Journal
JOURNAL OF GENERAL PHYSIOLOGY
Volume 147, Issue 2, Pages 175-188Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1085/jgp.201511494
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Funding
- Russian Foundation for Basic Research (RFBR) [13-04-00973]
- St. Petersburg State University research grants [1.50.1621.2013, 1.38.231.2014]
- Danish Research Council [09-063499]
- Novo Nordisk Foundation [NNF14OC0012731, 10559]
- Swedish Research Council [K2013-55X-14191-12-3]
- Strategic Research Program in Diabetes at Karolinska Institutet
- RFBR [14-04-00094, 14-04-01232]
- National Institutes of Health [1 R01 AR063710]
- Novo Nordisk Fonden [NNF16OC0021186, NNF14OC0010559, NNF14OC0012731] Funding Source: researchfish
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The Na,K-ATPase is essential for the contractile function of skeletal muscle, which expresses the alpha 1 and alpha 2 subunit isoforms of Na,K-ATPase. The alpha 2 isozyme is predominant in adult skeletal muscles and makes a greater contribution in working compared with noncontracting muscles. Hindlimb suspension (HS) is a widely used model of muscle disuse that leads to progressive atrophy of postural skeletal muscles. This study examines the consequences of acute (6-12 h) HS on the functioning of the Na,K-ATPase alpha 1 and alpha 2 isozymes in rat soleus (disused) and diaphragm (contracting) muscles. Acute disuse dynamically and isoform-specifically regulates the electrogenic activity, protein, and mRNA content of Na,K-ATPase alpha 2 isozyme in rat soleus muscle. Earlier disuse-induced remodeling events also include phospholemman phosphorylation as well as its increased abundance and association with alpha 2 Na,K-ATPase. The loss of alpha 2 Na,K-ATPase activity results in reduced electrogenic pump transport and depolarized resting membrane potential. The decreased alpha 2 Na,K-ATPase activity is caused by a decrease in enzyme activity rather than by altered protein and mRNA content, localization in the sarcolemma, or functional interaction with the nicotinic acetylcholine receptors. The loss of extrajunctional alpha 2 Na,K-ATPase activity depends strongly on muscle use, and even the increased protein and mRNA content as well as enhanced alpha 2 Na,K-ATPase abundance at this membrane region after 12 h of HS cannot counteract this sustained inhibition. In contrast, additional factors may regulate the subset of junctional alpha 2 Na,K-ATPase pool that is able to recover during HS. Notably, acute, low-intensity muscle workload restores functioning of both alpha 2 Na,K-ATPase pools. These results demonstrate that the alpha 2 Na,K-ATPase in rat skeletal muscle is dynamically and acutely regulated by muscle use and provide the first evidence that the junctional and extrajunctional pools of the alpha 2 Na,K-ATPase are regulated differently.
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