Team 3 / Theme 4

Drapeau FrançaisIDENTIFICATION OF PHYSIOPATHOLOGY AND MOLECULAR MECANISMS IN FSHD

FSHD is a highly heterogeneous disease characterized by a broad set of defects, including skeletal muscle weakness, inflammation, wasting and fibrosis, increased fatigability, vascular and myocardial dysfunction and non-muscular symptoms. FSHD is an autosomal dominant disease caused by reduction in the copy number of D4Z4 repeats at chromosome 4q35. D4Z4 contraction is associated with epigenetic changes that affect the expression of genes within this region and allow the expression of genes with myopathic potential. Particularly, each D4Z4 array includes the double homeobox 4 (DUX4) gene that is activated in FSHD muscle cells. 

Increased DUX4 expression levels cause the deregulation of many genes involved in the oxidative stress response and myogenesis, leading particularly to muscle atrophy, differentiation defectsand activation of germline genes. The hypothesis that oxidative stress responses might be specifically altered in FSHD is supported by the deregulation of enzymes involved in oxidative stress and the consequent increased susceptibility to oxidative agents observed in primary FSHD myoblasts. Moreover, we recently reported that reduced physical performance in patients with FSHD is associated with important redox unbalance and oxidative stress in blood.

équipe 3 FSHD fig 2Hence, we hypothesized that insufficient intake of antioxidant vitamins and minerals may reduce the body capacity to regulate free radical insults, leading to a condition known as oxidative stress that could affect muscle function performance in patients with FSHD. We thus conducted a pilot randomized double-blind placebo-controlled trial to test whether oral administration of vitamins and minerals could improve the physical performance of patients with FSHD. The results of this pilot clinical trial show that vitamins and minerals may improve skeletal muscle function in patients with FSHD.

Fig. 1 : Turki A et al., Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction. Free Radic Biol Med. 2012 Sep 1;53(5):1068-79.

équipe 3 FSHD fig 1They also suggest that an anti-oxidant strategy adapted to the FSHD-specific “oxidative stress” may be a relevant therapeutic approach for these patients.

Fig. 2 : Passerieux E et al., Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: A double-blind randomized controlled clinical trial. Free Radic Biol Med. 2014.

 

Our project focuses on three essential objectives:

1/ To investigate the long-term effects of this antioxidant supplementation and optimize the dosage of these vitamins and minerals to achieve the maximal benefit.

2/ To investigate the feasibility, safety, and effectiveness of NMES strength training to counteract quadriceps muscle weakness in patients affected by FSHD. One of the major problems of patients affected by FSHD is the limitation in performing daily activities induced by the progressive muscle weakness. This sedentary lifestyle can cause a “debilitative cycle,” and neuromuscular deconditioning can even aggravate the muscular deficiencies. Recent studies have indicated the safety and the effectiveness of moderate aerobic training programs in patients with FSHD. However, these training programs have limited applicability in patients with more severe muscular weakness. Artificial strength training by means of neuromuscular electrical stimulation (NMES) appears to be a promising rehabilitation strategy for FSHD patients suffering from neuromuscular disorders. Our objectives are to improve rehabilitation procedures for patients affected by FSHD, in an attempt to increase comfort, mobility, and help with activities of daily living.

In addition, in the past few years we developed and optimised an in vitro cell model of FSHD myogenesis. In a previous study, we analysed the vulnerability to oxidative stress, differentiation capacity and morphological abnormalities of muscle precursor cells from muscles of patients with FSHD. We showed that satellite cell-derived myoblasts from both clinically unaffected and affected muscles of patients with FSHD are more susceptible to oxidative stress than control myoblasts. Moreover, although myoblasts from patients with FSHD fully differentiated into multinucleated myotubes, they fused to form thin and branched myotubes with aligned nuclei.

culture comparative de cellule musculaires saines et pathologiques3/ hence, our objective is to identify key genes and mechanisms involved in FSHD oxidative stress and investigate whether natural antioxidant compounds administration might change the oxidative stress response in FSHD.

 

 

 

Fig 3 : Barro M. et al. Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects. J Cell Mol Med. 2010 Jan;14(1-2):275-89.    

  • In collaboration with A. Belayew and F. Coppée (Belgium) and Y. Vassetzki (France), we have already contributed to several studies conducted on FSHD muscle biopsies and primary cell cultures. Other scientific collaborations are developed, with J. Pincemail (Belgium), N. Maffiuletti (Switzerland), M.C. Dabauvalle (Germany) and T. Verrips (The Netherlands). Our project should generate new insights into our knowledge of the molecular and cellular mechanisms involved in FSHD and may identify new areas of injury related to oxidative stress and FSHD. The selection and evaluation of polyphenols, acting on identified targets represent an interesting option for therapeutic research. Our research is developed in partnership with patients’ associations (Amis FSH Europe, Stichting FSHD).

Collaborations :

  • A. et F. Coppée Belayew (Belgique)
  • Y. Vassetzki (France),
  • NN Maffiuletti (Suisse)
  • MC Dabauvalle (Allemagne)
  • T. Verrips (Pays-Bas)
  • Amis FSH Europe et la Fondation hollandaise FSHD
  • Pr Florence Portet (PH), (Département : psychiatrie adulte Exploration métabolique, CHU Montpellier)

Financial supports :

  • Stichting FSHD (The Netherlands),
  • Amis FSH Europe (France),
  • Montpellier University Hospital (AOI)

Major publications :

 Coordinator :

Laoudj-Chenivesse Dalila

Participants :

arbogast-sandrine

Hugon Gérald

Mercier Jacques

Fedou Christine

Raynaud de Mauverger éric

Brun Jean-Frédéric

Ayoub Bronia

Bommart Sébastien

Dias Wilson Vinicius