Effects of Individualized Treadmill Endurance Training on Oxidative Stress in Skeletal Muscles of Transgenic Sickle Mice.

Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O2 peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in the gastrocnemius, in the plantaris, and in the soleus muscles. Maximal aerobic speed and V̇O2 peak were significantly reduced in sickle compared to healthy mice (-57% and -17%; p < 0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in the gastrocnemius of sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice (p = 0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in the gastrocnemius, but neither in the plantaris nor in the soleus of trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training.

The genetic basis and evolution of red blood cell sickling in deer.

Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human ß-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non-sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates.

Haemorheological studies of the sickle cell phenomenon in European red deer (Cervus elaphus).

It was demonstrated that the appearance of sickle-shaped erythrocytes can be induced by oxygenating the blood of European red deer (Cervus elaphus). The process was reversible. Blood cell counts with the exception of a slight reduction in red cell number and protein fractions did not show any abnormal values. The blood, which was examined at least 18 h after sampling, exhibited considerable deviations of blood gas values. In addition, highly significant haemorheological changes due to the sickle-shaped and oxygenated erythrocytes were detected.

Fusiform erythrocytes resembling sickle cells in angora goats: light and electron microscopic observations.

Fresh blood from nine mature non-pregnant angora goats was found to contain a varying proportion of spindle-shaped, fusiform, triangular, pear-shaped, and other bizarre forms of erythrocytes in addition to normal discoid biconcave erythrocytes. The number of spindled and fusiform erythrocytes varied from 2 to 66 per cent, with two goats having such cells in excess of 50 per cent. Other aberrant forms of erythrocytes ranged from 3 to 54 per cent. Although the aberrant erythrocytes seemed to be present intravascularly, all goats studied were clinically normal and exhibited no other haematological abnormality. Light and electron microscopic observations indicated that polymerisation of haemoglobin in the form of longitudinal tubular fibres was responsible for conferring the fusiform and spindle shapes to erythrocytes, a phenomenon akin to that seen in sickle-shaped human and deer erythrocytes.

In vivo erythrocyte sickling in the Japanese sika deer (Cervus nippon): methodology.

The Japanese sika deep (Cervus nippon) proved to be a suitable animal model for the study of acute phases of in vivo erythrocyte sickling. Ophthalmologic studies can be conducted during or after 1 to 6 hours of effective in vivo sickling. Intravenous administration of 1.75 to 3.5% sodium bicarbonate solution at a rate of 500 to 1,000 ml per hour produced a transient state of alkalosis and in vivo erythrocyte sickling in the sika deer. The percentage of sickled erythrocytes increased as the blood pH increased. Concurrently, the packed cell volume decreased. Sickling was enhanced by 100% oxygen ventilation after endotracheal intubation and light anesthetization. After the induction of erythrocyte sickling, a sickling-reversal phenomenon occurred despite continued bicarbonate administration. During the course of this reversal, the percentage of sickled erythrocytes steadily decreased, the venous blood pH decreased, and the packed cell volume slowly increased. Because of the sickling-reversal phenomenon, chronic erythrocyte sickling was not achieved.

Ophthalmic manifestations of induced sickling of erythrocytes in Japanese sika deer (Cervus nippon).

Nine female Japanese sika deer (Cervus nippon) were used in a total of 25 experiments in which sickling was chemically induced. During these experiments, color fundic and color fluorescein photographs were taken. Fundic changes included retinal vascular attenuation, blood column pallor, and decreased tapetal reflectivity. These changes were most likely directly associated with a decreased hematocrit and a generalized shocklike condition. Three deer had a congested appearance in retinal blood vessels and tapetum lucidum. Two of the 3 deer developed serous detachment of the retina. These changes seemingly were associated with severe venous statis; all 3 deer died shortly after the experiment was terminated. These experiments yielded data only for the acutely affected deer. None of the ocular changes could be considered the result of chronic sickling because of the reversal of sickling that occurred despite continued intravenous administration of bicarbonate. None of the deer developed ocular changes characteristic of sickle cell retinopathy in human beings. The changes in human beings probably result from continued stress and prolongation of sickling, and especially from a multiplicity of repeated severe episodes of sickling occurring over many years.