Excitability and calcium signaling in normal and diseased skeletal muscle
Our research is focused on the physiology and pathophysiology of skeletal muscle function. It aims at understanding how mechanisms involved in the control of skeletal muscle Ca2++ homeostasis and excitation-contraction (EC) coupling operate under normal and disease conditions. For this we use a combination of molecular biology, biochemistry, in vivo gene transfer and simultaneous electrophysiology and fluorescence detection on cultured cells and on single isolated differentiated muscle fibers.
From January 1, 2027, the team will be led by Binnaz Yalcin, in collaboration with Vincent Jacquemond, with the aim of identifying novel genes responsible for rare neurodevelopmental disorders and investigating the mechanisms by which these conditions affect both the central nervous system and skeletal muscle.
PROJECTS
Our research is focused on the physiology and pathophysiology of skeletal muscle function. It aims at understanding how specific mechanisms involved in the control of skeletal muscle Ca2+homeostasis and excitation-contraction (EC) coupling operate under normal and disease conditions. Muscle contraction is initiated when action potentials fired at the end-plate of the muscle cells propagate throughout the plasma membrane and trigger a conformational change of the CaV1.1 protein which gates open a Ca2+release channel (type 1 ryanodine receptor, RyR1) in the sarcoplasmic reticulum (SR) membrane. Ca2+then gets released from the SR into the cytosol and triggers contraction. Besides Ca2+release from the SR there is also Ca2+entry from the extracellular medium.
Our main current projects aim at:
1- Understanding basic mechanisms involved in the regulation of CaV1.1 and of RyR1 function.
2- Demonstrating how excitability and/or EC coupling are altered by specific disease mutations affecting the genes encoding CaV1.1, RyR1 and also other proteins involved in the function and/or maintenance of the EC coupling machinery.
The overall project stands on a set of methods and expertise that includes molecular biology and biochemistry, in vivo gene transfer and a state of the art combination of electrophysiology and fluorescence detection on single isolated differentiated muscle cells from mouse.
Our goal is to identify new functions for the cells located in the microenvironment of muscle cells beside their canonical properties (e.g., regulation of inflammation for macrophages, supply of oxygen and nutriments for vessel cells) and how muscle stem cells and myofibers are controlled by their closest environment in both normal and pathological contexts. The identification of new molecules or novel functions of already known pathways are the basis for expanding our current understanding about skeletal muscle homeostasis and its pathophysiology.
PROJECTS
Stem cells are important in the maintenance and repair of many tissues all along the life span. It is the case in skeletal muscle, which presents high plasticity and regenerative properties to keep constant physiological parameters (homeostasis). Normal skeletal muscle mobilizes tissue-associated endogenous stem cells, mainly satellite cells, to repair damaged myofibers. Indeed, muscle stem cells sustain regeneration that is crucial for muscle homeostasis, as well as the self-renewal mechanisms that maintain their pool constant.
A key issue we address is the tissue environment in which muscle stem cells are activated. Environment plays important roles in the behavior of muscle stem cells and myogenic cells, although the mechanisms are poorly unknown. Various cell types in the vicinity of stem cells communicate with each other to correctly drive regeneration. We explore the roles of immune cells (inflammation), endothelial and peri-endothelial cells (angiogenesis) and interstitial cells (fibrosis) on myogenic cell fate in normal healthy regenerating muscle and during muscular dystrophies. Indeed, myopathies are characterized by the alteration in the environment of muscle stem cells, such as the presence of chronic inflammation and fibrosis, which are detrimental for both tissue repair and cell therapies.