Faculté de médecine Faculté de médecine

Maud Frieden

Research

 

Skeletal muscle cells are very large cells (up to several tens of centimeters), multi-nucleated and unable to divide.

Following muscular lesions, such as those caused by intense physical exercise, the tissue is able to repair itself thanks to the presence of satellite cells, the muscle stem cells present in adults. These satellite cells are usually quiescent, but after an injury, they become activated and proliferate to form myoblasts. This phase is initiated by tissue inflammation following injury. When the inflammation decreases, the myoblasts stop proliferating and begin to differentiate into muscle cells and then fuse to form immature myotubes.

The mechanisms involved are numerous and include the generation of calcium signals and the activation of transcription factors. This results in the synthesis of muscle-specific proteins, contractile apparatus and ion channels involved in excitation-contraction coupling. At the same time, the very complex internal organization of mature myotubes takes place.

FRIEDEN_muscle_maturation_schemeENG.png

 

Our research group studies the mechanisms involved in the regeneration of human skeletal muscle, with two main research axes:

  • Highlight the specific role of proteins involved in calcium signaling during the differentiation stages: transformation of myoblasts into immature myotubes, then maturation of myotubes.
  •  Determine the mechanisms that allow the activation, but also the maintenance or the return to a quiescent state of muscle stem cells. These mechanisms are essential to maintain the necessary muscle homeostasis throughout life, the alteration of these mechanisms leading to the loss of muscle mass and being at the basis of various myopathies.

 

In vitro model of human myoblast culture

We study the mechanism of skeletal muscle differentiation and maturation using an in vitro model obtained from purified human muscle stem cells. One of our objectives is to improve and optimize this cell culture model in order to follow and study the formation of muscle cells on time scales of a few weeks.

 

In vitro study of myotubes and stem cells

Using this cellular model, we study how and in what order the different molecular mechanisms of muscle regeneration are activated. In particular, we study the role of different molecules involved in calcium signaling and in calcium fluxes between the cell membrane and the sarcoplasmic reticulum. These molecules include the calcium sensors of the sarcoplasmic reticulum (STIM1 and STIM2), as well as the ion channels present at the plasma membrane (ORAI and TRPC).

Our in vitro cell model also allows us to study the mechanisms of formation (self-renewal) and maintenance of muscle stem cells as well as their different activation mechanisms. We are particularly interested in studying the interactions between stem cells and myotubes during their maturation. These studies, based for example on the imaging of cells at different stages of their development, allow us to follow the maturation of myotubes, the activation of stem cells as well as the calcium fluxes.

 

 

In vivo study of the role of STIM1L

In parallel, we use a transgenic mouse model lacking an isoform of the STIM1 molecule (STIM1L) to understand at the entire muscle level the role of this protein in the formation of skeletal muscle and in the resistance to fatigue of the animal.