Isoform-specific role of Na/K-ATPase α1 in skeletal muscle

The distribution of Na/K-ATPase alpha-isoforms in skeletal muscle is unique, with alpha 1 as the minor (15%) isoform and alpha 2 comprising the bulk of the Na/K-ATPase pool. The acute and isoform-specific role of alpha 2 in muscle performance and resistance to fatigue is well known, but the isoform-specific role of alpha 1 has not been as thoroughly investigated. In vitro, we reported that alpha 1 has a role in promoting cell growth that is not supported by alpha 2. To assess whether alpha 1 serves this isoform-specific trophic role in the skeletal muscle, we used Na/K-ATPase alpha 1-haploinsufficient (alpha 1(+/-)) mice. A 30% decrease of Na/K-ATPase alpha 1 protein expression without change in alpha 2 induced a modest yet significant decrease of 10% weight in the oxidative soleus muscle. In contrast, the mixed plantaris and glycolytic extensor digitorum longus weights were not significantly affected, likely because of their very low expression level of alpha 1 compared with the soleus. The soleus mass reduction occurred without change in total Na/K-ATPase activity or glycogen metabolism. Serum analytes including K+, fat tissue mass, and exercise capacity were not altered in alpha 1(+/-) mice. The impact of alpha 1 content on soleus muscle mass is consistent with a Na/K-ATPase alpha 1-specific role in skeletal muscle growth that cannot be fulfilled by alpha 2. The preserved running capacity in alpha 1(+/-) is in sharp contrast with previously reported consequences of genetic manipulation of alpha 2. Taken together, these results lend further support to the concept of distinct isoform-specific functions of Na/K-ATPase alpha 1 and alpha 2 in skeletal muscle.