human muscle; SOCE; EGFR; myoblast differentiation; myogenic transcription factors; calcium; membrane potential; ionic channels; TRPC
Saüc Sophie, Bulla Monica, Nunes Paula, Orci Lelio, Marchetti Anna, Antigny Fabrice, Bernheim Laurent, Cosson Pierre, Frieden Maud, Demaurex Nicolas (2015), STIM1L traps and gates Orai1 channels without remodeling the cortical ER., in Journal of cell science
, 128(8), 1568-79.
Antigny Fabrice, Koenig Stéphane, Bernheim Laurent, Frieden Maud (2014), During post-natal human myogenesis, normal myotube size requires TRPC1- and TRPC4-mediated Ca²⁺ entry., in Journal of cell science
, 126(Pt 11), 2525-33.
Antigny Fabrice, Konig Stéphane, Bernheim Laurent, Frieden Maud (2014), Inositol 1,4,5 trisphosphate receptor 1 is a key player of human myoblast differentiation., in Cell calcium
, 56(6), 513-21.
Leroy Marina C, Perroud Julie, Darbellay Basile, Bernheim Laurent, Konig Stephane (2013), Epidermal growth factor receptor down-regulation triggers human myoblast differentiation., in PloS one
, 8(8), 71770-71770.
Myoblast proliferation and differentiation into myofibers is a crucial event occurring during both embryogenesis and post-natal muscle growth and regeneration. The aim of our laboratory is to decipher the cellular and molecular mechanisms that control the transition from proliferation to differentiation of human primary myoblasts. In our previous work, we showed that activation of Ca2+-dependent signaling molecules, calcineurin and CaMK, lead to the induction of myogenin and MEF2 transcription factors, both required for the initiation of myogenesis. More recently, we identified two early events that allow the initiation of myoblast differentiation: (i) activation of Store-Operated Ca2+ Entry (SOCE) due to STIM activation and opening of Orai channels, and (ii) down-regulation of Epidermal Growth Factor Receptor (EGFR). This down-regulation is required for myoblast differentiation as it induces Kir2.1 channel activation that is responsible for a membrane hyperpolarization, which in turn enhances Ca2+ entry. We propose that these two events result in the generation of two Ca2+ signals. The aim of the present proposal is to characterize these two Ca2+ signals and to elucidate their role in the activation of downstream pathways. Specifically we will study:1. The molecular mechanisms that induce the expression of myogenin and MEF2 transcription factors. We will focus on the role of Ca2+-dependent pathways (calcineurin and CaMK) in the induction of these factors.2. The role of STIM/Orai and other Ca2+ entry channels (TRPC, transient receptor potential canonical) in the activation of calcineurin and CaMK. We intend to study whether the different routes of Ca2+ entry are associated with specific downstream signaling events. In addition, the role of TRPC channels in later events (fusion) will be investigated.3. The regulation of EGFR and its implication in Kir2.1 activation. We shall study the processes leading to EGFR degradation in differentiating myoblasts, and the putative Ca2+-dependence of EGFR and Kir2.1 regulation.These three projects will improve our understanding of human myoblast differentiation. In addition, our work should bring new highlights regarding the role of Ca2+ signals and ionic channels on cellular differentiation.