Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

Nicol C Voermans,Coen AC Ottenheijm,Barbara H Janssen,Saskia Lassche,George W Padberg,Maria T Hopman,Ger JM Stienen,Silvère M van der Maarel,Henk-Jan Westeneng,Baziel GM van Engelen

doi:10.1186/1471-2377-13-144

Abstract

BackgroundAlthough muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD.Methods/DesignEvaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments.DiscussionThis study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.

Highlights

Muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown
The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention
FSHD1 (OMIM #158900), the most common type of FSHD, is an autosomal dominant disorder caused by a contraction of the D4Z4 repeat array, a macrosatellite repeat array consisting of 3.3 kb large D4Z4 units located on chromosome 4q

Summary

Introduction

Muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary myopathy, affecting 1:15,000-20,000 people [1]. FSHD derives its name from the characteristic early involvement of the muscles of the face, shoulder girdle and upper arm, which, in contrast to other muscular dystrophies, is often asymmetrical. Residual repeat length is roughly and inversely correlated to disease severity and onset. Patients having 1 – 3 repeats usually show infantile onset and rapid disease progression [7]. The repeat array contraction leads to a more open D4Z4 chromatin configuration, which is hypothesized to permit transcription of otherwise epigenetically silenced genes located on chromosome 4 [5,6]

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