vitro HIF-1α induction by CoCl2 treatment on C2C12 mouse muscle cells. HIF-1α mRNA and protein levels were found to be constitutively higher in the more glycolytic muscles compared with the more oxidative muscles. Our results gave rise to the hypothesis that the oxygen homeostasis regulation system depends on the fiber type

Differentiation of Human Adipose-Derived Stem Cells into “Brite” (Brown-in-White) Adipocytes

It is well established now that adult humans possess active brown adipose tissue (BAT) which represents a potential pharmacological target to combat obesity and associated diseases. Moreover thermogenic brown-like adipocytes (“brite adipocytes”) appear also in mouse white adipose tissue (WAT) upon β3-adrenergic stimulation. We had previously shown that human multipotent adipose-derived stem cells (hMADS) are able to differentiate into cells which exhibit the key properties of human white adipocytes, and then to convert into functional brown adipocytes upon PPARγ activation. In light of a wealth of data indicating that thermogenic adipocytes from BAT and WAT have a distinct cellular origin, we have characterized at the molecular level UCP1 positive hMADS adipocytes from both sexes as brite adipocytes. Conversion of white to brown hMADS adipocytes is dependent on PPARγ activation with rosiglitazone as the most potent agonist and is inhibited by a PPARγ antagonist. In contrast to mouse cellular models, hMADS cells conversion into brown adipocytes is weakly induced by BMP7 treatment and not modulated by activation of the Hedgehog pathway. So far no primary or clonal precursor cells of human brown adipocytes have been obtained that can be used as a tool to develop therapeutic drugs and to gain further insights into the molecular mechanisms of brown adipogenesis in humans. Thus hMADS cells represent a suitable human cell model to delineate the formation and/or the uncoupling capacity of brown/brite adipocytes that could help to dissipate caloric excess intake among individuals

Differences in birch tar composition are explained by adhesive function in the central European Iron Age

Birch bark tar is the most widely documented adhesive in prehistoric Europe. More recent periods attest to a diversification in terms of the materials used as adhesives and their application. Some studies have shown that conifer resins and beeswax were added to produce compound adhesives. For the Iron Age, no comparative large-scale studies have been conducted to provide a wider perspective on adhesive technologies. To address this issue, we identify adhesive substances from the Iron Age in north-eastern France. We applied organic residue analysis to 65 samples from 16 archaeological sites. This included residues adhering to ceramics, from vessel surface coatings, repaired ceramics, vessel contents, and adhesive lumps. Our findings show that, even during the Iron Age in north-eastern France, birch bark tar is one of the best-preserved adhesive substances, used for at least 400 years. To a lesser extent, Pinaceae resin and beeswax were also identified. Through statistical analyses, we show that molecular composition differs in samples, correlating with adhesive function. This has implications for our understanding of birch bark tar production, processing and mode of use during the Iron Age in France and beyond

Fibronectin Extra Domains tune cellular responses and confer topographically distinct features to fibril networks

International audienceCellular fibronectin (FN; also known as FN1) variants harboring one or two alternatively spliced so-called extra domains (EDB and EDA) play a central bioregulatory role during development, repair processes and fibrosis. Yet, how the extra domains impact fibrillar assembly and function of the molecule remains unclear. Leveraging a unique biological toolset and image analysis pipeline for direct comparison of the variants, we demonstrate that the presence of one or both extra domains impacts FN assembly, function and physical properties of the matrix. When presented to FN-null fibroblasts, extra domain-containing variants differentially regulate pH homeostasis, survival, and TGF- β by tuning the magnitude of cellular responses, rather than triggering independent molecular switches. Numerical analyses of fiber topologies highlight significant differences in variant-specific structural features and provide a first step for the development of a generative model of FN networks to unravel assembly mechanisms and investigate the physical and functional versatility of extracellular matrix landscapes

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Involvement of polyunsaturated fatty acids in the control of energy storage and expenditure

International audienc

Caractérisation de trois nouveaux gènes impliqués dans le développement et les adaptations fonctionnelles du muscle squelettique (BTBD1, SMHS1 et myoduline)

Ce travail de thèse a été focalisé sur la caractérisation moléculaire et fonctionnelle de trois nouveaux gènes exprimés préférentiellement dans le muscle squelettique et impliqués soit dans le déterminisme musculaire pour BTBD1, soit dans les adaptations fonctionnelles du muscle lors de changement d'activité pour SMHS1 et la myoduline. L'étude de BTBD1, protéine liant la DNA topoisomérase 1 (Topo1), a montré qu'il s'agissait d'une protéine spécifiquement impliquée dans la différenciation du muscle squelettique. En effet, la surexpression d'une forme tronquée de BTBD1 dans des cellules myoblastiques, entraîne un dysfonctionnement de la différenciation musculaire, mais pas de l'adipogenèse, associée semble t'il à une dérégulation de l'activité de Topo1. L'expression des gènes de SMHS1 et de la myoduline est altérée dans les phénomènes d'atrophie et/ou d'hypertrophie musculaire du rat. Dans le cas de SMHS1, nous avons démontré son implication dans les adaptations du muscle squelettique à un changement métabolique, et cela en parallèle avec le gène de HIF-1a. La myoduline a pu être caractérisée comme étant une protéine membranaire du système musculo-tendineux. De plus, nous avons démontré in vitro, que la surexpression de la myoduline par des cellules musculaires a pour conséquence de favoriser la capacité invasive de cellules endothéliales. La myoduline semble donc posséder les caractéristiques d'un facteur pro-angiogénique, qui pourrait être restreint aux muscles squelettiques. Au final, ce travail de thèse a donc permis d'avancer la caractérisation de ces trois gènes (BTBD1, SMHS1 et la myoduline) et ouvre de nouvelles perspectives pour une meilleure compréhension des mécanismes de différenciation et de modification de la plasticité musculaire.The objective of this study was to characterise from molecular and functional points of view, three novel genes preferentially expressed in skeletal muscle and involved in muscular determination for BTBD1, or in skeletal muscle adaptations during activity modification for SMHS1 and myodulin. The study of BTBD1, a DNA topoisomerase 1 (Topo1) interacting protein, described it as an essential and specific protein for the skeletal muscle differentiation. Indeed, a truncated BTBD overexpression in myoblasts induces a myogenesis disruption, but these cells are able to promote adipogenesis. This effect may be linked to a Topo1 activity alteration. SMHS1 and myodulin gene expression is altered in rat skeletal muscle atrophy and hypertrophy. For SMHS1, it has been demonstrated that its expression level, concomitant to HIF-1a gene expression, is involved in skeletal muscle adaptations to metabolism switch. Myodulin is a membrane protein expressed in the myotendinous system. Moreover, it has been demonstrated that in vitro, myodulin overexpression by muscle cells promotes invasive capacity of endothelial cells. This protein seems to have pro-angiogenic properties which may be restricted to skeletal muscle. Based on this study, three novel genes (coding for BTBD1, SMHS1 and myodulin) have been therefore molecularly and functionally characterised, and new perspectives are now opened for a better understanding of muscular differentiation and plasticity modification.NICE-BU Sciences (060882101) / SudocSudocFranceF

Control of bone and fat mass by oxytocin

International audienceOsteoporosis and overweight/obesity constitute major worldwide public health burdens. Aging is associated with a decrease in hormonal secretion, lean mass and bone mass, and an increase in fat accumulation. It is established that both obesity and osteoporosis are affected by genetic and environmental factors, bone remodeling and adiposity are both regulated through the hypothalamus and sympathetic nervous system. Oxytocin (OT), belongs to the pituitary hormone family and regulates the function of peripheral target organs, its circulating levels decreased with age. Nowadays, it is well established that OT plays an important role in the control of bone and fat mass and their metabolism. Of note, OT and oxytocin receptor knock out mice develop bone defects and late-onset obesity. Thus OT emerges as a promising molecule in the treatment of osteoporosis and obesity as well as associated metabolic disorders such as type 2 diabetes and cardiovascular diseases. In this review, we will discuss findings regarding the OT effects on bone and fat mass

New Strategies Protecting from Ischemia/Reperfusion

This Special Issue aims to highlight new avenues in the management of Ischemia/Reperfusion (I/R) injury [...