Hypoxic exercise training causes erythrocyte senescence and rheological dysfunction by depressed Gardos channel activity

Abstract

Despite enhancing cardiopulmonary and muscular fitness, the effect of hypoxic exercise training (HE) on hemorheological regulation remains unclear. This study investigates how HE modulates erythrocyte rheological properties and further explores the underlying mechanisms in the hemorheological alterations. Twenty-four sedentary males were randomly divided into hypoxic (HE; n = 12) and normoxic (NE; n = 12) exercise training groups. The subjects were trained on 60% of maximum work rate under 15% (HE) or 21% (NE) O(2) condition for 30 min daily, 5 days weekly for 5 wk. The results demonstrated that HE 1) downregulated CD47 and CD147 expressions on erythrocytes, 2) decreased actin and spectrin contents in erythrocytes, 3) reduced erythrocyte deformability under shear flow, and 4) diminished erythrocyte volume changed by hypotonic stress. Treatment of erythrocytes with H(2)O(2) that mimicked in vivo prooxidative status resulted in the cell shrinkage, rigidity, and phosphatidylserine exposure, whereas HE enhanced the eryptotic responses to H(2)O(2). However, HE decreased the degrees of clotrimazole to blunt ionomycin-induced shrinkage, rigidity, and cytoskeleton breakdown of erythrocytes, referred to as Gardos effects. Reduced erythrocyte deformability by H(2)O(2) was inversely related to the erythrocyte Gardos effect on the rheological function. Conversely, NE intervention did not significantly change resting and exercise erythrocyte rheological properties. Therefore, we conclude that HE rather than NE reduces erythrocyte deformability and volume regulation, accompanied by an increase in the eryptotic response to oxidative stress. Simultaneously, this intervention depresses Gardos channel-modulated erythrocyte rheological functions. Results of this study provide further insight into erythrocyte senescence induced by HE.

Intradialytic Hypoxemia and Clinical Outcomes in Patients on Hemodialysis

“…Although we have no data on ROS in our population, it is tempting to speculate that the inflammatory laboratory phenotype observed in patients with PIH may be related to oxidative stress. Of note, oxidative stress also impairs erythrocyte function; in particular, it may result in reduced cell deformability and thus, contribute to increased erythrocyte removal from the circulation and reduced lifespan (44,45).…”

Hemolysis is a primary ATP-release mechanism in human erythrocytes

“…For example, the Ca 21 -activated K 1 channel (Gardos channel), by controlling RBC dehydration, participates in the regulation of erythrocyte deformability and its activity is suppressed in senescent cells. 22 Moreover, elevated intracellular calcium is known to increase RBCs' osmotic fragility, which may in part involve specific Ca 21 -induced lytic vulnerability of membrane, 46 eg, via activation of scramblase and calpain and subsequent lysis of cytoskeletal proteins. 22,47 In summary, the results presented here call into question current views on the mechanism of stimulated ATP release from RBCs and show that hemolysis is the primary release mechanism in these cells.…”

“…13,19 However, hemolysis also is an important source of extracellular ATP, and intravascular hemolysis occurs in vivo as a consequence of hypoxia and mechanical trauma to RBCs. [20][21][22] Some degree of hemolysis is unavoidable during in vitro studies. Although it has been considered to be a potential factor contributing to stimulated ATP release in most previous investigations, its actual involvement has not yet been systematically investigated, eg, by paired measurement of free hemoglobin and ATP in each and every sample.…”

“…Interestingly, hypoxia was shown to decrease deformability of RBCs and increase susceptibility to cell damage. 22,38 Thus, the increment of extracellular ATP induced by hypoxia and hypoxia together with shear stress could be attributed to augmented cell lysis.The results presented here contradict much previously published experimental data on ATP-release mechanism(s) in RBCs. Owing to the absence of intracellular organelles, mature mammalian RBCs were considered as the ultimate example of a cell system where ATP release occurs exclusively via conductive pathways.…”

The effect of 4 weeks fixed and mixed intermittent hypoxic training (IHT) on respiratory metabolic and acid-base response of capillary blood during submaximal bicycle exercise in male elite Taekwondo players

“…Besides, on exercise at high altitude and hypoxic environments, PO2 of the arterial blood decreases and this leads to metabolic acidosis through increased ATP synthesis by anaerobic metabolic process, increase of hydrogen ion, and decrease of pH 10, 15, 21 . In high intensity exercise, skeletal muscle fatigue is caused due to increase of hydrogen ion by response of CO2 and HCO3 -, and damage to actin-myosin cross-bridge cycling by anaerobic glycolysis and accumulation of blood lactate, and lowering the sensitivity of calcium ion to troponin 15, 25, 26, 36 .…”