Erythropoietin Treatment Enhances Muscle Mitochondrial Capacity in Humans

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.

Effect of Exercise Training on Red Blood Cell Distribution Width as a Marker of Impaired Exercise Tolerance in Patients With Coronary Artery Disease

“…A previous study demonstrated that exogenous erythropoietin treatment resulted in an increase of hemoglobin concentration leading to increased oxygen delivery and improved exercise capacity. [12][13][14][15] These results seem at first sight to be opposite to our results. However, we assessed that exercise training decreased RDW leading to increase oxygen binding with hemoglobin and oxygen delivery, and improved exercise capacity.…”

Effects of an 8-weeks erythropoietin treatment on mitochondrial and whole body fat oxidation capacity during exercise in healthy males

“…Participants also performed another graded cycling exercise test (test 2) until exhaustion to confirm the VO 2max values from test 1. The detailed description of test 2 has been reported in Plenge et al 2012. No differences were observed between VO 2max values measured by either test 1 or 2.…”

“…Results describing basic haematological changes are shown in Table I, whereas maximal mitochondrial respiratory capacity and haematocrit changes after EPO administration to these participants have already been published (Plenge et al, 2012). Participants were asked to maintain their daily physical activity level as usual throughout the entire study.…”

“…The treatment aimed to increase the haematocrit to approximately 50% and to maintain that value throughout the study period, and the procedures followed have been described previously in full detail (Plenge et al, 2012). Briefly, participants were given one daily subcutaneous rhEPO (NeoRecormon, Roche, Schweiz) injection for 1 week (5000 IU) and followed by titrating the recombinant erythropoietin dosage depending on their haematocrit level (giving either 0, 2500, or 5000 IU) once per week for 7 weeks.…”

Mitochondrial Quality Control as a Therapeutic Target

“…Furthermore, recombinant protein increases OXPHOS in human skeletal muscle (Plenge et al, 2012). The enhancement and recovery of cellular functions through stimulation of hemoglobin production and mitochondrial activity in nonhematopoietic cells by EPO-like drugs might be a testable therapeutic strategy for certain ischemic or mitochondrial diseases in carefully selected patient populations, although the procoagulant effects of EPO administration have raised a legitimate caution.…”