Short-Term Mild Hypoxia Modulates Na,K-ATPase to Maintain Membrane Electrogenesis in Rat Skeletal Muscle

Abstract

The Na,K-ATPase plays an important role in adaptation to hypoxia. Prolonged hypoxia results in loss of skeletal muscle mass, structure, and performance. However, hypoxic preconditioning is known to protect against a variety of functional impairments. In this study, we tested the possibility of mild hypoxia to modulate the Na,K-ATPase and to improve skeletal muscle electrogenesis. The rats were subjected to simulated high-altitude (3000 m above sea level) hypobaric hypoxia (HH) for 3 h using a hypobaric chamber. Isolated diaphragm and soleus muscles were tested. In the diaphragm muscle, HH increased the α2 Na,K-ATPase isozyme electrogenic activity and stably hyperpolarized the extrajunctional membrane for 24 h. These changes were accompanied by a steady increase in the production of thiobarbituric acid reactive substances as well as a decrease in the serum level of endogenous ouabain, a specific ligand of the Na,K-ATPase. HH also increased the α2 Na,K-ATPase membrane abundance without changing its total protein content; the plasma membrane lipid-ordered phase did not change. In the soleus muscle, HH protected against disuse (hindlimb suspension) induced sarcolemmal depolarization. Considering that the Na,K-ATPase is critical for maintaining skeletal muscle electrogenesis and performance, these findings may have implications for countermeasures in disuse-induced pathology and hypoxic therapy.

Chronic Ouabain Targets Pore-Forming Claudin-2 and Ameliorates Radiation-Induced Damage to the Rat Intestinal Tissue Barrier

“…Both exogenous and endogenous ouabain are now recognized as multimodal cell modulators with broad therapeutic potential [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Endogenous ouabain normally circulates in the subnanomolar concentration range, but its levels can vary significantly in a number of physiological and pathophysiological conditions [ 37 , 38 , 40 , 66 , 67 , 68 ]. In animal models of inflammation, low concentrations of ouabain have been shown to attenuate oxidative stress and lipid peroxidation impairment [ 50 ] and also protect against NF-κB activation [ 41 , 44 ].…”

“…To enhance the concentration of circulating ouabain, intraperitoneal injections of ouabain at doses of 1–1.8 µg/kg are widely used [ 49 , 50 , 68 , 71 ]. In our study, we found that chronic administration of exogenous ouabain (1 μg/kg) increased circulating ouabain levels approximately twofold (from 0.7 nM in control to 1.5 nM).…”