Insulin/IGF-1 Signaling, including Class II/III PI3Ks, β-Arrestin and SGK-1, Is Required in C. elegans to Maintain Pharyngeal Muscle Performance during Starvation

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.

Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants

“…Loss-of-function mutations in the daf-2 gene are associated with constitutive dauer formation (a hibernation-like state of diapause) [26], defects in associative learning [27], and failure to recover pharyngeal pumping during starvation [28]. The latter finding was the starting point for the current studies.…”

“…Two genes, unc-64 and unc-31 , regulate insulin secretion in C. elegans [32], control dauer formation at the restrictive temperature of 27°C [33], and, in the case of unc-64 , affect recovery of pharyngeal pumping during starvation, which requires insulin signaling [28]. UNC-64 (syntaxin) is involved in release from both dense-core vesicles and synaptic vesicles, whereas UNC-31 (Ca ++ -dependent activator protein for secretion, CAPS) mainly regulates release from dense-core vesicles.…”

“…To account for these findings, we [28] previously proposed that the major signaling molecule Akt downstream of the insulin receptor regulates via phosphorylation a variety of ion channels, including voltage-gated Ca ++ channels and the ketamine target UNC-68 (ryanodine receptor) [52]. …”

Multiple excitatory and inhibitory neural signals converge to fine‐tuneCaenorhabditis elegansfeeding to food availability

“…Furthermore, it was observed that worms carrying mutations in the gene unc-31, which encodes calcium-activated protein for secretion (CAPS), a calcium-binding protein required for exocytosis (41) pumped constitutively in the absence of food (42). Additional work has investigated C. elegans pharyngeal function in different behavioral contexts and during starvation (4,(43)(44)(45)(46). These suggest a complex shifting behavioral response of the pharyngeal system, which is dependent on the "on" and "off" food context.…”

Food deprivation and nicotine correct akinesia and freezing in Na+‐leak current channel (NALCN)‐deficient strains of Caenorhabditis elegans

“…Previously, we discovered that the NALCN is involved in the recovery of pharyngeal pumping in response to food deprivation, which we attributed to its effects on insulin secretion (Dwyer & Aamodt ). During those studies, we noticed that NALCN‐deficient strains ( nca‐1;nca‐2 , unc‐79 and unc‐80 ) exposed to overnight starvation showed surprising and dramatic improvements in locomotion.…”