Distinct α2 Na,K-ATPase membrane pools are differently involved in early skeletal muscle remodeling during disuse

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.