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wth Study and the ALSPAC cohort at age 11 y are provided. Acknowledgments The authors wish to thank all of the study members for their previous and continued involvement in the Newcastle Preterm Birth Growth Studies. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and Odanacatib supplier laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. Dr SM Korada is acknowledged for his contribution to clinical follow-up of the PTBGS cohort and Dr Catherine Potter for her helpful comments during preparation of the manuscript. ~~ Erythropoietin is the main regulator of erythropoiesis. The primary site for Epo production is the kidney, where it is produced in a hypoxia-dependent manner. However, small amounts are also produced in the liver and brain. Epo binds to a specific receptor, that belongs to the cytokine receptor superfamily and activates the JAK/STAT, PI3-kinase, NF-kB/ IKK, and/or the Ras/MAP kinase pathways. Through these pathways Epo exerts anti-apoptotic effects during the later stages of erythroid progenitor cell development in the bone marrow, by decreasing the rate of cell death and hence inducing these cells to proliferate and mature. Epo-Rs have been identified on a variety of different cell types including renal, endothelial, vascular smooth muscle, gastric mucosal, and Leydig cells, as well as cells of the placenta, certain cancer cells, cardiomyocytes, astrocytes, and neurons. The main biological function of Epo in these cells is to facilitate proliferation, angiogenesis, and cytoprotection. Furthermore, Epo-Rs are expressed in vitro on murine myoblasts and primary satellite cells, both of which exhibit a proliferative response to Epo stimulation. Recently, the Epo-R was also discovered on human skeletal muscle cells; however, the physiological role of Epo in this tissue remains uncertain. Several studies have investigated changes in mRNA levels of pertinent proteins and structural changes in muscle after Epo Receptor Expression in Skeletal Muscle recombinant human Epo administration with conflicting results. Thus, even though the Epo-R has been identified in human skeletal muscle tissue, its role remains incompletely understood. Investigations of the activation of the signalling cascades related to the Epo-R, could give insight into the physiological role of the Epo-R in skeletal muscle tissue. To our knowledge, no previous studies have analysed Epo induced intracellular signalling pathways in human skeletal muscle in vivo. We therefore investigated the activation of a variety of molecules involved in signalling from the Epo-R and gene transcripts in response to acute stimulation of the Epo-R by rHuEpo. Lyn is a non-receptor protein tyrosine kinase, which acts as a docking protein that is preassociated with the Epo-R and bind to the Epo-R and Jak2. Lyn mediates the phosphorylation of the Epo-R and activation of the signalling cascades STAT5, PI3-K and NF-kB. The main signalling PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22189254 pathways through which Epo signals are STAT5, MAPK, PI3-K/akt, and NF-kB/IKK, each of these pathways were investigated here. Epo-R signalling is reversibly inhibited by SOCS-3, wherefore its gene transcript was measured. Furthermore, IGF-I expression was measured to rule out any GH induced activation of the signalling cascades of interest. Moreover, we also identified chang

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