Abstract
In C. elegans, pharyngeal pumping is regulated by the presence of bacteria. In response to food deprivation, the pumping rate rapidly declines by about 50–60%, but then recovers gradually to baseline levels on food after 24 hr. We used this system to study the role of insulin/IGF-1 signaling (IIS) in the recovery of pharyngeal pumping during starvation. Mutant strains with reduced function in the insulin/IGF-1 receptor, DAF-2, various insulins (INS-1 and INS-18), and molecules that regulate insulin release (UNC-64 and NCA-1; NCA-2) failed to recover normal pumping rates after food deprivation. Similarly, reduction or loss of function in downstream signaling molecules (e.g., ARR-1, AKT-1, and SGK-1) and effectors (e.g., CCA-1 and UNC-68) impaired pumping recovery. Pharmacological studies with kinase and metabolic inhibitors implicated class II/III phosphatidylinositol 3-kinases (PI3Ks) and glucose metabolism in the recovery response. Interestingly, both over- and under-activity in IIS was associated with poorer recovery kinetics. Taken together, the data suggest that optimum levels of IIS are required to maintain high levels of pharyngeal pumping during starvation. This work may ultimately provide insights into the connections between IIS, nutritional status and sarcopenia, a hallmark feature of aging in muscle.
Highlights
Insulin/insulin-like growth factor signaling (IIS) regulates various facets of growth and reproductive maturation, including energy metabolism, forkhead box O (FOXO) activity, and apoptosis [1,2,3]
When insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) activity is partially reduced in C. elegans temperature-sensitive daf-2 mutants by shifting the culture temperature from 15uC to 20uC, lifespan is significantly extended in all animals in the population
These findings suggest that AGE-1 normally inhibits recovery of pharyngeal pumping in response to starvation, and that LY294002 targets a different class of phosphatidylinositol 3-kinases (PI3Ks) (II and/or III) to inhibit the response
Summary
Insulin/insulin-like growth factor signaling (IIS) regulates various facets of growth and reproductive maturation, including energy metabolism, forkhead box O (FOXO) activity, and apoptosis [1,2,3]. This pathway controls the rate of development and aging in a wide range of organisms from C. elegans to man [4,5,6,7]. By contrast, when IIS is further reduced by growth at 25uC, roughly half of the animals die prematurely, whereas the other half lives much longer than wild-type controls [4]. The findings in C. elegans are especially intriguing because the animals are genetically identical, yet die at very different ages
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