The cardiac glycoside binding site on the Na,K-ATPase α2 isoform plays a role in the dynamic regulation of active transport in skeletal muscle
Open Access
- 24 February 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (8), 2565-2570
- https://doi.org/10.1073/pnas.0804150106
Abstract
The physiological significance of the cardiac glycoside-binding site on the Na,K-ATPase remains incompletely understood. This study used a gene-targeted mouse (α2R/R) which expresses a ouabain-insensitive α2 isoform of the Na,K-ATPase to investigate whether the cardiac glycoside-binding site plays any physiological role in active Na+/K+ transport in skeletal muscles or in exercise performance. Skeletal muscles express the Na,K-ATPase α2 isoform at high abundance and regulate its transport over a wide dynamic range under control of muscle activity. Na,K-ATPase active transport in the isolated extensor digitorum longus (EDL) muscle of α2R/R mice was lower at rest and significantly enhanced after muscle contraction, compared with WT. During the first 60 s after a 30-s contraction, the EDL of α2R/R mice transported 70.0 nmol/g·min more 86Rb than WT. Acute sequestration of endogenous ligand(s) in WT mice infused with Digibind to sequester endogenous cardiac glycoside(s) produced similar effects on both resting and contraction-induced 86Rb transport. Additionally, the α2R/R mice exhibit an enhanced ability to perform physical exercise, showing a 2.1- to 2.8-fold lower failure rate than WT within minutes of the onset of moderate-intensity treadmill running. Their enhanced exercise performance is consistent with their enhanced contraction-induced Na,K-ATPase transport in the skeletal muscles. These results demonstrate that the Na,K-ATPase α2 isozyme in skeletal muscle is regulated dynamically by a mechanism that utilizes the cardiac glycoside-binding site and an endogenous ligand(s) and that its cardiac glycoside-binding site can play a physiological role in the dynamic adaptations to exercise.Keywords
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