Age-Dependent Changes in Gluco-Glyceroneogenesis and Fat Synthesis Sustain Copulation Fitness in C. Elegans Males
Loading...
Date
2021-03-11
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Genetics, diet, and environment alter stereotypical cognitive and locomotive decline with age. In C. elegans males, dysregulated metabolism contributes to behavioral decline due to increases in neuromuscular excitability. Behavioral decline can also be exacerbated by excessive metabolic production of ROS disrupting calcium handling and damaging biomolecules. Previous work showed age-dependent increases in metabolic genes encoding PEPCK (pck-1/2) and Stearoyl CoA fatty acid desaturases (fat-5/6/7). In order to understand how shifts in fuel utilization result in behavioral dysfunction, we addressed the role of increased gluco- and glyceroneogenesis (pck-1/2) and fatty acid synthesis (fat-6/7) in sustaining mating behavior over the first 48 hours of adulthood.
Through mating potency and fitness assays, we found that during early adulthood, epidermal PEPCK maintains the metabolic needs of neuromuscular circuitry regulating male mating behavior. We used glucose supplementation to show epidermal PEPCK-dependent gluconeogenesis supports neuromuscular function on day 1 of adulthood. To explore how PEPCK is regulated we characterized a mutant of succinate dehydrogenase (SDHA), subunit A of complex II of the electron transport chain, shown to increase PEPCK levels. We found, in SDHA mutants, increases in the transcript levels of metabolic genes involved in shunting metabolites away from the TCA cycle. Finally, we found that inhibition of ETC and TCA cycle separately did not elevate PEPCK to similar levels seen in SDHA suggesting metabolic disruption of both pathways are necessary to induce PEPCK based gluco-glyceroneogenesis.
We addressed the role of fatty acid synthesis in maintaining mating behavior during the first 48 hrs of adulthood. We observed, using mating potency and fitness assays, day 2 epidermal FAT-6, used in fatty acid synthesis, circumvents increased fatty acid oxidation disrupting the neuromuscular circuitry regulating male mating behavior. We observed aging males underwent food deprivation dependent degradation of FAT-6, which was compensated by transcriptionally active fat-6 on day 2 of adulthood. Furthermore, using Markov modeling we found the preference for food in aging wild type males decreases on day 2 of adulthood. Finally, the lack of FAT-6 and FAT-7 results in dysregulation of ERG K+ channels which inappropriately hyperpolarizes the mating circuitry responsible for spicule insertion.
Description
Keywords
FAT-5, FAT-6, FAT-7, PCK-1, PCK-2, SDHA-1, UNC-103, EGL-2, CaMKII, SOD-4, TCA, GCaMP, YFP