title: RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.
abstract: Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side effects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with vehicle or olanzapine for 24h using a dose leading to a mild hyperglycemia. RNA-Seq was performed on gastrocnemius muscle, followed by alignment of the data with the Rat Genome Assembly 5.0. Olanzapine altered expression of 1347 out of 26407 genes. Genes encoding skeletal muscle fiber-type specific sarcomeric, ion channel, glycolytic, O2- and Ca2+-handling, TCA cycle, vascularization and lipid oxidation proteins and pathways, along with NADH shuttles and LDH isoforms were affected. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes (e.g., type 1), while up regulating those for the most glycolytic and least metabolically flexible, fast twitch fiber type, IIb. Protein turnover genes, necessary to bring about transition, were also up regulated. Potential upstream regulators were also identified. Olanzapine appears to be rapidly affecting the muscle transcriptome to bring about a change to a fast-glycolytic fiber type. Such fiber types are more susceptible than slow muscle to atrophy, and such transitions are observed in chronic metabolic diseases. Thus these effects could contribute to the altered body composition and metabolic disease olanzapine causes. A potential interventional strategy is implicated because aerobic exercise, in contrast to resistance exercise, can oppose such slow to fast fiber transitions.
authors.affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.
authors.forename: Andras
authors.initials: A
authors.lastname: Hajnal
authors.affiliation: Department of Public Health Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Salzberg
authors.affiliation: Department of Pharmacology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America; Department of Biochemistry and Molecular Biology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America; The Institute for Personalized Medicine, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.
authors.forename: Yuka Imamura
authors.initials: YI
authors.lastname: Kawasawa
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism*; D000077152:Olanzapine; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D001569:Benzodiazepines; D000077152:Olanzapine