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

Abstract

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 alpha(1)- and alpha(2)-isoforms may play different roles in skeletal muscle contraction.

The α1 Isoform of Na,K-ATPase Regulates Cardiac Contractility and Functionally Interacts and Co-localizes with the Na/Ca Exchanger in Heart

“…On the basis of these data, it was proposed that the ␣2 isoform mediates positive cardiac inotropy, whereas the ␣1 isoform mediates the toxic effects of cardiac glycosides. A number of studies re-enforced the importance of the ␣2 isoform in the regulation of Ca 2ϩ transients during contraction (7)(8)(9)12). Also, we confirmed that the ␣2 isoform mediates the positive cardiac inotropy observed at low concentrations of ouabain, by comparing the effect of ouabain on cardiac contractility in wild type hearts expressing the ouabain-sensitive ␣2 isoform with that in hearts expressing a genetically modified, ouabain-resistant ␣2 isoform (13).…”

Deficiency in Na,K-ATPase α Isoform Genes Alters Spatial Learning, Motor Activity, and Anxiety in Mice

“…The ␣2 ϩ/Ϫ mice also showed reduced locomotor activity compared with wild-type mice, whereas the ␣3 ϩ/Ϫ mice were hyperactive. The ␣1 ϩ/Ϫ and ␣2 ϩ/Ϫ mice have been examined previously for muscle contractile function and muscle fatigue by performing electrical stimulation of extensor digitorum longus (EDL) muscle, a fast-twitch muscle in the lower leg (He et al, 2001). EDL muscle from the ␣1 ϩ/Ϫ displayed hypocontractility, whereas the ␣2 ϩ/Ϫ muscle was hypercontractile.…”

Deletion of the Na/K-ATPase $alpha;1-subunit gene (Atp1a1) does not prevent cavitation of the preimplantation mouse embryo

“…We have tested this hypothesis by characterizing preimplantation development in a mouse line lacking both copies of the Na/K-ATPase a1-subunit (Atp1a1), using embryos acquired from matings between Atp1a1 heterozygous mice (James et al, 1999). Animals heterozygous for this mutation appear healthy and are fertile, although changes in muscle contractile properties have been observed in adult animals (James et al, 1999;He et al, 2001). However, matings between heterozygous animals do not produce homozygous mutant offspring, indicating an essential function of the Na/K-ATPase a1-subunit during normal embryonic development (James et al, 1999).…”