Molecular and cellular defects involved in muscular and cardiac diseases may contribute to the contractile dysfunction. For a given NMD, the cascade of events leading to reduced muscular performance remains at least partially unknown due to its complexity.

 

 

From in vitro motility assays (Coirault et al, 2002) and mathematical model (Coirault et al, 1997 ; Lecarpentier et al, 1998), we analyze the contractile performance of the contractile apparatus including the different steps of actomyosin interactions.
This allows us to determine the functional consequences and the kinetics of the different steps of the acto-myosin interactions in animal models such as the mdx mouse (Coirault et al, 1999 ; Coirault et al, 2002) and in a cardiac model linked to metabolic defects (Guellich et al, 2007). The contributive role of oxidative stress has been determined (Coirault et al. 2007).
In patients with arythmogenic right ventricular dysplasia, we identify also functional abnormalities of myosin and linked them to abnormal lipid metabolism within cardiomyocytes (Djouadi et al. 2009). Taken as a whole, our results underline the important role of oxidative stress in post-translational modifications of myosin. Current project and prospectives evaluate the effects of sepsis and mechanical ventilation in the diaphragm of aged rat.

 

 

In collaboration with Lucie Carrier’ team (Hambourg), we report the functional consequences of an homozygous myosin mutation in FHC (Keller et al. 2004) and demonstrate that cMyBP-C has important role in the power stroke step (Lecarpentier et al. 2008). As a consequence, mutations linked to FHC may favour energetic imbalance of cardiomyocytes, a finding consistent with the proposal that FHC involves a common pathophysiological mechanism (Crilley et al. 2003).

 

 

In collaboration with O Agbulut, (Paris), M Pucéat, (ISTEM, Evry), P Ménaché (HEGP, Paris), we show that myotubes expressing GFP exhibit impaired excitation-contraction coupling. These abnormalities are due to competitive inhibition between GFP and actin (Agbulut et al. 2007) and lead to muscular weakness (Agbulut et al. 2006). These results confirmed by others (Nishimura et al. 2006; Sekar et al. 2007), lead to propose the preferential utilization of GFP coupled to another cell protein, so as to control the expression, cell localization and potential toxicity  of the GFP protein (Agbulut et al. 2008).

 

 

Tridimensional culture (3D) of cardiomyocytes and engineering of cardiac tissue are promising issues for the therapy of cardiac diseases. We recently developed a cardiac contractile tissue based on a collagen matrix already approved in clinical use. Integrin receptors being non available in natural collagen matrice, we develop an original method allowing the covalent binding of the tripeptide Arg-Gly-Asp (RGD). This peptide is required for integrin activation. Our main results indicate that RGD binding to collagen scaffold improves the differentiation, the contractile performance, and survival of cardiomyocytes (Schussler et al. 2009). 

 

 

The current projects and perspectives evaluate the use of 3D cultures with control and mutated myoblastes. Engineering muscle tissue (EMT) are then used to investigate the pathophysiological mechanisms involved in muscular disease and to evaluate the effects of therapies.