Abstract
Initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are regulated by a tyrosine phosphorylation. Using human primary myoblast culture, we investigated a possible role of various receptor tyrosine kinases in the induction of the differentiation process. We found that Epidermal Growth Factor Receptor (EGFR) is a key regulator of myoblast differentiation. EGFR activity is down-regulated during early human myoblast differentiation, and this event is required for normal differentiation to take place. Furthermore, EGFR silencing in proliferation conditions was able to trigger the differentiation program. This occurs through an increase of Kir2.1 channel activity that, via a rise of store-operated Ca2+ entry, leads to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, Myocyte Enhancer Factor 2 (MEF2), Myosin Heavy Chain (MyHC)). Finally, blocking myoblast cell cycle in proliferation conditions using a cdk4 inhibitor greatly decreased myoblast proliferation but was not able, on its own, to promote myoblast differentiation. Taken together, these results show that EGFR down-regulation is an early event that is required for the induction of myoblast differentiation.
Highlights
Skeletal muscle regeneration is a complex process that relies on the presence of satellite cells, the muscle stem cells
We looked for a receptor tyrosine kinase (RTK) with a high activity in proliferating myoblasts and whose activity decreases within the first hours of differentiation
Our present work shows that epidermal growth factor receptor (EGFR) plays a major role during the onset of human myoblast differentiation
Summary
Skeletal muscle regeneration is a complex process that relies on the presence of satellite cells, the muscle stem cells. Located all along the muscular fibers, between the plasma membrane and the sarcolemma, these myogenic precursors are in a quiescent state. Upon activation, such as with a muscular injury, these cells proliferate as a pool of myoblasts that will first differentiate and fuse either together to form new fibers or with pre-existing fibers [1]. The myogenic differentiation is a well-coordinated multistep process starting with the drop of the membrane potential of myoblasts This hyperpolarization induces an increase in the driving force for calcium amplifying the influxes requested for the expression of myogenic transcription factors (TFs) [2,3,4]. Two families of TFs are involved in myogenesis: the muscle regulatory factors (MRFs consisting of MyoD, Myf, Myogenin and MRF4) and the MEF2s [2,5,6,7]
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