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1. 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, Steve Lancel, CHU Lille, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), 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), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Piétri-Rouxel, France, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), 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), ANR-16-IDEX-0004,ULNE,ULNE(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires [RNMCD - U1011], Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 [PHYCELL], Inovarion, and Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD)

Subjects
[SDV]Life Sciences [q-bio], Cell Biology, General Medicine, [SDV] Life Sciences [q-bio], Mice, Sarcoplasmic Reticulum, Nuclear Receptor Subfamily 1, Group D, Member 1, Mice, Inbred mdx, Muscle Biology, Animals, Homeostasis, Muscle, Calcium, Muscle, Skeletal
Abstract

International audience; 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

2. 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, Capucine Trollet, BRUNEL, Nadège, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
ECM, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adipogenesis, Endothelins, Muscle Fibers, Skeletal, Skeletal muscle, Pharyngeal muscle, Fibrosis, Endothelin, Feedback, TGFβ, Mice, Muscular Dystrophy, Oculopharyngeal, Transforming Growth Factor beta, FAPs, Physiology (medical), OPMD, Regeneration, Animals, Humans, Orthopedics and Sports Medicine, Muscle, Skeletal, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract

International audience; 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 < 0.01 and FibMOP +15.1%, P < 0.01). This effect is likely linked to the increased activation of the canonical TGFβ-SMAD pathway in FAPs from fibrotic muscles evidenced by pSMAD3 immunostaining (P < 0.05). In addition to the profibrogenic TGFβ pathway, we identified endothelin as a new actor implicated in the altered cross-talk between muscle cells and fibrotic FAPs, confirmed by an improvement of the fusion index in the presence of bosentan, an endothelin receptor antagonist (from 33.8 ± 10.9% to 52.9 ± 10.1%, P < 0.05).Conclusions: Our data demonstrate the key role of FAPs and their cross-talk with muscle cells through a paracrine signalling pathway in fibrosis of human skeletal muscle and identify endothelin as a new druggable target to counteract human muscle fibrosis

Published
2022

3. 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

4. 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

5. 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

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