Janus‐Faced Role of ATP1B4 Gene Co‐option in Mammalian Evolution

ATP1B4 genes represent a rare instance of orthologous vertebrate gene co‐option (evolutionary changes of functions of the genes, which are present in a single unambiguous copy in all known vertebrate genomes) that radically changed functions of the encoded BetaM proteins, which are the Na, K‐ATPase subunits in lower vertebrates. In placental mammals, BetaM proteins gained entirely different properties through changes in the structure of N‐terminal domains. As a result of these evolutionary alterations, eutherian BetaM completely lost its ancestral role and became the only currently known skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane, where it functions as a regulator of gene expression. Expression of BetaM is the highest in myocytes during late fetal and early postnatal development and is also robustly induced in regenerating adult muscle. Evolutionarily acquired new functions and a unique pattern of expression of BetaM proteins suggest that those new physiological functions are essential, might be necessary for survival of placental mammals in natural conditions, and provide an evolutionary advantage. To characterize BetaM function directly in vivo, the Atp1b4 knockout mouse model was generated. We have shown that loss of BetaM results in significantly lower body size and weight, growth retardation and high mortality of Atp1b4 knockout neonates. T ranscriptome analysis by mRNA sequencing of skeletal muscle from neonatal wild type and knockout littermates revealed strong down‐regulation of fast‐twitch and up‐regulation of slow‐twitch muscle genes, and broad changes in expression of genes regulating lipid metabolism. These results imply that BetaM plays an important role during a critical period of perinatal and neonatal development of placental mammals and its damage or malfunction can cause birth and growth defects in humans. Most importantly, our experiments revealed a somewhat unexpected and profound beneficial effect of Atp1b4 disruption on metabolic parameters in adult male mice. We have shown that Atp1b4 knockout males, which survived to adulthood, have a significantly lower percentage of body fat, exhibit enhanced metabolic rate and insulin sensitivity, and are resistant to high‐fat diet‐induced obesity. These robust changes in mouse metabolic parameters induced by Atp1b4 disruption clearly demonstrate that eutherian BetaM plays the important role in development of pathways regulating metabolism of adult mice. Finally, ablation of the evolutionarily acquired functions of Atp1b4 gene in mice is in fact a simulation of the alternative pathway of mammalian evolution. Support or Funding Information This work was supported by Department of Physiology & Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo College of Medicine. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .