Isoform-specific Na,K-ATPase and membrane cholesterol remodeling in motor endplates in distinct mouse models of myodystrophy

Na,K-ATPase is a membrane transporter that is critically important for skeletal muscle function. Mdx and Bla/J mice are the experimental models of Duchenne muscular dystrophy and dysferlinopathy that are known to differ in the molecular mechanism of the pathology. This study examines the function of alpha 1- and alpha 2-Na,K-ATPase isozymes in respiratory diaphragm and postural soleus muscles from mdx and Bla/J mice compared with control C57Bl/6 mice. In diaphragm muscles, the motor endplate structure was severely disturbed (manifested by defragmentation) in mdx mice only. The endplate membrane of both Bla/J and mdx mice was depolarized due to specific loss of the alpha 2-Na,K-ATPase electrogenic activity and its decreased membrane abundance. Total FXYD1 subunit (modulates Na,K-ATPase activity) abundance was decreased in both mouse models. However, the alpha 2-Na,K-ATPase protein content as well as mRNA expression were specifically and significantly reduced only in mdx mice. The endplate membrane cholesterol redistribution was most pronounced in mdx mice. Soleus muscles from Bla/J and mdx mice demonstrated reduction of the alpha 2-Na,K-ATPase membrane abundance and mRNA expression similar to the diaphragm muscles. In contrast to diaphragm, the alpha 2-Na,K-ATPase protein content was altered in both Bla/J and mdx mice; membrane cholesterol re-distribution was not observed. Thus, the alpha 2-Na,K-ATPase is altered in both Bla/J and mdx mouse models of chronic muscle pathology. However, despite some similarities, the alpha 2-Na,K-ATPase and cholesterol abnormalities are more pronounced in mdx mice.