Molecular Responses to Whole-Body Dehydration in a Sequenced Vertebrate, Xenopus Laevis: Regulation of Antioxidants and Metabolism by the Sirtuin Protein Deacetylases

Luu, Bryan E.

doi:10.22215/etd/2018-13363

Cited by 1 publication

(7 citation statements)

References 60 publications

(98 reference statements)

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“…This phosphorylation, along with interactions with other proteins, promotes the nuclear exclusion of FoxO3a inhibiting its influence on transcriptional activities. In this thesis, the relative Ser253 phosphorylation on FoxO3a remained constant suggesting that although Akt is downregulated during dehydration its influence on FoxO3a has not been reversed (Luu, 2018). In C2C12 myoblasts, Tong et al (2009) demonstrated that insulin growth factor treatment enhanced cytoplasmic FoxO3a phosphorylation at Thr318/321 and reduced nuclear FoxO3a contents.…”

Section: Discussionmentioning

confidence: 76%

“…This was demonstrated through a correlation between c-Raf activation and the phosphorylation of its downstream targets which ultimately led to an increase in STAT3 phosphorylation (regulates translation) and RSK1 phosphorylation (regulates translation) during high dehydration (Malik and Storey 2009a). In addiiton, previous work by Luu (2011Luu ( , 2018 on X. laevis, demonstrated that phosphorylation cascades regulated cell cycle arrest and protein translation signals. Luu demonstrated that in response to whole animal dehydration, Akt protein and phosphorylation levels are reduced in liver and skeletal muscle of X. laevis and as a result, the mTORC1 pathway that regulates protein synthesis is dissociated and suppressed.…”

Section: Post-translational Regulation By Protein Phosphorylationmentioning

confidence: 89%

“…Since it has been demonstrated that plasma glucose levels increase in highly dehydrated X. laevis to as much as 5.8 mM it is likely that HK is functioning maximally during dehydration, quickly converting glucose to glucose-6-phosphate (G6P) which locks the substrate into the cell (Malik and Storey 2009a) ( Figure 1). However, the efficiency of glucose transport into skeletal muscle cells during dehydration remains unknown, although work has demonstrated that transcript levels of the GLUT4 glucose transporter remain stable (Luu 2018 Balinsky et al 1967a;Hillman 1978a;Malik and Storey 2009. In addition to modifications of glycolytic enzymes, glutamate dehydrogenase (GDH) also showed altered properties in response to dehydration. Affinity for α-KG decreased under high dehydration conditions with an 8.39-fold increase in the Km for α-KG (up to 0.24mM) while also gaining affinity for glutamate with the Km decreasing down to 3.59mM (Appendix 1).…”

Section: Metabolic Enzymesmentioning

confidence: 99%

“…Therefore, the interaction between these two signals details the crosstalk between AMPK and mTORC1 signaling on ULK1 (Egan et al 2011). The signaling through adenylate ratios and the activation of AMPK in X. laevis skeletal muscle is unknown, although mTOR signals have previously been reported to be downregulated (Luu, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…This thesis shows that an interruption of regular circulation leads to adjusted metabolic enzyme function and altered energy stress signalling in skeletal muscle (Hillman 1978a;Hillman and Sommerfeldt 1981;Storey 2016, 2019). Previously, Luu (2018) demonstrated that important proteins involved in fatty acid oxidation were suppressed in skeletal muscle, along with glycolytic genes and pyruvate dehydrogenase kinases. Furthermore, this thesis demonstrates that the stress signalling is regulated to promote fatty acid synthesis through reduced ACC1 phosphorylation (Chapter 4).…”

Section: Introductionmentioning

confidence: 99%

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Reversible Enzyme Phosphorylation as a Mechanism for Metabolic Adaptation to Dehydration in the Skeletal Muscle of the African Clawed Frog, Xenopus laevis

Childers¹

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The undersigned hereby recommend to the Faculty of Graduate Studies and Research acceptance of this thesis:Reversible enzyme phosphorylation as a mechanism for metabolic adaptation to dehydration in the skeletal muscle of the African clawed frog, Xenopus laevis. AbstractXenopus laevis, although mainly an aquatic frog, lives in seasonally arid regions of southern Africa where well-developed dehydration tolerance is needed when ponds dry up. Frogs can endure about 40% loss of total body water leading to increased hematocrit and blood viscosity that restrict blood and oxygen delivery to tissues, elevate tissue osmolality, and lead to accumulation of lactate and urea. As one response to dehydration, frogs show restricted blood flow to skeletal muscle to preferentially maintain supply to the brain and internal organs. I hypothesized that dehydration stress triggers modifications to cellular energy production in skeletal muscle and could recruit alternative fuel use. This thesis explores metabolic regulation of enzymes (aldolase, CK, IDH), and energy stress signaling (via AMPK) in skeletal muscle of X. laevis. A particular focus was put on regulation via protein posttranslational phosphorylation to adapt enzyme activity and substrate affinity to changing physiological needs during dehydration. Analysis of kinetic parameters found that aldolase, CK and IDH all showed reduced maximal velocities and altered substrate affinities during dehydration.Downregulation of aldolase suggested a reduction in glycolytic rate during dehydration, moderating the use of glucose, whereas CK regulation modulates phosphocreatine consumption. Substrate affinities of both CK and IDH were dependent on magnesium concentrations. CK was more active at higher Mg 2+ concentrations that occur as tissues dehydrate whereas IDH showed increased affinity for Mg 2+ that could shift the reaction to favor α-KG production during dehydration. I hypothesized that changes to muscle energetics would stimulate the action of AMPK and its downstream effectors to promote a fuel switching from carbohydrates to include fats during dehydration. However, iv phosphorylated AMPK (activated) did not increase and the regulation of two key downstream AMPK targets, acetyl-coA carboxylase and Unc-51 like autophagy activating kinase 1, did not indicate recruitment of fatty acid metabolism or autophagy for energy during dehydration in skeletal muscle. Overall, these studies showed that reversible protein phosphorylation has a prominent role in controlling X. laevis skeletal muscle enzyme function and reorganization of metabolic pathways during whole animal dehydration.v

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Section: Discussionmentioning

confidence: 76%