AMPKα1 Deletion Shortens Erythrocyte Life Span in Mice ROLE OF OXIDATIVE STRESS

AMP-activated protein kinase (AMPK) is an energy sensor essential for maintaining cellular energy homeostasis. Here, we report that AMPK alpha 1 is the predominant isoform of AMPK in murine erythrocytes and mice globally deficient in AMPK alpha 1 (AMPK alpha 1(-/-)), but not in those lacking AMPK alpha 2, and the mice had markedly enlarged spleens with dramatically increased proportions of Ter119-positive erythroid cells. Blood tests revealed significantly decreased erythrocyte and hemoglobin levels with increased reticulocyte counts and elevated plasma erythropoietin concentrations in AMPK alpha 1(-/-) mice. The life span of erythrocytes from AMPK alpha 1(-/-) mice was less than that in wild-type littermates, and the levels of reactive oxygen species and oxidized proteins were significantly increased in AMPK alpha 1(-/-) erythrocytes. In keeping with the elevated oxidative stress, treatment of AMPK alpha 1(-/-) mice with the antioxidant, tempol, resulted in decreased reticulocyte counts and improved erythrocyte survival. Furthermore, the expression of Foxo3 and reactive oxygen species scavenging enzymes was significantly decreased in erythroblasts from AMPK alpha 1(-/-) mice. Collectively, these results establish an essential role for AMPK alpha 1 in regulating oxidative stress and life span in erythrocytes.