The α1- and α2-isoforms of Na-K-ATPase play different roles in skeletal muscle contractility

The Na-K-ATPase, which maintains the Na+ and K+ gradients across the plasma membrane, can play a major role in modulation of skeletal muscle contractility. Although both alpha (1)- and alpha (2)-isoforms of the Na-K-ATPase are expressed in skeletal muscle, the physiological significance of these isoforms in contractility is not known. Evaluation of the contractile parameters of mouse extensor digitorum longus (EDL) was carried out using gene-targeted mice lacking one copy of either the alpha (1)- or alpha (2)-isoform gene of the Na-K-ATPase. The EDL muscles from heterozygous mice contain approximately one-half of the alpha (1)- or alpha (2)-isoform, respectively, which permits differentiation of the functional roles of these isoforms. EDL from the alpha (+/-)(1) mouse shows lower force compared with wild type, whereas that from the alpha (+/-)(2) mouse shows greater force. The different functional roles of these two isoforms are further demonstrated because inhibition of the alpha (2)-isoform with ouabain increases contractility of alpha (+/-)(1) EDL. These results demonstrate that the Na-K-ATPase a,and alpha (2)-isoforms may play different roles in skeletal muscle contraction.