Fasting prevents hypoxia-induced defects of proteostasis in C. elegans

TLDR: It is shown that that worms can be protected from hypoxia-induced protein aggregation if they are fasted (removed from their food source) prior to experiencingHypoxia, and a non-canonical role for the insulin/IGF-like signaling pathway in coordinating the effects of hypoxIA and nutritional state on proteostasis is suggested.

Abstract: Low oxygen conditions (hypoxia) can impair essential physiological processes and cause cellular damage and death. We have shown that specific hypoxic conditions disrupt protein homeostasis in C. elegans , leading to protein aggregation and proteotoxicity. Here, we show that nutritional cues regulate this effect of hypoxia on proteostasis. Animals fasted prior to hypoxic exposure develop dramatically fewer protein aggregates compared to their fed counterparts, indicating that the effect of hypoxia is abrogated. Fasting is effective at protecting against hypoxia-induced proteostasis defects in multiple developmental stages, tissues, and in different models of misfolded or aggregation prone proteins. Our data also demonstrate that the effect of fasting is induced and reversed quite rapidly, suggesting that the nutritional environment experienced at the onset of hypoxia dictates at least some aspects of the physiological response to hypoxia. We further demonstrate that the insulin/IGF-like signaling pathway plays a role in mediating the protective effects of fasting in hypoxia. Animals with mutations in daf-2 , the C. elegans insulin-like receptor, display wild-type levels of hypoxia-induced protein aggregation upon exposure to hypoxia when fed, but are not protected by fasting. However, we found that DAF-2 acts independently of the FOXO transcription factor, DAF-16, to mediate the protective effects of fasting. These results suggest a non-canonical role for the insulin/IGF-like signaling pathway in coordinating the effects of hypoxia and nutritional state on proteostasis.