Abstract
AMP-activated protein kinase (AMPK) is an energy sensor essential for maintaining cellular energy homeostasis. Here, we report that AMPKalpha1 is the predominant isoform of AMPK in murine erythrocytes and mice globally deficient in AMPKalpha1 (AMPKalpha1(-/-)), but not in those lacking AMPKalpha2, 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 AMPKalpha1(-/-) mice. The life span of erythrocytes from AMPKalpha1(-/-) mice was less than that in wild-type littermates, and the levels of reactive oxygen species and oxidized proteins were significantly increased in AMPKalpha1(-/-) erythrocytes. In keeping with the elevated oxidative stress, treatment of AMPKalpha1(-/-) 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 AMPKalpha1(-/-) mice. Collectively, these results establish an essential role for AMPKalpha1 in regulating oxidative stress and life span in erythrocytes.
Highlights
Reactive oxygen species (ROS)2 are ubiquitously generated in living cells, including erythrocytes, and overwhelming evidence indicates that they play key roles in essential cellular functions
The absence of these antioxidant protections can result in moderate hemolysis [10]; a normal erythrocyte life span depends on an adequate antioxidant response [11]
AMPK␣1 Is the Predominant Isoform in Murine Erythrocytes—We found that AMPK␣1 is the predominant isoform of AMPK␣ in murine film) and analyzed densitometrically
Summary
Reactive oxygen species (ROS)2 are ubiquitously generated in living cells, including erythrocytes, and overwhelming evidence indicates that they play key roles in essential cellular functions. These data indicate that a deficiency of AMPK␣1 caused moderate anemia, characterized by a significant decrease in red cell count, hematocrit, and hemoglobin in peripheral blood relative to wildtype littermate controls.
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