Abstract
BackgroundPreconditioning environments or therapeutics, to suppress the cellular damage associated with severe oxygen deprivation, is of interest to our understanding of diseases associated with oxygen deprivation. Wildtype C. elegans exposed to anoxia enter into a state of suspended animation in which energy-requiring processes reversibly arrest. C. elegans at all developmental stages survive 24-hours of anoxia exposure however, the ability of adult hermaphrodites to survive three days of anoxia significantly decreases. Mutations in the insulin-like signaling receptor (daf-2) and LIN-12/Notch (glp-1) lead to an enhanced long-term anoxia survival phenotype.Methodology/Principal FindingsIn this study we show that the combined growth environment of 25°C and a diet of HT115 E. coli will precondition adult hermaphrodites to survive long-term anoxia; many of these survivors have normal movement after anoxia treatment. Animals fed the drug metformin, which induces a dietary-restriction like state in animals and activates AMPK in mammalian cell culture, have a higher survival rate when exposed to long-term anoxia. Mutations in genes encoding components of AMPK (aak-2, aakb-1, aakb-2, aakg-2) suppress the environmentally and genetically induced long-term anoxia survival phenotype. We further determine that there is a correlation between the animals that survive long-term anoxia and increased levels of carminic acid staining, which is a fluorescent dye that incorporates in with carbohydrates such as glycogen.Conclusions/SignificanceWe conclude that small changes in growth conditions such as increased temperature and food source can influence the physiology of the animal thus affecting the responses to stress such as anoxia. Furthermore, this supports the idea that metformin should be further investigated as a therapeutic tool for treatment of oxygen-deprived tissues. Finally, the capacity for an animal to survive long bouts of severe oxygen deprivation is likely dependent on specific subunits of the heterotrimeric protein AMPK and energy stores such as carbohydrates.
Highlights
Oxygen deprivation is central to many life-threatening human health issues including blood loss, pulmonary disorders, stroke and myocardial infarction
In this study we show that the combined environment of 25uC growth condition and the feeding of HT115 E. coli strain will precondition adult hermaphrodites so that they have an enhanced long-term anoxia survival phenotype
We further determine that there is a correlation between the animals that survive long-term anoxia and increased levels of carminic acid, which is a fluorescent dye that incorporates in with carbohydrates such as glycogen. These results show that environmental effects such as E. coli food source and growth temperature, and pharmacological agents such as metformin, can influence the ability of C. elegans to survive anoxia
Summary
Oxygen deprivation is central to many life-threatening human health issues including blood loss, pulmonary disorders, stroke and myocardial infarction. Human organs such as the heart and brain are vulnerable to oxygen and nutrient deprivation caused by blood loss or a decrease in blood delivery [1,2]. Preconditioning is a protective technique in which organisms, prior to ischemic bouts, are exposed to a specific environment or a cellular change is induced genetically or pharmacologically. An understanding of the molecular changes that influence an organisms’ ability to survive severe oxygen deprivation is of interest to understanding human health related injuries induced by ischemia and reperfusion. Mutations in the insulin-like signaling receptor (daf-2) and LIN-12/Notch (glp-1) lead to an enhanced long-term anoxia survival phenotype
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