Abstract
Erythropoietin (Epo) treatment has been shown to induce mitochondrial biogenesis in cardiac muscle along with enhanced mitochondrial capacity in mice. We hypothesized that recombinant human Epo (rhEpo) treatment enhances skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity in humans. In six healthy volunteers rhEpo was administered by sub-cutaneous injection over 8 weeks with oral iron (100 mg) supplementation taken daily. Mitochondrial OXPHOS was quantified by high-resolution respirometry in saponin-permeabilized muscle fibers obtained from biopsies of the vastus lateralis before and after rhEpo treatment. OXPHOS was determined with the mitochondrial complex I substrates malate, glutamate, pyruvate, and complex II substrate succinate in the presence of saturating ADP concentrations, while maximal electron transport capacity (ETS) was assessed by addition of an uncoupler. rhEpo treatment increased OXPHOS (from 92 ± 5 to 113 ± 7 pmol·s−1·mg−1) and ETS (107 ± 4 to 143 ± 14 pmol·s−1·mg−1, p < 0.05), demonstrating that Epo treatment induces an upregulation of OXPHOS and ETS in human skeletal muscle.
Highlights
Erythropoiesis is regulated through activation of the erythropoietin (Epo) receptor (Epo-R) present on erythroid progenitor cells stimulating growth and differentiation of the red blood cell precursors (Jelkmann, 1992)
The main finding in this study is that recombinant human Epo (rhEpo) treatment in humans increased skeletal muscle mitochondrial respiratory capacity
oxidative phosphorylation capacity (OXPHOS) capacity with substrates providing electrons to complex I and II of the electron transport chain was elevated by 22% with rhEPO treatment (Figure 2)
Summary
Erythropoiesis is regulated through activation of the erythropoietin (Epo) receptor (Epo-R) present on erythroid progenitor cells stimulating growth and differentiation of the red blood cell precursors (Jelkmann, 1992). The functionality of the Epo-R in mediating the effect of Epo in non-hematopoietic cells is currently debated (Sinclair et al, 2010), Epo treatment in the mouse has been found to induce mitochondrial biogenesis in cardiac and skeletal muscle accompanied by an increase in state 3 mitochondrial respiratory capacity (Carraway et al, 2010) Consistent with this pattern, mice electrotransfected with Epo gain less body fat when on a high fat diet as compared to matched control mice (Hojman et al, 2009), and there is some evidence for a shift in skeletal muscle fiber type in mice with Epo treatment (Cayla et al, 2008). The purpose of the present study was to test the hypothesis that rhEpo treatment leads to enhanced skeletal muscle mitochondrial oxidative phosphorylation capacity (OXPHOS) in humans
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