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

Séverine Lamon,Aaron P Russell

doi:10.3389/fphys.2013.00176

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.

Highlights

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)
The EPO-R protein was detected in total muscle extracts from muscle biopsies (Rundqvist et al, 2009; Christensen et al, 2012a). These results strongly suggest that the EPO-R mRNA is present in muscle tissue, differences may exist between species and cell lines
It has been suggested that EPO could have a positive effect on skeletal muscle regeneration, growth, oxidative capacity and angiogenesis

Summary

Lamon and Russell

EPO and skeletal muscle transcription of its target genes (Damen et al, 1995; Pallard et al, 1995; Penta and Sawyer, 1995; Klingmuller et al, 1996; Quelle et al, 1996). EXPRESSION OF THE EPO-R AND ITS ROLE IN INTRACELLULAR SIGNALING Ogilvie and colleagues first reported that the EPO-R gene and protein were expressed in primary satellite cells isolated from mouse skeletal muscle and in cultured C2C12 myoblasts. EPO-R mRNA expression was not detected in the skeletal muscle of adult transgenic mice expressing the human EPO-R gene (Liu et al, 1994, 1997), it was not detected in any other non-hematopoietic tissue either. The EPO-R protein was detected in total muscle extracts from muscle biopsies (Rundqvist et al, 2009; Christensen et al, 2012a) These results strongly suggest that the EPO-R mRNA is present in muscle tissue, differences may exist between species and cell lines. These positive and negative controls should be species specific for human and murine EPO-R proteins and include information relating to protein sequencing of the detected EPO-R protein bands

EFFECTS OF EPO IN SKELETAL MUSCLE

Human Muscle

CONCLUSION