A load of mice to hypergravity causes AMPKα repression with liver injury, which is overcome by preconditioning loads via Nrf2.

Sang Gil Lee,Choong Sik Oh,Sang Geon Kim,Hong Min Wu,So Won Chung,Chan Gyu Lee

doi:10.1038/srep15643

Abstract

An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures for aerospace missions. This study investigated whether a single or multiple load(s) of mice to hypergravity has an effect on molecules associated with energy metabolism. In the liver, AMPKα level and its signaling were repressed 6 h after a load to +9 Gz hypergravity for 1 h, and then gradually returned toward normal. AMPKα level was restored after 3 loads to +9 Gz, suggestive of preconditioning adaptation. In cDNA microarray analyses, 221 genes were differentially expressed by +9 Gz, and the down-regulated genes included Nrf2 targets. Nrf2 gene knockout abrogated the recovery of AMPKα elicited by 3 loads to +9 Gz, indicating that Nrf2 plays a role in the adaptive increase of AMPKα. In addition, +9 Gz stress decreased STAT3, FOXO1/3 and CREB levels, which was attenuated during the resting time. Similarly, apoptotic markers were enhanced in the liver, indicating that the liver may be vulnerable to hypergravity stress. Preconditioning loads prevented hepatocyte apoptosis. Overall, a load of mice to +9 Gz hypergravity causes AMPKα repression with liver injury, which may be overcome by multiple loads to hypergravity as mediated by Nrf2.

Highlights

An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures for aerospace missions
In view of the lack of an understanding on the effect of hypergravity stress and the impact of accompanying changes in hemodynamic circulation and sheer stress on biological system, this study investigated whether a single or multiple load(s) to + 3 Gz or + 9 Gz hypergravity has a detrimental effect on the integrity of the liver, skeletal muscle and kidney in a mouse model, and the molecules associated with energy metabolism, and cell viability, particular focusing on those associated with energy homeostasis in the liver
To assess the effects of hypergravity forces on major organs, we first measured the activities of aminotransferases, creatine phosphate kinase (CPK), blood urea nitrogen (BUN) and creatinine contents in serum as representative injury markers of the liver, skeletal muscle and kidney, respectively, immediately after an exposure of mice to + 3 or + 9 Gz hypergravity (Fig. 1B)

Summary

Introduction

An understanding of the effects of hypergravity on energy homeostasis is necessary in managing proper physiological countermeasures for aerospace missions. This study investigated whether a single or multiple load(s) of mice to hypergravity has an effect on molecules associated with energy metabolism. Alteration of gravity (hypergravity and/or microgravity) represents a powerful physical cue to exert modeling effects on both anatomy and function of living organisms[1,2,3,4,5,6,7,8,9]. In addition to the direct pressure changes on the hepatic cell during aerospace craft launch or take-off and the accompanying temporal changes in physical integrity of cellular organelles, altered hemodynamic circulation and sheer stress would have an effect on macromolecules associated with metabolism in the liver and energy production. AMP-activated protein kinase (AMPK), an intracellular energy sensor, plays a key role in the regulation of transcription factors such as STAT3, FoxO1/3 and CREB, inhibiting hepatic gluconeogenesis and synthesis of glycogen, fatty acid and cholesterol[26,27,28,29,30]

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