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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.

SUBMITTER: Lynch CJ

PROVIDER: S-EPMC4404103 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

Lynch Christopher J CJ Xu Yuping Y Hajnal Andras A Salzberg Anna C AC Kawasawa Yuka Imamura YI

PloS one 20150420 4

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 ...[more]

PMID: 25893406

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Project description:The purpose of this study was to examined the acute actions of the second generation antipsychotic (SGA), olanzapine, on skeletal muscle (gastrocnemius) of Sprague Dawley Rats. SGAs cause metabolic side effects including leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. These effects are preceded by glucose intolerance and increased FFA flux and metabolism in peripheral tissues. Skeletal muscle is a likely target of glucose intolerance, therefore understanding how olanzapine affects the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats freely fed on normal chow with comparable body weights (vehicle: 373±9g, olanzapine: 388±11g, p=0.34) were infused with vehicle or olanzapine for 24h using a dosing regimen leading to mild hyperglycemia (vehicle, 98±2mg/dl; olanzapine 127±4mg/dl, p=0.0023). For the olanzapine group, the venous catheter was attached to a syringe pump (Model NE-300) filled with olanzapine (Dr. Reddy’s Laboratories Ltd, Hyderabad, India) in sterile saline (infusion: 1mg/100g BW loading dose for 0.5h and then 0.04mg/100g/h continuously for 23.5h). Gastrocnemius was then surgically removed under isoflurane anesthesia (carried with 100% O2), and frozen between two aluminum blocks cooled to the temperature of liquid nitrogen and then stored at -80oC until RNA was isolated. With anesthesia gas flow continuing, the animals were euthanized by cutting the diaphram and removing the heart. The mRNA was isolated from from these muscles and used for RNA-Seq followed by alignment of the data with the rat genome assembly 5.0. To determine significant differences in FPKM values between control and olanzapine groups, the DEGexp function of the DEGseq 1.18.0 R package was used with the Likelihood Ratio Test (LRT) and default parameters. In the uploaded excel file, P values with p<0.05 and p<0.001 are shown for each row in different columns indicated by the number 1. The value 0 indicates the row is not significantly different.

Project description:This study evaluated the effects of muscle fiber characteristics on meat quality traits in 45 female fast- and slow-growing ducks. Three duck breeds at typical market ages were selected and slaughtered, including fast-growing ducks (Cherry Valley duck) and slow-growing ducks (Small-sized Beijing duck and Liancheng White duck). M. pectoralis major (PM), m. soleus (SOL), m. gastrocnemius (GAS) and m. extensor digitorum longus (EDL) were used to assess muscle fiber characteristics as well as meat quality properties. The results showed that the fiber compositions in PM, GAS, and EDL muscles only consisted of fast-twitch fibers irrespective of the breeds, while a low percentage of slow-twitch fibers were observed in slow-growing ducks (17.03% and 29.14%). The significant clear differences of fiber diameter, fiber density and fiber cross-sectional area (CSA) was observed among three duck breeds. Small-sized Beijing ducks had the highest diameter and cross-sectional fiber area coupled with a dramatically lowest fiber density when compared to other 2 breeds both in breast and leg muscles. In addition, the meat quality traits such as moisture content, release water, and intramuscular fat content were significantly affected by the breeds. Slow-growing ducks, especially Liancheng White ducks, exhibited higher release water, intramuscular fat content, as well as lower moisture content (P < 0.05) compared to the fast-growing ducks. The lower pH24 h value and shear force tended to be present in breast of Liancheng White ducks (P < 0.05). The higher protein content and collagen content were detected in breast of Liancheng White ducks and the leg muscle of Small-sized Beijing ducks (P < 0.05), respectively. Finally, the correlation coefficients between muscle fiber characteristics and meat quality showed that the diameter, density and CSA of fibers had a moderate or significant correlation with pH, shear force value, moisture content, and protein content of meat in fast-growing ducks. In slow-growing ducks, muscle fiber characteristics had a moderate or significant correlation with pH, shear force value, release water, protein content, and intramuscular fat content of meat. These results indicated that muscle fiber characteristics is a useful parameter to explain in parts the variation of meat quality including pH, shear force value, and protein content of meat, both in slow-growing ducks and fast-growing ducks.

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RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

Publications

RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

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