ATP regulates the differentiation of mammalian skeletal muscle by activation of a P2X5 receptor on satellite cells.
ATP is well known for its role as an intracellular energy source. However, there is increasing awareness of its role as an extracellular messenger molecule (Burnstock, 1997). Although evidence for the presence of receptors for extracellular ATP on skeletal myoblasts was first published in 1983 (Kolb and Wakelam), their physiological function has remained unclear. In this paper we used primary cultures of rat skeletal muscle satellite cells to investigate the role of purinergic signaling in muscle formation. Using immunocytochemistry, RT-PCR, and electrophysiology, we demonstrate that the ionotropic P2X5 receptor is present on satellite cells and that activation of a P2X receptor inhibits proliferation, stimulates expression of markers of muscle cell differentiation, including myogenin, p21, and myosin heavy chain, and increases the rate of myotube formation. Furthermore, we demonstrate that ATP application results in a significant and rapid increase in the phosphorylation of MAPKs, particularly p38, and that inhibition of p38 activity can prevent the effect of ATP on cell number. These results not only demonstrate the existence of a novel regulator of skeletal muscle differentiation, namely ATP, but also a new role for ionotropic P2X receptors in the control of cell fate.
Autonomic Neuroscience Institute, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, U.K.
Mina
M
Ryten
Philip M
PM
Dunn
Joseph T
JT
Neary
Geoffrey
G
Burnstock
D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D009119:Muscle Contraction / Q000502:physiology; D009124:Muscle Proteins / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058485:Receptors, Purinergic P2X5; D015398:Signal Transduction / Q000187:drug effects
D009124:Muscle Proteins; C546467:P2rx5 protein, rat; D018048:Receptors, Purinergic P2; D058485:Receptors, Purinergic P2X5; D000255:Adenosine Triphosphate