After erythropoietin (rHuEPO) therapy, patients with chronic renal failure (CRF) do not improve peak O2 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 O2 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 O2 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-1) 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. 31P-nuclear magnetic resonance spectra (31P-MRS) from the vastus medialis were obtained throughout the exercise protocol consisting of periods of 2 min exercise (at 1.67 Hz) at increasing work-loads 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 O2 delivery (QO2leg) and O2 uptake (VO2leg). 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 VO2leg, 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 pHi, at a given VO2leg, were below those observed in the control group. However, at a given pHi, no differences in 31P-MRS data were detected between post-rHuEPO and controls. After rHuEPO, at peak VO2, Qleg fell 20% (P < 0.04), limiting the change in QO2leg to 17%, a value that did not reach statistical significance. The corresponding O2 extraction ratio decreased from 73 +/- 4% to 68 +/- 8.2% (P < 0.03). These changes indicate that maximal O2 flow from microcirculation to mitochondria did not increase despite the 50% increase in [Hb] and explain how peak VO2leg and cellular bioenergetics (31P-MRS) did not change after rHuEPO. Differences in pHi, possibly due to lactate differences, between post-rHeEPO and controls appear to be a key factor in the abnormal muscle cell bioenergetics during exercise observed in CRF patients.
R M Marrades, J Alonso, J Roca, J M González de Suso, J M Campistol, J A Barberá, O Diaz, J V Torregrosa, J R Masclans, R Rodríguez-Roisin, P D Wagner
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JL Gamboa, B Roshanravan, T Towse, CA Keller, AM Falck, C Yu, WR Frontera, NJ Brown, TA Ikizler |
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HU Prommer, J Maurer, K Websky, C Freise, K Sommer, H Nasser, R Samapati, B Reglin, P Guimarães, AR Pries, U Querfeld |
Scientific Reports | 2018 |
Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants
Y Will, JA Dykens |
2018 | |
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GJ Kemp, RE Ahmad, K Nicolay, JJ Prompers |
Acta physiologica (Oxford, England) | 2014 |
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KP Strohl, JP Butler, A Malhotra |
Comprehensive Physiology | 2012 |
Mechanical properties of the upper airway
KP Strohl, JP Butler, A Malhotra |
Comprehensive Physiology | 2012 |
Mechanical properties of the upper airway
KP Strohl, JP Butler, A Malhotra |
Comprehensive Physiology | 2012 |
Decreased Hypoxia-Inducible Factor-1a in Gastrocnemius Muscle in Rats with Chronic Kidney Disease
M Flisinski, A Brymora, I Bartlomiejczyk, E Wisniewska, R Golda, A Stefanska, L Paczek, J Manitius |
Kidney and Blood Pressure Research | 2012 |
Clinical Assessment of Peripheral Muscle Function in Patients with Chronic Obstructive Pulmonary Disease
J Vilaro, R Rabinovich, JM Gonzalez-deSuso, T Troosters, D Rodríguez, JA Barberà, J Roca |
American Journal of Physical Medicine & Rehabilitation | 2009 |
Influence of Different Stages of Experimental Chronic Kidney Disease on Rats Locomotor and Postural Skeletal Muscles Microcirculation
M Flisiński, A Brymora, G Elminowska-Wenda, J Bogucka, K Walasik, A Stefańska, G Odrowąż;-Sypniewska, J Manitius |
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WJ Evans, CP Lambert |
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Pharmacotherapy of Cachexia
W Doehner |
Pharmacotherapy of Cachexia | 2005 |
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KL Johansen, J Doyle, GK Sakkas, JA Kent-Braun |
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology | 2005 |
Abnormal mitochondrial function and muscle wasting, but normal contractile efficiency, in haemodialysed patients studied non-invasively in vivo
GJ Kemp, AV Crowe, HK Anijeet, QY Gong, WE Bimson, SP Frostick, JM Bone, GM Bell, JN Roberts |
Nephrology Dialysis Transplantation | 2004 |
ATP synthesis and proton handling in muscle during short periods of exercise and subsequent recovery
D Bendahan, GJ Kemp, M Roussel, YL Fur, PJ Cozzone |
Journal of applied physiology | 2003 |
Uremic myopathy
JM Campistol |
Kidney International | 2002 |
Skeletal muscle mitochondrial function is preserved in young patients with chronic renal failure
Ò Miró, RM Marrades, J Roca, E Sala, F Masanés, JM Campistol, JV Torregrosa, J Casademont, PD Wagner, F Cardellach |
American Journal of Kidney Diseases | 2002 |
Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology
MR Nowrousian |
2002 | |
Intravenous l-carnitine increases plasma carnitine, reducesfatigue, and may preserve exercise capacity in hemodialysis patients
EP Brass, S Adler, KE Sietsema, WR Hiatt, AM Orlando, A Amato, CH Investigators |
American Journal of Kidney Diseases | 2001 |
Effects of Endurance Training on Skeletal Muscle Bioenergetics in Chronic Obstructive Pulmonary Disease
E Sala, J Roca, RM Marrades, J Alonso, JO de SUSO, A Moreno, JA Barberá, J Nadal, LL JOVER, R Rodriguez-Roisin, PD Wagner |
American journal of respiratory and critical care medicine | 1999 |
Physical benefits and challenges of exercise for people with chronic renal disease
SS Fitts |
Journal of Renal Nutrition | 1997 |