The role and regulation of erythropoietin (EPO) and its receptor in skeletal muscle: how much do we really know?

Abstract

Erythropoietin (EPO) primarily activates erythroid cell proliferation and growth and is active in several types of non-hematopoietic cells via its interaction with the EPO-receptor (EPO-R). This review focuses on the role of EPO in skeletal muscle. The EPO-R is expressed in skeletal muscle cells and EPO may promote myoblast differentiation and survival via the activation of the same signaling cascades as in hematopoietic cells, such as STAT5, MAPK and Akt. Inconsistent results exist with respect to the detection of the EPO-R mRNA and protein in muscle cells, tissue and across species and the use of non-specific EPO-R antibodies contributes to this problem. Additionally, the inability to reproducibly detect an activation of the known EPO-induced signaling pathways in skeletal muscle questions the functionality of the EPO-R in muscle in vivo. These equivocal findings make it difficult to distinguish between a direct effect of EPO on skeletal muscle, via the activation of its receptor, and an indirect effect resulting from a better oxygen supply to the muscle. Consequently, the precise role of EPO in skeletal muscle and its regulatory mechanism/s remain to be elucidated. Further studies are required to comprehensively establish the importance of EPO and its function in skeletal muscle health.

Prolonged erythropoietin treatment does not impact gene expression in human skeletal muscle

“…These findings on gene expression and Epo‐R protein presence support our previous finding of no activation of the signaling pathways downstream of Epo‐R in healthy humans after acute treatment with high‐dose rHuEpo . The results support the lack of a direct effect of Epo on human skeletal muscle fibers mediated through Epo‐R . Other potential factors and indirect effects of prolonged ESA treatment could also have affected gene expression, but this was not the case.…”

“…9–12 Furthermore, Epo effects previously observed in animal models cannot be replicated in humans. The sensitivity and specificity of the antibodies used to identify Epo‐R in skeletal muscle have been questioned extensively, 13–15 and caution should be taken when evaluating Epo‐R protein based on these antibodies . It has been reported that some of the commercially available antibodies cross react with heat shock protein 70 (Hsp70) or other proteins, thus possibly inducing a false positive signal.…”

IL23R (Interleukin 23 Receptor) Variants Protective against Inflammatory Bowel Diseases (IBD) Display Loss of Function due to Impaired Protein Stability and Intracellular Trafficking

“…Binding of Epo was shown to induce a scissor-like conformational change at the interface of the EpoR dimer that bring together JAK2 kinases associated with the EpoR cytosolic domains to allow for cross-phosphorylation and activation (Fig. 1A) (36,37). IL23R is composed of IL23R␣ and IL12R␤1.…”

Effect of Exercise on Oxidative Stress in Neurological Disorders

“…In muscle cells, BDNF not only increases phosphorylation of AMP kinase (AMPK) and Acetyl CoA Carboxylase (ACC), but enhances oxidation of fat both in vitro and ex vivo. In contrast, results on the involvement of erythropoietin have been inconsistent and inconclusive (Lamon and Russell 2013). AMPK is a key factor involved in modulation of exercise-mediated increase in fast-to-slow transition, a process that increases the proportion of oxidative fibers in the muscles (Narkar et al 2008).…”