Adaptations to Excess Choline in Insulin Resistant and Pcyt2 Deficient Skeletal Muscle

It was hypothesized that choline supplementation in insulin resistant (IR) CTP:phosphoethanolamine cytidylyltransferase deficient (Pcyt2+/-) mice would ameliorate muscle function by remodeling glucose and fatty acid (FA) metabolism. Pcyt2+/- mice either received no treatment or were allowed access to 2 mg/ml choline in drinking water for 4 weeks. Skeletal muscle was harvested from choline treated and untreated mice. Lipid analysis and metabolic gene expression and signaling pathways were compared between untreated Pcyt2+/- mice, treated Pcyt2+/- mice and Pcyt2+/+ mice. The major positive effect of choline supplementation on IR muscle was the reduction of glucose utilization for FA and TAG synthesis and increased muscle glucose storage as glycogen. Choline reduced the expression of genes for FA and TAG formation (Scd1, Fas, Srebp1c, Dgat1/2), upregulated the genes for FA oxidation (Cpt1, PparÎą, Pgc1Îą) and had minor effects on phospholipid and lipolysis genes. Pcyt2+/- muscle had reduced insulin signaling (IRS1), autophagy (LC3) and choline transport (CTL1) proteins that were restored by choline treatment. Additionally, choline activated AMPK and Akt while inhibiting mTORC1 phosphorylation. These data established that choline supplementation could restore muscle glucose metabolism by reducing lipogenesis and improving mitochondrial and intracellular signaling for protein and energy metabolism in insulin resistant Pcyt2 deficient mice.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author