Abstract

After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O-2 uptake (VO2, peak) as much as expected from the rise in hemoglobin concentration ([Hb]). In a companion study, we explain this phenomenon by the concurrent effects of fall in muscle blood flow after rHuEPO and abnormal capillary O-2 conductance observed in CRF patients, The latter is likely associated with a poor muscle microcirculatory network and capillary-myofiber dissociation due to uremic myopathy. Herein, cellular bioenergetics and its relationships with muscle O-2 transport, before and after rHuEPO therapy, were. examined in eight CRF patients (27+/-7.3 [SD] yr) studied pre- and post-rHuEPO ([Hb] = 7.8+/-0.7 vs, 11.7+/-0.7 g x dl-l) during an incremental cycling exercise protocol. Eight healthy sedentary subjects (26+/-3.1 yr) served as controls, We hypothesize that uremic myopathy provokes a cytosolic dysfunction but mitochondrial oxidative capacity is not abnormal. P-31-nuclear magnetic resonance spectra (P-31-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing workloads interspersed by resting periods of 2.5 min. On a different day, after an identical exercise protocol, arterial and femoral venous blood gas data were obtained together with simultaneous measurements of femoral venous blood flow (Qleg) to calculate O-2 delivery (QO(2)leg) and O-2 uptake (VO(2)leg). Baseline resting [phosphocreatine] to [inorganic phosphate] ratio ([PCr]/[Pi]) did not change after rHuEPO (8.9+/-1.2 vs, 8.8+/-1.2, respectively), but it was significantly lower than in controls (10.9+/-1.5) (P = 0.01 each). At a given submaximal or peak VO,leg, no effects of rHuEPO were seen on cellular bioenergetics ([PCr]/[Pi] ratio, %[PCr] consumption, halftime of [PCr] recovery after exercise), nor in intracellular pH (pHi). The post-rHuEPO bioenergetic status and pi-Ii, at a given VO(2)leg, were below those observed in the control group. However, at a given pHi, no differences in P-31-MRS data were detected between post-rHuEPO and controls, After rHuEPO, at peak VO2, Qleg fell 20% (P 0.04), limiting the change in QO(2)leg to +17%, a value that did not reach statistical significance, The corresponding O-2 extraction ratio decreased from 73+/-4% to 68+/-8.2% (P 0.03). These changes indicate that maximal O-2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO(2)leg and cellular bioenergetics (P-31-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHuEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.