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1. Different outcomes of endurance and resistance exercise in skeletal muscles of Oculopharyngeal muscular dystrophy

Author

Alexis Boulinguiez, Jamila Dhiab, Barbara Crisol, Laura Muraine, Ludovic Gaut, Corentin Rouxel, Justine Flaire, Hadidja‐Rose Mouigni, Mégane Lemaitre, Benoit Giroux, Lucie Audoux, Benjamin SaintPierre, Arnaud Ferry, Vincent Mouly, Gillian Butler‐Browne, Elisa Negroni, Alberto Malerba, and Capucine Trollet

Subjects
Atrophy, Exercise, Fibrosis, OPMD, PAPBN1, Skeletal muscle, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Exercise is widely considered to have beneficial impact on skeletal muscle aging. In addition, there are also several studies demonstrating a positive effect of exercise on muscular dystrophies. Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset autosomal dominant inherited neuromuscular disorder caused by mutations in the PAPBN1 gene. These mutations consist in short (1‐8) and meiotically stable GCN trinucleotide repeat expansions in its coding region responsible for the formation of PAPBN1 intranuclear aggregates. This study aims to characterize the effects of two types of chronic exercise, resistance and endurance, on the OPMD skeletal muscle phenotype using a relevant murine model of OPMD. Methods In this study, we tested two protocols of exercise. In the first, based on endurance exercise, FvB (wild‐type) and A17 (OPMD) mice underwent a 6‐week‐long motorized treadmill protocol consisting in three sessions per week of running 20 cm/s for 20 min. In the second protocol, based on resistance exercise generated by chronic mechanical overload (OVL), surgical removal of gastrocnemius and soleus muscles was performed, inducing hypertrophy of the plantaris muscle. In both types of exercise, muscles of A17 and FvB mice were compared with those of respective sedentary mice. For all the groups, force measurement, muscle histology, and molecular analyses were conducted. Results Following the endurance exercise protocol, we did not observe any major changes in the muscle physiological parameters, but an increase in the number of PABPN1 intranuclear aggregates in both tibialis anterior (+24%, **P = 0.0026) and gastrocnemius (+18%, ****P

Published
2024
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2. Expression of the Pro-Fibrotic Marker Periostin in a Mouse Model of Duchenne Muscular Dystrophy

Author

Jessica Trundle, Viktorija Cernisova, Alexis Boulinguiez, Ngoc Lu-Nguyen, Alberto Malerba, and Linda Popplewell

Subjects
Duchenne muscular dystrophy, muscle pathology, periostin, fibrosis, Biology (General), QH301-705.5
Abstract

Duchenne muscular dystrophy (DMD) is characterised by fibrotic tissue deposition in skeletal muscle. We assessed the role of periostin in fibrosis using mdx mice, an established DMD murine model, for which we conducted a thorough examination of periostin expression over a year. RNA and protein levels in diaphragm (DIA) muscles were assessed and complemented by a detailed histological analysis at 5 months of age. In dystrophic DIAs, periostin (Postn) mRNA expression significantly exceeded that seen in wildtype controls at all timepoints analysed, with the highest expression at 5 months of age (p < 0.05). We found Postn to be more consistently highly expressed at the earlier timepoints compared to established markers of fibrosis like transforming growth factor-beta 1 (Tgf-β1) and connective tissue growth factor (Ctgf). Immunohistochemistry confirmed a significantly higher periostin protein expression in 5-month-old mdx mice compared to age-matched healthy controls (p < 0.01), coinciding with a significant fibrotic area percentage (p < 0.0001). RT-qPCR also indicated an elevated expression of Tgf-β1, Col1α1 (collagen type 1 alpha 1) and Ctgf in mdx DIAs compared to wild type controls (p < 0.05) at 8- and 12-month timepoints. Accordingly, immunoblot quantification demonstrated elevated periostin (3, 5 and 8 months, p < 0.01) and Tgf-β1 (8 and 12 months, p < 0.001) proteins in the mdx muscle. These findings collectively suggest that periostin expression is a valuable marker of fibrosis in this relevant model of DMD. They also suggest periostin as a potential contributor to fibrosis development, with an early onset of expression, thereby offering the potential for timely therapeutic intervention and its use as a biomarker in muscular dystrophies.

Published
2024
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3. A negative feedback loop between fibroadipogenic progenitors and muscle fibres involving endothelin promotes human muscle fibrosis

Author

Mona Bensalah, Laura Muraine, Alexis Boulinguiez, Lorenzo Giordani, Victorine Albert, Victor Ythier, Jamila Dhiab, Alison Oliver, Valentine Hanique, Teresa Gidaro, Sophie Perié, Jean Lacau St‐Guily, Aurélien Corneau, Gillian Butler‐Browne, Anne Bigot, Vincent Mouly, Elisa Negroni, and Capucine Trollet

Subjects
Human, FAPs, Skeletal muscle, Pharyngeal muscle, Fibrosis, ECM, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695
Abstract

Abstract Background Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified. Methods Combining mass cytometry, transcriptome profiling, in vitro co‐culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT). Results We found that the proliferation rate of FAPs from fibrotic muscle is 3–4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co‐cultures in differentiation conditions (FibMCT +17.4%, P

Published
2022
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4. NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression

Author

Alexis Boulinguiez, Christian Duhem, Alicia Mayeuf-Louchart, Benoit Pourcet, Yasmine Sebti, Kateryna Kondratska, Valérie Montel, Stéphane Delhaye, Quentin Thorel, Justine Beauchamp, Aurore Hebras, Marion Gimenez, Marie Couvelaere, Mathilde Zecchin, Lise Ferri, Natalia Prevarskaya, Anne Forand, Christel Gentil, Jessica Ohana, France Piétri-Rouxel, Bruno Bastide, Bart Staels, Helene Duez, and Steve Lancel

Subjects
Cell biology, Muscle biology, Medicine
Abstract

The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions, such as myopathies. Here, we investigated whether the nuclear receptor subfamily 1 group D member (NR1D1, also called REV-ERBα) regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that NR1D1 deficiency in mice impaired sarco/endoplasmic reticulum calcium ATPase–dependent (SERCA-dependent) SR calcium uptake. NR1D1 acts on calcium homeostasis by repressing the SERCA inhibitor myoregulin through direct binding to its promoter. Restoration of myoregulin counteracted the effects of NR1D1 overexpression on SR calcium content. Interestingly, myoblasts from patients with Duchenne muscular dystrophy displayed lower NR1D1 expression, whereas pharmacological NR1D1 activation ameliorated SR calcium homeostasis and improved muscle structure and function in dystrophic mdx/Utr+/– mice. Our findings demonstrate that NR1D1 regulates muscle SR calcium homeostasis, pointing to its therapeutic potential for mitigating myopathy.

Published
2022
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5. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

Author

Vanessa Dubois, Céline Gheeraert, Wouter Vankrunkelsven, Julie Dubois‐Chevalier, Hélène Dehondt, Marie Bobowski‐Gerard, Manjula Vinod, Francesco Paolo Zummo, Fabian Güiza, Maheul Ploton, Emilie Dorchies, Laurent Pineau, Alexis Boulinguiez, Emmanuelle Vallez, Eloise Woitrain, Eric Baugé, Fanny Lalloyer, Christian Duhem, Nabil Rabhi, Ronald E van Kesteren, Cheng‐Ming Chiang, Steve Lancel, Hélène Duez, Jean‐Sébastien Annicotte, Réjane Paumelle, Ilse Vanhorebeek, Greet Van den Berghe, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute

Subjects
liver injury, NFIL3, PAR‐bZIP, sepsis, super‐enhancer, Biology (General), QH301-705.5, Medicine (General), R5-920
Abstract

Abstract Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver‐identity (LIVER‐ID) transcription factor (TF) network, initiated by rapid LIVER‐ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER‐ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co‐recruitment of LIVER‐ID TFs and decommissioning of BRD4 super‐enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER‐ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

Published
2020
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6. Glycogen Dynamics Drives Lipid Droplet Biogenesis during Brown Adipocyte Differentiation

Author

Alicia Mayeuf-Louchart, Steve Lancel, Yasmine Sebti, Benoit Pourcet, Anne Loyens, Stéphane Delhaye, Christian Duhem, Justine Beauchamp, Lise Ferri, Quentin Thorel, Alexis Boulinguiez, Mathilde Zecchin, Julie Dubois-Chevalier, Jérôme Eeckhoute, Logan T. Vaughn, Peter J. Roach, Christian Dani, Bartholomew A. Pederson, Stéphane D. Vincent, Bart Staels, and Hélène Duez

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Browning induction or transplantation of brown adipose tissue (BAT) or brown/beige adipocytes derived from progenitor or induced pluripotent stem cells (iPSCs) can represent a powerful strategy to treat metabolic diseases. However, our poor understanding of the mechanisms that govern the differentiation and activation of brown adipocytes limits the development of such therapy. Various genetic factors controlling the differentiation of brown adipocytes have been identified, although most studies have been performed using in vitro cultured pre-adipocytes. We investigate here the differentiation of brown adipocytes from adipose progenitors in the mouse embryo. We demonstrate that the formation of multiple lipid droplets (LDs) is initiated within clusters of glycogen, which is degraded through glycophagy to provide the metabolic substrates essential for de novo lipogenesis and LD formation. Therefore, this study uncovers the role of glycogen in the generation of LDs. : Lipid droplet formation is a major feature of brown adipocyte differentiation. Mayeuf-Louchart et al. characterize the different steps of brown adipocyte differentiation in the mouse embryo and report the essential role of glycogen production and degradation by glycophagy for lipid droplet biogenesis. Keywords: brown adipose tissue, adipocyte differentiation, lipid droplet biogenesis, lipid, glycogen, autophagy, glycophagy, embryonic development, adipocyte metabolism, BAT

Published
2019
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7. Les agrégats nucléaires dans la dystrophie musculaire oculopharyngée

Author

Alexis Boulinguiez, Fany Roth, Hadidja Rose Mouigni, Gillian Butler-Browne, Vincent Mouly, and Capucine Trollet

Subjects
General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

La dystrophie musculaire oculopharyngée est une des maladies en rapport avec des expansions pathologiques de triplets nucléotidiques. Sa physiopathologie est encore imparfaitement connue même si la présence d’agrégats au niveau des noyaux de la fibre musculaire semble jouer un rôle déterminant. Les travaux fondamentaux présentés ici permettent de mieux comprendre leur composition et leur rôle délétère. Autant d’éléments qui pourraient déboucher sur des voies thérapeutiques nouvelles.

Published
2022

8. The 2022 On-site Padua Days on Muscle and Mobility Medicine hosts the University of Florida Institute of Myology and the Wellstone Center, March 30 - April 3, 2022 at the University of Padua and Thermae of Euganean Hills, Padua, Italy: The collection of abstracts

Author

Alexis Boulinguiez, Ugo Carraro, and Capucine Trollet

Subjects
Orthopedics and Sports Medicine, Cell Biology, Neurology (clinical), Molecular Biology
Abstract

In the autumn of 2021, the 2022 Padua Days of Muscle and Mobility Medicine (PDM3) was planned to be held from March 30 to April 2, 2022. Despite the fact that Coronavirus COVID-19 outbreak continued to impose restrictions all over the world, the program was planned with Scientific Sessions to occur over three full days at either the University of Padua Aula Magna or the Hotel Petrarca on the Thermae of Euganean Hills (Padua), Italy. During the winter the epidemic worsened, but waned by early February 2022, allowing confirmation of the planned On-site Meeting. The success of submission of abstracts (over 100 abstracts, i. e., three times the previous years) is attributable to the fact that the 2022 On-site PDM3 is a combined meeting, hosting the spring Meeting of the Myology Institute and Wellstone Center of the University of Florida, USA. The first three days will include a large series of presentations of the University of Florida scientists and clinicians and of their Invited Speakers from Canada, France, Switzerland Italy and the U.K. European researchers and clinicians from France, Germany, Iceland, Ireland, Italy, Slovenia, Russia and UK fill the program of last two days. To provide slot times to young Speakers, the 2022 On-site PDM3 was extended to April 3, 2022. The Collection of Abstracts is e-published in the 32 (1) 2022 Issue of the European Journal of Translational Myology (EJTM), together with the detailed Program organized in the Aula Magna of the University of Padua (March 30) and for March 31 - April 3, 2022 at the Conference Halls of Hotel Petrarca of the Thermae of Euganean Hills (Padua), Italy. The Program ends late on Sunday April 3, 2022 with an invitation to join the 2023 PDM3, March 27 – 31 at the Thermae of Euganean Hills (Padua), Italy. You are invited to join and to submit your Communications to the European Journal of Translational Myology and to a Special Issue of the Journal diagnostics, MDPI, Basel. Both journals will provide 50% discount to the first 15 accepted typescripts.

Published
2022

9. Thirty years of translational research in Mobility Medicine: Collection of abstracts of the 2020 Padua Muscle Days

Author

Alexis Boulinguiez and Sudarshan Dayanidhi

Subjects
Gerontology, Imaging flow cytometry, Muscle ultrasound, Shear wave elastography, Rehabilitation, business.industry, medicine.medical_treatment, Translational research, 030229 sport sciences, Cell Biology, Functional recovery, 03 medical and health sciences, 0302 clinical medicine, Research centre, Myology, Medicine, Orthopedics and Sports Medicine, Neurology (clinical), business, Molecular Biology, 030217 neurology & neurosurgery
Abstract

More than half a century of skeletal muscle research is continuing at Padua University (Italy) under the auspices of the Interdepartmental Research Centre of Myology (CIR-Myo), the European Journal of Translational Myology (EJTM) and recently also with the support of the A&CM-C Foundation for Translational Myology, Padova, Italy. The Volume 30(1), 2020 of the EJTM opens with the collection of abstracts for the conference "2020 Padua Muscle Days: Mobility Medicine 30 years of Translational Research". This is an international conference that will be held between March 18-21, 2020 in Euganei Hills and Padova in Italy. The abstracts are excellent examples of translational research and of the multidimensional approaches that are needed to classify and manage (in both the acute and chronic phases) diseases of Mobility that span from neurologic, metabolic and traumatic syndromes to the biological process of aging. One of the typical aim of Physical Medicine and Rehabilitation is indeed to reduce pain and increase mobility enough to enable impaired persons to walk freely, garden, and drive again. The excellent contents of this Collection of Abstracts reflect the high scientific caliber of researchers and clinicians who are eager to present their results at the PaduaMuscleDays. A series of EJTM Communications will also add to this preliminary evidence.

Published
2020

10. Rev-erb-α controls skeletal muscle calcium homeostasis through myoregulin repression: implications in Duchenne Muscular Dystrophy

Author

Benoit Pourcet, Mathilde Zecchin, Kondratska K, Stéphane Delhaye, Piétri-Rouxel F, Montel, Alicia Mayeuf-Louchart, Bastide B, Lise Ferri, Alexis Boulinguiez, Quentin Thorel, Forand A, Hebras A, Natalia Prevarskaya, Christian Duhem, Yasmine Sebti, Steve Lancel, Bart Staels, Justine Beauchamp, Hélène Duez, Couvelaere M, Matías Giménez, and Christel Gentil

Subjects
Calcium metabolism, SERCA, Chemistry, Duchenne muscular dystrophy, chemistry.chemical_element, Skeletal muscle, Calcium, medicine.disease, Cell biology, medicine.anatomical_structure, Nuclear receptor, medicine, Myocyte, medicine.symptom, Myopathy
Abstract

The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions such as myopathies. Here, we investigated whether the nuclear receptor Rev-erb-α regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that Rev-erbα invalidation in mice impairs SERCA-dependent SR calcium uptake. Rev-erb-α acts on calcium homeostasis by repressing the SERCA inhibitor Myoregulin, through direct binding to its promoter. Restoration of Myoregulin counteracts the effects of REV-ERB-α overexpression on SR calcium content. Interestingly, myoblasts from Duchenne myopathy patients display downregulated REV-ERBα expression, whereas pharmacological Rev-erb activation ameliorates SR calcium homeostasis, and improves muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that Rev-erb-α regulates muscle SR calcium homeostasis, pointing to its therapeutic interest for mitigating myopathy.

Published
2021

11. Oculopharyngeal Muscular Dystrophy

Author

Capucine Trollet, Alexis Boulinguiez, Fanny Roth, Tanya Stojkovic, Butler-Browne, Gillian S., Teresinha Evangelista, Jean Lacau St Guily, Pascale Richard, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondation Ophtalmologique Adolphe de Rotschild, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
PABPN1, [SDV]Life Sciences [q-bio], OPMD, Triplet expansion disease
Abstract

International audience

Published
2020

12. Differential Unfolded Protein Response in skeletal muscle from non-diabetic glucose tolerant or intolerant patients with obesity before and after bariatric surgery

Author

François Pattou, Violeta Raverdy, Steve Lancel, Gregory Baud, Alexis Boulinguiez, Christian Duhem, Hélène Duez, Hélène Verkindt, Robert Caiazzo, Bart Staels, Camille Marciniak, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Chirurgie générale et endocrinienne [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), A.B. was supported by a PhD scholarship from Lille University-Région Hauts-de- France and by EGID funds. The authors acknowledge funding supports from INSERM, Contrat Plan Etat Région (CPER), Région Hauts-de-France/FEDER, CTRL-Lille Pasteur Institute, the European Genomic Institute for Diabetes (E.G.I.D., ANR-10-LABX-46), the European Foundation for the Study of Diabetes (EFSD), the Fondation Francophone pour la Recherche sur le Diabète (FFRD), sponsored by Fédération Française des Diabétiques (AFD), AstraZeneca, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk & Sanofi. BS is a recipient of an Advanced ERC Grant (694717)., European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Biopsy, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Skeletal muscle, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, CHOP, Cohort Studies, Unfolded protein response, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin resistance, Diabetes mellitus, Internal Medicine, medicine, Humans, Glucose homeostasis, Obesity, Muscle, Skeletal, Glucose intolerance, Bariatric surgery, biology, ATF6, business.industry, General Medicine, Glucose Tolerance Test, Endoplasmic Reticulum Stress, medicine.disease, Activating Transcription Factor 6, Obesity, Morbid, Surgery, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Gene Expression Regulation, Case-Control Studies, biology.protein, Female, Binding immunoglobulin protein, Insulin Resistance, business, Transcription Factor CHOP
Abstract

International audience; AIMS:Not all people with obesity become glucose intolerant, suggesting differential activation of cellular pathways. The unfolded protein response (UPR) may contribute to the development of insulin resistance in several organs, but its role in skeletal muscle remains debated. Therefore, we explored the UPR activation in muscle from non-diabetic glucose tolerant or intolerant patients with obesity and the impact of bariatric procedures.METHODS:Muscle biopsies from 22 normoglycemic (NG, blood glucose measured 120 min after an oral glucose tolerance test, G120

Published
2020

13. The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids

Author

Alexis Boulinguiez, Jean-Sébastien Annicotte, Laura Butruille, Anne Tailleux, Olivier Briand, Mohamed-Sami Trabelsi, Laure B. Bindels, Emilie Dorchies, Simon Peschard, Véronique Touche, Sandrine Caron, Emmanuelle Vallez, Sophie Lestavel, Sarah Ducastel, Steve Lancel, Oscar Chávez-Talavera, Nathalie M. Delzenne, Kadiombo Bantubungi, Bart Staels, Margaux Nawrot, UCL - SSS/LDRI - Louvain Drug Research Institute, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Metabolism and Nutrition Research Group [Bruxelles, Belgique], Louvain Drug Research Institute [Bruxelles, Belgique] (LDRI), Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), This work was supported by grants from 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46), European Commission and Agence Nationale pour la Recherche (ANR-FXREn). B.S. holds a 'European Research Council advanced Grant' (694717). A.B., M.N., O.C.T. and M.S.T. received a PhD fellowship from the French Ministry of Research., ANR-11-BSV1-0032,FXRen,Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique(2011), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Louvain Drug Research Institute [Bruxelles, Belgique], Université Catholique de Louvain (UCL)-Université Catholique de Louvain (UCL), Bodescot, Myriam, BLANC - Rôle du récepteur nucléaire Farnesoid X Receptor (FXR) dans l'homéostasie énergétique - - FXRen2011 - ANR-11-BSV1-0032 - BLANC - VALID, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Colon, medicine.drug_class, Receptors, Cytoplasmic and Nuclear, lcsh:Medicine, Incretin, 030209 endocrinology & metabolism, Enteroendocrine cell, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, 0302 clinical medicine, Nuclear receptors, Glucagon-Like Peptide 1, Internal medicine, medicine, Animals, Secretion, Gastrointestinal hormones, lcsh:Science, Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Mice, Knockout, Multidisciplinary, Bile acid, Chemistry, Microbiota, lcsh:R, digestive, oral, and skin physiology, Endocrine system and metabolic diseases, Nutrient signalling, Fatty Acids, Volatile, Glucagon-like peptide-1, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Nuclear receptor, Preclinical research, lcsh:Q, Farnesoid X receptor
Abstract

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

Published
2020

14. Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass

Author

Alicia Mayeuf-Louchart, Quentin Thorel, Stéphane Delhaye, Justine Beauchamp, Christian Duhem, Anne Danckaert, Steve Lancel, Benoit Pourcet, Estelle Woldt, Alexis Boulinguiez, Lise Ferri, Mathilde Zecchin, Bart Staels, Yasmine Sebti, and Hélène Duez

Subjects
Mice, Knockout, Transcriptional Activation, Adipogenesis, viruses, lcsh:R, lcsh:Medicine, Cell Differentiation, Article, body regions, Repressor Proteins, Mice, Muscular Atrophy, Liver, Muscular Diseases, Nuclear Receptor Subfamily 1, Group D, Member 1, Autophagy, Animals, lcsh:Q, lcsh:Science, skin and connective tissue diseases, Muscle, Skeletal
Abstract

The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and thermogenesis. We have previously demonstrated that Rev-erb-α is also an important regulator of skeletal muscle mitochondrial biogenesis and function, and autophagy. As such, Rev-erb-α over-expression in skeletal muscle or its pharmacological activation improved mitochondrial respiration and enhanced exercise capacity. Here, in gain- and loss-of function studies, we show that Rev-erb-α also controls muscle mass. Rev-erb-α-deficiency in skeletal muscle leads to increased expression of the atrophy-related genes (atrogenes), associated with reduced muscle mass and decreased fiber size. By contrast, in vivo and in vitro Rev-erb-α over-expression results in reduced atrogenes expression and increased fiber size. Finally, Rev-erb-α pharmacological activation blocks dexamethasone-induced upregulation of atrogenes and muscle atrophy. This study identifies Rev-erb-α as a promising pharmacological target to preserve muscle mass.

Published
2017

15. Mitochondria and endoplasmic reticulum: Targets for a better insulin sensitivity in skeletal muscle?

Author

Hélène Duez, Bart Staels, Alexis Boulinguiez, Steve Lancel, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), AB is supported by a PhD scholarship from Lille University-Région Nord Pas-de-Calais. The authors acknowledge funding supports from INSERM, Contrat Plan Etat Région (CPER), Région Nord Pas-de-Calais/FEDER, the European Genomic Institute for Diabetes (E.G.I.D., ANR-10-LABX-46) and the European Commission. Research Grant from the European Foundation for the Study of Diabetes (EFSD) (to HD), the Fondation Francophone pour la Recherche sur le Diabète (FFRD) (to HD), the European Commission (FP7) consortium Eurhythdia. BS is a member of the Institut Universitaire de France., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), European Project: 278397,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,EURHYTHDIA(2011), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Derudas, Marie-Hélène, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, and Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardiometabolic risk in the European working population - EURHYTHDIA - - EC:FP7:HEALTH2011-10-01 - 2017-06-30 - 278397 - VALID

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Adipose tissue, Skeletal muscle, Type 2 diabetes, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Insulin, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscle, Skeletal, Molecular Biology, biology, Cell Biology, Lipid, medicine.disease, Obesity, 3. Good health, Mitochondria, Insulin receptor, Glucose, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Lipotoxicity, biology.protein, Endoplasmic reticulum
Abstract

International audience; Obesity and its associated metabolic disorders represent a major health burden, with economic and social consequences. Although adapted lifestyle and bariatric surgery are effective in reducing body weight, obesity prevalence is still rising. Obese individuals often become insulin-resistant. Obesity impacts on insulin responsive organs, such as the liver, adipose tissue and skeletal muscle, and increases the risk of cardiovascular diseases, type 2 diabetes and cancer. In this review, we discuss the effects of obesity and insulin resistance on skeletal muscle, an important organ for the control of postprandial glucose. The roles of mitochondria and the endoplasmic reticulum in insulin signaling are highlighted and potential innovative research and treatment perspectives are proposed.

Published
2017

17. A452 Differential Unfolded Protein Response expression in skeletal muscle from patients with obesity with normal or impaired glucose tolerance before and after bariatric surgery

Author

François Pattou, Violeta Raverdy, Robert Caiazzo, Gregory Baud, Camille Marciniak, Christian Duhem, Steve Lancel, Hélène Verkindt, Hélène Duez, Bart Staels, and Alexis Boulinguiez

Subjects
Impaired glucose tolerance, medicine.medical_specialty, medicine.anatomical_structure, business.industry, Unfolded protein response, Medicine, Skeletal muscle, Surgery, business, medicine.disease, Obesity
Published
2019

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