Abstract

Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials.

Details

Title
Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches
Author
Mariot, Virginie 1 ; Joubert, Romain 2   VIAFID ORCID Logo  ; Hourdé, Christophe 3 ; Léonard Féasson 4 ; Hanna, Michael 5 ; Muntoni, Francesco 6 ; Maisonobe, Thierry 7 ; Servais, Laurent 8 ; Bogni, Caroline 9 ; Rozen Le Panse 10 ; Benvensite, Olivier 10 ; Stojkovic, Tanya 11 ; Machado, Pedro M 12   VIAFID ORCID Logo  ; Voit, Thomas 1 ; Buj-Bello, Ana 9 ; Dumonceaux, Julie 1 

1  NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK 
2  Genethon, INSERM U951, Univ Evry, Université Paris-Saclay, Evry, France; Unité Physiologie et Pathologie Moléculaires des Rétrovirus Endogènes et Infectieux, CNRS UMR 9196, Institut Gustave Roussy, Villejuif, France 
3  Inter-University Laboratory of Human Movement Biology (LIBM)–EA7424 Université Savoie Mont Blanc, Campus Scientifique Technolac, Le Bourget du Lac Cedex, France 
4  Laboratoire Interuniversitaire de Biologie de la Motricité–EA 7424, Univ Lyon, UJM-Saint-Etienne, Unité de Myologie, Centre Référent Maladies Neuromusculaires Rares Rhône-Alpes, CHU Saint-Etienne, Saint-Étienne, France 
5  Department of Molecular Neuroscience, MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK 
6  NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK 
7  Groupe Hospitalier Pitié-Salpêtrière Département de Neurophysiologie Clinique, Paris cedex 13, France 
8  I-Motion–Research Center for Pediatric Neuromuscular Diseases, Armand Trousseau Hospital, Paris, France; Pediatric Department, Centre Hospitalier Universitaire de Liège, Université de Liège, Liège, Belgium 
9  Genethon, INSERM U951, Univ Evry, Université Paris-Saclay, Evry, France 
10  Sorbonne Universités, UPMC Univ Paris 06, Centre de Recherche en Myologie, INSERM UMRS974, Institut de Myologie, Paris, France 
11  Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France 
12  Department of Molecular Neuroscience, MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, London, UK; Centre for Rheumatology, Division of Medicine, University College London, London, UK 
Pages
1-8
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01486-4
ProQuest document ID
1970628251
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.