Impaired glycogen breakdown and synthesis in phosphoglucomutase 1 deficiency.

OBJECTIVE: We investigated metabolism and physiological responses to exercise in an 18-year-old woman with multiple congenital abnormalities and exertional muscle fatigue, tightness, and rhabdomyolysis. METHODS: We studied biochemistry in muscle and fibroblasts, performed mutation analysis, assessed physiological responses to forearm and cycle-ergometer exercise combined with stable-isotope techniques and indirect calorimetry, and evaluated the effect of IV glucose infusion and oral sucrose ingestion on the exercise response. RESULTS: Phosphoglucomutase type 1 (PGM1) activity in muscle and fibroblasts was severely deficient and PGM1 in muscle was undetectable by Western blot. The patient was compound heterozygous for missense (R422W) and nonsense (Q530X) mutations in PGM1. Forearm exercise elicited no increase in lactate, but an exaggerated increase in ammonia, and provoked a forearm contracture. Comparable to patients with McArdle disease, the patient developed a 'second wind' with a spontaneous fall in exercise heart rate and perceived exertion. Like in McArdle disease, this was attributable to an increase in muscle oxidative capacity. Carbohydrate oxidation was blocked during exercise, and the patient had exaggerated oxidation of fat to fuel exercise. Exercise heart rate and perceived exertion were lower after IV glucose and oral sucrose. Muscle glycogen level was low normal. CONCLUSIONS: The second wind phenomenon has been considered to be pathognomonic for McArdle disease, but we demonstrate that it can also be present in PGM1 deficiency. We show that severe loss of PGM1 activity causes blocked muscle glycogenolysis that mimics McArdle disease, but may also limit glycogen synthesis, which broadens the phenotypic spectrum of this disorder.

Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms.

Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low Vo(2peak) (28 ± 9% of predicted) and exaggerated systemic O(2) delivery relative to O(2) utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/VO(2peak), (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and Ve/VCO(2peak)(,) (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in ΔVE/ΔVCO(2) (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa(CO(2)) and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated VE/VO(2), VE/VCO(2), and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation.

Moderate altitude but not additional endurance training increases markers of oxidative stress in exhaled breath condensate.

Oxidative stress occurs at altitude, and physical exertion might enhance this stress. In the present study, we investigated the combined effects of exercise and moderate altitude on redox balance in ten endurance exercising biathletes, and five sedentary volunteers during a 6-week-stay at 2,800 m. As a marker for oxidative stress, hydrogen peroxide (H(2)O(2)) was analyzed by the biosensor measuring system Ecocheck, and 8-iso prostaglandin F2alpha (8-iso PGF2alpha) was determined by enzyme immunoassay in exhaled breath condensate (EBC). To determine the whole blood antioxidative capacity, we measured reduced glutathione (GSH) enzymatically using Ellman's reagent. Exercising athletes and sedentary volunteers showed increased levels of oxidative markers at moderate altitude, contrary to our expectations; there was no difference between both groups. Therefore, all subjects' data were pooled to examine the oxidative stress response exclusively due to altitude exposure. H(2)O(2) levels increased at altitude and remained elevated for 3 days after returning to sea level (p < or = 0.05). On the other hand, 8-iso PGF2alpha levels showed a tendency to increase at altitude, but declined immediately after returning to sea level (p < or = 0.001). Hypoxic exposure during the first day at altitude resulted in elevated GSH levels (p < or = 0.05), that decreased during prolonged sojourn at altitude (p < or = 0.001). In conclusion, a stay at moderate altitude for up to 6 weeks increases markers of oxidative stress in EBC independent of additional endurance training. Notably, this oxidative stress is still detectable 3 days upon return to sea level.

Long-term intermittent hypoxia increases O2-transport capacity but not VO2max.

Long-term intermittent hypoxia, characterized by several days or weeks at altitude with periodic stays at sea level, is a frequently occurring pattern of life in mountainous countries demanding a good state of physical performance. The aim of the study was to determine the effects of a typical South American type of long-term intermittent hypoxia on VO2max at altitude and at sea level. We therefore compared an intermittently exposed group of soldiers (IH) who regularly (6 months) performed hypoxic-normoxic cycles of 11 days at 3550 m and 3 days at sea level with a group of soldiers from sea level (SL, control group) at 0 m and in acute hypoxia at 3550 m. VO2max was determined in both groups 1 day after arrival at altitude and at sea level. At altitude, the decrease in VO2max was less pronounced in IH (10.6 +/- 4.2%) than in SL (14.1 +/- 4.7%). However, no significant differences in VO2max were found between the groups either at sea level or at altitude, although arterial oxygen content (Ca(O(2) )) at maximum exercise was elevated (p < 0.001) in IH compared to SL by 11.7% at sea level and by 8.9% at altitude. This higher Ca(O(2) ) mainly resulted from augmented hemoglobin mass (IH: 836 +/- 103 g, SL: 751 +/- 72 g, p < 0.05) and at altitude also from increased arterial O(2)-saturation. In conclusion, acclimatization to long-term intermittent hypoxia substantially increases Ca(O(2) ), but has no beneficial effects on physical performance either at altitude or at sea level.

Lactate and Energy Metabolism During Exercise in Patients With Blocked Glycogenolysis (McArdle Disease).

CONTEXT: Patients with blocked muscle glycogen breakdown (McArdle disease) have severely reduced exercise capacity compared to healthy individuals and are not assumed to produce lactate during exercise. OBJECTIVES: The objectives were: 1) to quantify systemic and muscle lactate kinetics and oxidation rates and muscle energy utilization during exercise in patients with McArdle disease; and 2) to elucidate the role of lactate formation in muscle energy production. DESIGN AND SETTING: This was a single trial in a hospital. PARTICIPANTS: Participants were four patients with McArdle disease and seven healthy subjects. INTERVENTION: Patients and healthy controls were studied at rest, which was followed by 40 minutes of cycle-ergometer exercise at 60% of the patients' maximal oxygen uptake (∼35 W). MAIN OUTCOME MEASURES: Main outcome measures were systemic and leg skeletal muscle lactate, alanine, fatty acid, and glucose kinetics. RESULTS: McArdle patients had a marked decrease in plasma lactate concentration at the onset of exercise, and the concentration remained suppressed during exercise. A substantial leg net lactate uptake and subsequent oxidation occurred over the entire exercise period in patients, in contrast to a net lactate release or no exchange in the healthy controls. Despite a net lactate uptake by the active leg, a simultaneous unidirectional lactate release was observed in McArdle patients at rates that were similar to the healthy controls. CONCLUSION: Lactate is an important energy source for contracting skeletal muscle in patients with myophosphorylase deficiency. Although McArdle patients had leg net lactate consumption, a simultaneous release of lactate was observed at rates similar to that found in healthy individuals exercising at the same very low workload, suggesting that lactate formation is mandatory for muscle energy generation during exercise.

Blood volume and hemoglobin mass in endurance athletes from moderate altitude.

PURPOSE: To determine whether total hemoglobin (tHb) mass and total blood volume (BV) are influenced by training, by chronic altitude exposure, and possibly by the combination of both conditions. METHODS: Four groups (N = 12, each) either from locations at sea level or at moderate altitude (2600 m) were investigated: 1) sea-level control group (UT-0 m), 2) altitude control group (UT-2600 m), 3) professional cyclists from sea level (C-0 m), and 4) professional cyclists from altitude (C-2600 m). All subjects from altitude were born at about 2600 m and lived all their lives (except during competitions at lower levels) at this altitude. tHb and BV were determined by the CO-rebreathing method. RESULTS: VO2max (mL x kg(-1) x min(-1)) was significantly higher in UT-0 m (45.3 +/- 3.2) than in UT-2600 m (39.6 +/- 4.0) but did not differ between C-0 m (68.2 +/- 2.7) and C-2600 m (69.9 +/- 4.4). tHb (g x kg(-1)) was affected by training (UT-0 m: 11.0 +/- 1.1, C-0 m: 15.4 +/- 1.3) and by altitude (UT-2600 m: 13.4 +/- 0.9) and showed both effects in C-2600 m (17.1 +/- 1.4). Because red cell volume showed a behavior similar to tHb and because plasma volume was not affected by altitude but by training, BV (mL x kg(-1)) was increased in C-0 m (UT-0 m: 78.3 +/- 7.9; C-0 m: 107.0 +/- 6.2) and in UT-2600 m (88.2 +/- 4.8), showing highest values in the C-2600 m group (116.5 +/- 11.4). CONCLUSION: In endurance athletes who are native to moderate altitude, tHb and BV were synergistically influenced by training and by altitude exposure, which is probably one important reason for their high performance.

Non-erythroid functions of erythropoietin.

The oxygen-dependent, renal cytokine eythropoietin (Epo) is well known to increase red cell production. Binding of Epo to the Epo receptor (EpoR) represses apoptosis of erythroid progenitor cells, thereby allowing their final maturation. We and others showed that Epo and its receptor are expressed in many other tissues, including brain, spinal cord, retina and testis. The presence of a blood barrier suggests that Epo plays a local role in these organs. Indeed, therapeutically applied or hypoxically induced Epo has been shown to reduce the infarct volume in various stroke animal models, to prevent retinal degeneration, and to ameliorate spinal cord injury. In a study conducted by Ehrenreich and colleagues, stroke patients treated with Epo showed reduced infarct volume, fast neurological recovery and improved clinical outcome. In analogy to its function on erythroid progenitor cells, this neuroprotective effect of Epo might be explained by repression of programmed cell death. Apart from neuroprotection, there is an assumption that Epo present in breast milk has the potential to protect against mother-to-infant transmission of HIV. When using Epo at high doses for longer time periods; however, care has to be taken to control the resulting chronic polycythemia that most probably caused enlarged cerebral infarct volumes in a transgenic mouse model that due to Epo-overexpression reached hematocrit levels of about 0.8. Overall, these data strongly support the notion that Epo will soon find new applications in the clinic.

Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla.

Carbon-13 magnetic resonance spectroscopy (13C MRS) offers a noninvasive method to assess glycogen levels in skeletal muscle and to identify excess glycogen accumulation in patients with glycogen storage disease (GSD). Despite the clinical potential of the method, it is currently not widely used for diagnosis or for follow-up of treatment. While it is possible to perform acceptable 13C MRS at lower fields, the low natural abundance of 13C and the inherently low signal-to-noise ratio of 13C MRS makes it desirable to utilize the advantage of increased signal strength offered by ultra-high fields for more accurate measurements. Concomitant with this advantage, however, ultra-high fields present unique technical challenges that need to be addressed when studying glycogen. In particular, the question of measurement reproducibility needs to be answered so as to give investigators insight into meaningful inter-subject glycogen differences. We measured muscle glycogen levels in vivo in the calf muscle in three patients with McArdle disease (MD), one patient with phosphofructokinase deficiency (PFKD) and four healthy controls by performing 13C MRS at 7T. Absolute quantification of the MRS signal was achieved by using a reference phantom with known concentration of metabolites. Muscle glycogen concentration was increased in GSD patients (31.5±2.9 g/kg w. w.) compared with controls (12.4±2.2 g/kg w. w.). In three GSD patients glycogen was also determined biochemically in muscle homogenates from needle biopsies and showed a similar 2.5-fold increase in muscle glycogen concentration in GSD patients compared with controls. Repeated inter-subject glycogen measurements yield a coefficient of variability of 5.18%, while repeated phantom measurements yield a lower 3.2% system variability. We conclude that noninvasive ultra-high field 13C MRS provides a valuable, highly reproducible tool for quantitative assessment of glycogen levels in health and disease.

The effect of rowing ergometry and resistive exercise on skeletal muscle structure and function during bed rest.

Exposure to microgravity causes functional and structural impairment of skeletal muscle. Current exercise regimens are time-consuming and insufficiently effective; an integrated countermeasure is needed that addresses musculoskeletal along with cardiovascular health. High-intensity, short-duration rowing ergometry and supplemental resistive strength exercise may achieve these goals. Twenty-seven healthy volunteers completed 5 wk of head-down-tilt bed rest (HDBR): 18 were randomized to exercise, 9 remained sedentary. Exercise consisted of rowing ergometry 6 days/wk, including interval training, and supplemental strength training 2 days/wk. Measurements before and after HDBR and following reambulation included assessment of strength, skeletal muscle volume (MRI), and muscle metabolism (magnetic resonance spectroscopy); quadriceps muscle biopsies were obtained to assess muscle fiber types, capillarization, and oxidative capacity. Sedentary bed rest (BR) led to decreased muscle volume (quadriceps: -9 ± 4%, P < 0.001; plantar flexors: -19 ± 6%, P < 0.001). Exercise (ExBR) reduced atrophy in the quadriceps (-5 ± 4%, interaction P = 0.018) and calf muscle, although to a lesser degree (-14 ± 6%, interaction P = 0.076). Knee extensor and plantar flexor strength was impaired by BR (-14 ± 15%, P = 0.014 and -22 ± 7%, P = 0.001) but preserved by ExBR (-4 ± 13%, P = 0.238 and +13 ± 28%, P = 0.011). Metabolic capacity, as assessed by maximal O2 consumption, (31)P-MRS, and oxidative chain enzyme activity, was impaired in BR but stable or improved in ExBR. Reambulation reversed the negative impact of BR. High-intensity, short-duration rowing and supplemental strength training effectively preserved skeletal muscle function and structure while partially preventing atrophy in key antigravity muscles. Due to its integrated cardiovascular benefits, rowing ergometry could be a primary component of exercise prescriptions for astronauts or patients suffering from severe deconditioning.

Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNA(Ile) mutation.

The differential diagnosis of myoglobinuria includes multiple etiologies, such as infection, inflammation, trauma, endocrinopathies, drugs toxicity, and primary metabolic disorders. Metabolic myopathies can be due to inherited disorders of glycogen metabolism or to defects of fatty acid oxidation. Primary respiratory chain dysfunction is a rare cause of myoglobinuria, but it has been described in sporadic cases with mutations in genes encoding cytochrome b or cytochrome c oxidase (COX) subunits and in four cases with tRNA mutations. We describe a 39-year-old woman with myalgia and exercise-related recurrent myoglobinuria, who harbored a novel mitochondrial DNA mutation at nucleotide 4281 (m.4281A>G) in the tRNA-isoleucine gene. Her muscle biopsy revealed ragged-red and COX-deficient fibers. No deletions or duplication were detected by Southern blot analysis. The m.4281A>G mutation was present in the patient's muscle with a mutation load of 46% and was detected in trace amounts in urine and cheek mucosa. Single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient (65%) than in normal fibers (45%). This novel mutation has to be added to the molecular causes of recurrent myoglobinuria.

Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction.

AIMS: Peak oxygen uptake (VO(2)) is diminished in patients with heart failure with preserved ejection fraction (HFpEF) suggesting impaired cardiac reserve. To test this hypothesis, we assessed the haemodynamic response to exercise in HFpEF patients. METHODS AND RESULTS: Eleven HFpEF patients (73 ± 7 years, 7 females/4 males) and 13 healthy controls (70 ± 4 years, 6 females/7 males) were studied during submaximal and maximal exercise. The cardiac output (Q(c), acetylene rebreathing) response to exercise was determined from linear regression of Q(c) and VO(2) (Douglas bags) at rest, ∼30% and ∼60% of peak VO(2), and maximal exercise. Peak VO(2) was lower in HFpEF patients than in controls (13.7 ± 3.4 vs. 21.6 ± 3.6 mL/kg/min; P < 0.001), while indices of cardiac reserve were not statistically different: peak cardiac power output [CPO = Q(c) × mean arterial pressure (MAP); HFpEF 1790 ± 509 vs. controls 2119 ± 581 L/mmHg/min; P = 0.20]; peak stroke work [SW = stroke volume (SV) × MAP; HFpEF 13 429 ± 2269 vs. controls 13 200 ± 3610 mL/mmHg; P = 0.80]. The ΔQ(c)/ΔVO(2) slope was abnormally elevated in HFpEF patients vs. controls (11.2 ±3.6 vs. 8.3 ± 1.5; P = 0.015). CONCLUSION: Contrary to our hypothesis, cardiac reserve is not significantly impaired in well-compensated outpatients with HFpEF. The abnormal haemodynamic response to exercise (decreased peak VO(2), increased ΔQ(c)/ΔVO(2) slope) is similar to that observed in patients with mitochondrial myopathies, suggesting an element of impaired skeletal muscle oxidative metabolism. This impairment may limit functional capacity by two mechanisms: (i) premature skeletal muscle fatigue and (ii) metabolic signals to increase the cardiac output response to exercise which may be poorly tolerated by a left ventricle with impaired diastolic function.

Effect of changes in fat availability on exercise capacity in McArdle disease.

BACKGROUND: The major fuel for exercising muscle at low exercise intensities is fat. OBJECTIVE: To investigate the role of fat metabolism in McArdle disease (also known as glycogen storage disease type V), an inborn error of muscle glycogenolysis, by manipulating free fatty acid availability for oxidation during exercise. DESIGN: Randomized, placebo-controlled, crossover trial. SETTING: Hospitalized care. PATIENTS: Ten patients (8 men and 2 women) with McArdle disease. INTERVENTIONS: Patients cycled at a constant workload corresponding to 70% of their maximum oxygen consumption. In random order and on separate days, patients received nicotinic acid (a known blocker of lipolysis) to decrease the availability of free fatty acids or 20% Intralipid infusion to increase free fatty acid availability during exercise. Results were compared with placebo (isotonic sodium chloride solution infusion) and glucose infusion trials. MAIN OUTCOME MEASURES: Exercise tolerance was assessed by heart rate response to exercise during different infusions. RESULTS: Free fatty acid levels more than tripled by Intralipid infusion and were halved by nicotinic acid administration. Heart rate was significantly higher during exercise in the Intralipid infusion and nicotinic acid trials compared with the placebo and glucose infusion trials, an effect that was observed before and after the patients had experienced the second wind phenomenon. CONCLUSIONS: Lipids are an important source of fuel for exercising muscle in McArdle disease, but maximal rates of fat oxidation seem limited and cannot be increased above physiologically normal rates during exercise. This limitation is probably caused by a metabolic bottleneck in the tricarboxylic acid cycle due to impaired glycolytic flux in McArdle disease. Therapies aimed at enhancing fat use in McArdle disease should be combined with interventions targeting expansion of the tricarboxylic acid cycle.

Magnetic resonance imaging of the lumbar spine and blood volume in professional cyclists.

Stimulated hematopoiesis is observed in the bone marrow of endurance-trained athletes by magnetic resonance imaging (MRI) independent of the hemoglobin concentration (hematocrit or erythrocyte count) or circulating reticulocytes, but may be related to blood volume (BV). This study determined whether hyperplasia of hematopoietic bone marrow of professional cyclists correlates with their red cell volume (RCV). Twelve male professional cyclists (mean +/- SD; 20.2 +/- 1.4 years, 69.0 +/- 4.5 kg, VO2max 64.4 +/- 4.6 ml/min/kg, BV 7257 +/- 884 ml, RCV 2990 +/- 299 g) completed an MRI of the lumbar spine, a total BV determination using a CO-rebreathing method and a graded exercise testing within two consecutive days. Significant correlations were found between performance and BV data. A significant correlation existed also between the signal intensity of the Turbo inversion-recovery sequence with short inversion time (Turbo-STIR) and BV (r (2) = 0.47, P < 0.05), RCV (r (2) = 0.56, P < 0.05) and plasma volume (r (2) = 0.39, P < 0.05) per kilogram body mass. The present study provides evidence of stimulated erythropoiesis with hyperplasia of the hematopoietic bone marrow of endurance athletes explaining their large RCV.

Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration.

To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.

Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man.

While it is well established that highlanders have optimized their oxygen transport system, little is known about the acclimatization of those who move between different altitudes. The purpose of this study was to establish whether the acclimatization to long-term intermittent hypoxic exposure in members of the Chilean Army who frequently move from sea level to 3,550 m altitude is correlated with acute acclimatization or chronic adaptation to hypoxia. A group of officers was exposed intermittently to hypoxia for about 22 years (OI, officers at intermittent hypoxia) and a group of soldiers for 6 months (SI, soldiers at intermittent hypoxia). Both groups were compared to residents at altitude (RA) and to soldiers at sea level (SL). When compared to SL, we observed an 11% increase in total hemoglobin mass (tHb) as well as a corresponding increase in red cell volume (RCV), hemoglobin concentration and hematocrit in all three groups at altitude. Plasma volume (PV) and blood volume (BV) decreased at altitude but increased when OI and SI returned to sea level. Moreover, intermittent hypoxic exposure of OI and SI resulted in increased plasma erythropoietin (Epo) levels, which peaked on day 2 at high altitude followed by decreasing levels during the successive days, and reaching pre-altitude values in SI even when staying at altitude. In conclusion, with regard to tHb and RCV, the acclimatization to long-term intermittent hypoxia resembles the adaptation to chronic hypoxia, while PV and BV regulation mimicked acclimatization to acute hypoxia. Remarkably, finely controlled regulation of Epo expression still occurs after up to 22 years of weekly exposure to altitude.

Transgenic mice overexpressing erythropoietin adapt to excessive erythrocytosis by regulating blood viscosity.

Severe elevation of red blood cell number is often associated with hypertension and thromboembolism resulting in severe cardiovascular complications. However, some individuals such as high altitude dwellers cope well with an increased hematocrit level. We analyzed adaptive mechanisms to excessive erythrocytosis in our transgenic (tg) mice that, due to hypoxia-independent erythropoietin (Epo) overexpression, reached hematocrit values of 0.8 to 0.9 without alteration of blood pressure, heart rate, or cardiac output. Extramedullar erythropoiesis occurred in the tg spleen, leading to splenomegaly. Upon splenectomy, hematocrit values in tg mice decreased from 0.89 to 0.62. Tg mice showed doubled reticulocyte counts and an increased mean corpuscular volume. In tg mice, plasma volume was not elevated whereas blood volume was up to 25% of the body weight compared with 8% in wild-type (wt) siblings. Although plasma viscosity did not differ between tg and wt mice, tg whole-blood viscosity increased to a lower degree (4-fold) than expected from corresponding hemoconcentrated wt blood (8-fold). This moderate increase in viscosity is explicable by the up to 3-fold higher elongation of tg erythrocytes at physiologic shear rates. Apart from the nitric oxide-mediated vasodilation we reported earlier, adaptation to high hematocrit levels in tg mice involves regulated elevation of blood viscosity by increasing erythrocyte flexibility.