Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches

Virginie Mariot, Romain Joubert, Christophe Hourdé, Léonard Féasson, Michael Hanna, Francesco Muntoni, Thierry Maisonobe, Laurent Servais, Caroline Bogni, Rozen Panse, Olivier Benvensite, Tanya Stojkovic, Pedro M. Machado, Thomas Voit, Ana Buj-Bello and Julie Dumonceaux ()
Additional contact information
Virginie Mariot: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust
Romain Joubert: Univ Evry, Université Paris-Saclay
Christophe Hourdé: Campus Scientifique Technolac
Léonard Féasson: CHU Saint-Etienne
Michael Hanna: University College London
Francesco Muntoni: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust
Thierry Maisonobe: Groupe Hospitalier Pitié-Salpêtrière Département de Neurophysiologie Clinique
Laurent Servais: Armand Trousseau Hospital
Caroline Bogni: Univ Evry, Université Paris-Saclay
Rozen Panse: Institut de Myologie
Olivier Benvensite: Institut de Myologie
Tanya Stojkovic: Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris
Pedro M. Machado: University College London
Thomas Voit: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust
Ana Buj-Bello: Univ Evry, Université Paris-Saclay
Julie Dumonceaux: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01486-4

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