Loss of the clock protein PER2 shortens the erythrocyte life span in mice.

Cell proliferation and release from the bone marrow have been demonstrated to be controlled by circadian rhythms in both humans and mice. However, it is unclear whether local circadian clocks in the bone marrow influence physiological functions and life span of erythrocytes. Here, we report that loss of the clock gene significantly decreased erythrocyte life span. Mice deficient in were more susceptible to acute stresses in the erythrocytes, becoming severely anemic upon phenylhydrazine, osmotic, and HO challenges. H NMR-based metabolomics analysis revealed that the depletion causes significant changes in metabolic profiles of erythrocytes, including increased lactate and decreased ATP levels compared with wild-type mice. The lower ATP levels were associated with hyperfunction of Na/K-ATPase activity in -null erythrocytes, and inhibition of Na/K-ATPase activity by ouabain efficiently rescued ATP levels. -null mice displayed increased levels of Na/K-ATPase α1 (ATP1A1) in the erythrocyte membrane, and transfection of cDNA into the erythroleukemic cell line TF-1 inhibited expression. Furthermore, we observed that PER2 regulates transcription through interacting with trans-acting transcription factor 1 (SP1). Our findings reveal that function in the bone marrow is required for the regulation of life span in circulating erythrocytes.