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ANR funded project

Accueil de Chercheurs de Haut Niveau (ACHN) 2016
Projet MUSCLE - FORCES

In vivo quantification and manipulation of mechanical forces across muscle attachment sites and sarcomeric proteins during muscle morphogenesis

The contractile unit of all muscles is the sarcomere. Sarcomeres are arrayed into chains called myofibrils, which span the entire muscle fiber. Both muscle fiber ends are attached via tendon cells to the skeleton. Thus, coordinated contraction of the sarcomeres results in a defined body movement. We use the Drosophila flight muscles to investigate the molecular mechanisms of how myofibrils and sarcomeres are built such that they span the entire muscle in a highly regular pattern. We have shown previously by in vivo imaging that myofibrils are assembled simultaneously throughout the entire muscle fiber during muscle development. Thus, the earliest myofibrils already span the entire muscle and are anchored at the muscle attachment sites to tendon cells by integrin adhesion complexes. We have demonstrated that myofibrillogenesis is preceded by a significant build-up of mechanical tension across the myotendinous system leading us to hypothesize that tension acts as a molecular compass to coordinate and orient the assembly of the different sarcomeric protein complexes into regular myofibrils. Here, we propose to directly investigate, which proteins bear mechanical forces before and during myofibril assembly and to test if the mechanical properties of these proteins indeed impact myofibrillogenesis. We plan to construct a molecular tension sensor in the integrin adaptor protein Talin by inserting a FRET pair between the head and rod of Talin (Aim 1). This FRET pair is separated by a molecular spring, which is calibrated to open at defined forces ranging from 7 and 11 pN. Thus, molecular forces across Talin in wild type and mutants with defects in myofibrillogenesis will be directly investigated in vivo. We further propose to integrate a similar tension sensor into the gigantic sarcomeric protein Titin in order to investigate if a comparable force range is also present throughout every sarcomere during myofibrillogenesis (Aim 2). We believe that Titin is a good candidate for a mechano-sensitive protein, as it contains an intrinsic spring-like protein domain. Finally, we would like to test if the length of the spring domain in Titin, as well as its kinase domain, which is thought to be activated by mechanical strain, are critical for sarcomerogenesis and muscle function (Aim 3). Together, these experiments will mechanistically investigate the impact of mechanical forces on the assembly of the contractile structures common to all muscles, the myofibrils and sarcomeres. Thus, our work will have a general impact in muscle biology, including a better understanding of myopathies and cardiomyopathies.

Partners

CNRS DR12 _IBDM UMR7288 Centre National de la Recherche Scientifique délégation Provence et Corse - Institut de Biologie du Développement

ANR grant: 600 000 euros
Beginning and duration: février 2016 - 48 mois

 

ANR Programme: Accueil de Chercheurs de Haut Niveau (ACHN) 2016

Project ID: ANR-16-ACHN-0015

Project coordinator:
Monsieur Frank SCHNORRER (Centre National de la Recherche Scientifique délégation Provence et Corse - Institut de Biologie du Développement)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.