FOXO1 activates glutamine synthetase gene in mouse skeletal muscles (820.10)

Abstract

Skeletal muscle is the largest organ in the human body, and is a reservoir of energy in the form of protein (amino acids). FOXO1 is a forkhead‐type transcription factor, whose expression increases during conditions such as protein degradation, starvation and exercise. We have previously generated transgenic mice overexpressing FOXO1 specifically in skeletal muscles (FOXO1‐Tg mice), which exhibited muscle atrophy. In this study, we found that glutamine levels and glutamine synthetase (GS) expression increased in skeletal muscles of FOXO1‐Tg mice. During fasting, FOXO1 and GS expression markedly increased in wild‐type mice, but the increase in GS expression was attenuated in mice with a skeletal muscle‐specific knockout of FOXO1 (FOXO1‐KO mice). In a transient transfection reporter assay, FOXO1 dose dependently activated the GS reporter construct. Moreover, FOXO1 was strongly recruited to the 3’ region of GS in C2C12 myoblasts, as analyzed by ChIP assay. These results suggest that FOXO1 directly upregulates GS expression. Meanwhile, blood ammonia levels were significantly increased in FOXO1‐KO mice and inversely correlated with suppressed GS expression, which is considered to be involved in ammonia clearance in skeletal muscles. In conclusion, FOXO1 in skeletal muscles may play a role in amino acid metabolism, particularly in glutamine metabolism.