A load of hypergravity inhibits AMPKα and causes liver injury in mice, which can be prevented by preconditioning loads

Abstract

An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures to assure safe and effective aerospace missions and human survival. This study investigated whether a single or multiple load(s) of mice to hypergravity has an effect on the molecules associated with energy metabolism. In the liver, AMPKα level and its signaling pathway were repressed 6 h after a load of +9 Gz hypergravity for 1 h, and then gradually returned toward normal up to 24 h. AMPK β1 and γ1/2/3 levels were unchanged. AMPKα level was restored after 3 consecutive daily loads to +9 Gz, suggestive of adaptation of animals to repetitive preconditioning. In cDNA microarray analyses, 221 genes were differentially expressed by +9 Gz (P<0.05 and a 1.5‐fold cutoff), and the down‐regulated genes included Nrf2 targets. Nrf2 knockout abrogated the recovery of AMPKα elicited by 3 loads to +9 Gz, indicative of the role of Nrf2 in the adaptive increase of AMPKα. In addition, +9 Gz stress inhibited other transcription factors including STAT3, FOXO1/3 and CREB, and this effect was attenuated during the resting time. Similarly, apoptotic markers were enhanced with liver injury 6 h after a load of hypergravity, indicating that the liver may be vulnerable to hypergravity stress. Hepatocyte death was also abolished after multiple hypergravity loads. Our results show that a load of mice to +9 Gz hypergravity causes AMPKα repression with liver injury, which can be overcome by multiple loads to hypergravity as mediated by Nrf2.Support or Funding InformationAs supported by the NRF grant funded by the Korea government (NRF‐2014M1A3A3A02034698)