| First Author | Radzyukevich TL | Year | 2013 |
| Journal | J Biol Chem | Volume | 288 |
| Issue | 2 | Pages | 1226-37 |
| PubMed ID | 23192345 | Mgi Jnum | J:193876 |
| Mgi Id | MGI:5469806 | Doi | 10.1074/jbc.M112.424663 |
| Citation | Radzyukevich TL, et al. (2013) Tissue-specific role of the Na,K-ATPase alpha2 isozyme in skeletal muscle. J Biol Chem 288(2):1226-37 |
| abstractText | The Na,K-ATPase alpha2 isozyme is the major Na,K-ATPase of mammalian skeletal muscle. This distribution is unique compared with most other cells, which express mainly the Na,K-ATPase alpha1 isoform, but its functional significance is not known. We developed a gene-targeted mouse (skalpha2(-/-)) in which the alpha2 gene (Atp1a2) is knocked out in the skeletal muscles, and examined the consequences for exercise performance, membrane potentials, contractility, and muscle fatigue. Targeted knockout was confirmed by genotyping, Western blot, and immunohistochemistry. Skeletal muscle cells of skalpha2(-/-) mice completely lack alpha2 protein and have no alpha2 in the transverse tubules, where its expression is normally enhanced. The alpha1 isoform, which is normally enhanced on the outer sarcolemma, is up-regulated 2.5-fold without change in subcellular targeting. skalpha2(-/-) mice are apparently normal under basal conditions but show significantly reduced exercise capacity when challenged to run. Their skeletal muscles produce less force, are unable to increase force to match demand, and show significantly increased susceptibility to fatigue. The impairments affect both fast and slow muscle types. The subcellular targeting of alpha2 to the transverse tubules is important for this role. Increasing Na,K-ATPase alpha1 content cannot fully compensate for the loss of alpha2. The increased fatigability of skalpha2(-/-) muscles is reproduced in control extensor digitorum longus muscles by selectively inhibiting alpha2 enzyme activity with ouabain. These results demonstrate that the Na,K-ATPase alpha2 isoform performs an acute, isoform-specific role in skeletal muscle. Its activity is regulated by muscle use and enables working muscles to maintain contraction and resist fatigue. |
