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

Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI - PLoS ONE (2015)

Bottom Line: Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.

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.

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Simplified schematic summarization of muscle fiber types and the pathways affected by olanzapine infusion in skeletal muscle.Striated skeletal muscle fibers can be categorized into three or more different types such as (1) slow-twitch oxidative (SO, red), type I, (2) fast-twitch oxidative-glycolytic (FOG, intermediate twitch) and in rats (3) the fastest-twitch glycolytic (FG, white), type IIb. Gastrocnemius, the muscle examined in this paper, normally contains all of these. Fiber types differ in twitch speed and metabolic flexibility. They are frequently categorized into the above types based one or more of the following: myosin heavy chain isoform content or myosin ATPase activity or gene expression. Compared to SO fibers, FG fibers have: (a) fewer mitochondria, reduced vascularity and myoglobin (Mb) for O2 handling making them whiter in appearance compared to the redder SO fibers; (b) lower expression of genes in FFA, glucose and amino acid oxidation pathways, (c) increased expression of most genes in the glycolysis to lactate pathway; (d) different NADH shuttles; (e) fiber type specific expression of specific sarcomere components, and (f) specific isoforms of calcium and monovalent cation handling or transport proteins. Our data suggest that acute exposure to olanzapine is beginning a process that will eventually cause a fiber type transition from a mixed type to a whiter FG (IIb) type. Whiter muscle has been reported to be more susceptible than other fiber types to atrophy, and such fiber type transitions changes are associated with metabolic disease and obesity.
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pone.0123966.g003: Simplified schematic summarization of muscle fiber types and the pathways affected by olanzapine infusion in skeletal muscle.Striated skeletal muscle fibers can be categorized into three or more different types such as (1) slow-twitch oxidative (SO, red), type I, (2) fast-twitch oxidative-glycolytic (FOG, intermediate twitch) and in rats (3) the fastest-twitch glycolytic (FG, white), type IIb. Gastrocnemius, the muscle examined in this paper, normally contains all of these. Fiber types differ in twitch speed and metabolic flexibility. They are frequently categorized into the above types based one or more of the following: myosin heavy chain isoform content or myosin ATPase activity or gene expression. Compared to SO fibers, FG fibers have: (a) fewer mitochondria, reduced vascularity and myoglobin (Mb) for O2 handling making them whiter in appearance compared to the redder SO fibers; (b) lower expression of genes in FFA, glucose and amino acid oxidation pathways, (c) increased expression of most genes in the glycolysis to lactate pathway; (d) different NADH shuttles; (e) fiber type specific expression of specific sarcomere components, and (f) specific isoforms of calcium and monovalent cation handling or transport proteins. Our data suggest that acute exposure to olanzapine is beginning a process that will eventually cause a fiber type transition from a mixed type to a whiter FG (IIb) type. Whiter muscle has been reported to be more susceptible than other fiber types to atrophy, and such fiber type transitions changes are associated with metabolic disease and obesity.

Mentions: Pathway analyses revealed significant changes in glycolysis (p = 1.3E-7), the citrate cycle (TCA cycle, p = 7.7e-14), fatty acid metabolic processes (p = 6.4e-7), and oxidative phosphorylation (p = 1.8e-38) including fatty acid and branched chain amino acid oxidation (p = 1.8e-7). Consistent with a slower to faster fiber type transition, olanzapine increased the expression of most genes in glycolysis (Fig 2A, S3 Table). However, a rate-controlling step in glycolysis, catalyzed by the skeletal muscle isoform of hexokinase (HK2), decreased -1.9 fold (Fig 2A, S3 Table). This may be related to the observation that muscle hexokinase, HK2, is expressed at higher levels in slower compared to more glycolytic fibers, e.g.: [57]. Notably, muscle hexokinase activity is also depressed in insulin resistance and diabetes [58, 59]. Therefore changes in HK2 are also consistent with the concept of a slow to fast twitch fiber type transition and olanzapine’s effect on (Fig 3). FG fibers are more likely to convert pyruvate from glycolysis to lactate and export the lactate rather than oxidizing the pyruvate in mitochondria. Thus consistent with a fiber type transition being underway, olanzapine increased the expression of Ldha and Slc16a3 normally involved in non-oxidative glucose metabolism and cellular lactate efflux, and decreased expression of the genes coding isoforms of lactate dehydrogenase and lactate transporter that have been associated with increased lactate influx and metabolism, Ldhb and Slc16a1 (also called MCT1, see Fig 2A) [60]. Creatine kinase gene expression (CKM) was also increased by olanzapine (S1 Table and S2 Table), this too is associated with fiber type switching and anaerobic ATP formation in T2D [61].


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

Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI - PLoS ONE (2015)

Simplified schematic summarization of muscle fiber types and the pathways affected by olanzapine infusion in skeletal muscle.Striated skeletal muscle fibers can be categorized into three or more different types such as (1) slow-twitch oxidative (SO, red), type I, (2) fast-twitch oxidative-glycolytic (FOG, intermediate twitch) and in rats (3) the fastest-twitch glycolytic (FG, white), type IIb. Gastrocnemius, the muscle examined in this paper, normally contains all of these. Fiber types differ in twitch speed and metabolic flexibility. They are frequently categorized into the above types based one or more of the following: myosin heavy chain isoform content or myosin ATPase activity or gene expression. Compared to SO fibers, FG fibers have: (a) fewer mitochondria, reduced vascularity and myoglobin (Mb) for O2 handling making them whiter in appearance compared to the redder SO fibers; (b) lower expression of genes in FFA, glucose and amino acid oxidation pathways, (c) increased expression of most genes in the glycolysis to lactate pathway; (d) different NADH shuttles; (e) fiber type specific expression of specific sarcomere components, and (f) specific isoforms of calcium and monovalent cation handling or transport proteins. Our data suggest that acute exposure to olanzapine is beginning a process that will eventually cause a fiber type transition from a mixed type to a whiter FG (IIb) type. Whiter muscle has been reported to be more susceptible than other fiber types to atrophy, and such fiber type transitions changes are associated with metabolic disease and obesity.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4404103&req=5

pone.0123966.g003: Simplified schematic summarization of muscle fiber types and the pathways affected by olanzapine infusion in skeletal muscle.Striated skeletal muscle fibers can be categorized into three or more different types such as (1) slow-twitch oxidative (SO, red), type I, (2) fast-twitch oxidative-glycolytic (FOG, intermediate twitch) and in rats (3) the fastest-twitch glycolytic (FG, white), type IIb. Gastrocnemius, the muscle examined in this paper, normally contains all of these. Fiber types differ in twitch speed and metabolic flexibility. They are frequently categorized into the above types based one or more of the following: myosin heavy chain isoform content or myosin ATPase activity or gene expression. Compared to SO fibers, FG fibers have: (a) fewer mitochondria, reduced vascularity and myoglobin (Mb) for O2 handling making them whiter in appearance compared to the redder SO fibers; (b) lower expression of genes in FFA, glucose and amino acid oxidation pathways, (c) increased expression of most genes in the glycolysis to lactate pathway; (d) different NADH shuttles; (e) fiber type specific expression of specific sarcomere components, and (f) specific isoforms of calcium and monovalent cation handling or transport proteins. Our data suggest that acute exposure to olanzapine is beginning a process that will eventually cause a fiber type transition from a mixed type to a whiter FG (IIb) type. Whiter muscle has been reported to be more susceptible than other fiber types to atrophy, and such fiber type transitions changes are associated with metabolic disease and obesity.
Mentions: Pathway analyses revealed significant changes in glycolysis (p = 1.3E-7), the citrate cycle (TCA cycle, p = 7.7e-14), fatty acid metabolic processes (p = 6.4e-7), and oxidative phosphorylation (p = 1.8e-38) including fatty acid and branched chain amino acid oxidation (p = 1.8e-7). Consistent with a slower to faster fiber type transition, olanzapine increased the expression of most genes in glycolysis (Fig 2A, S3 Table). However, a rate-controlling step in glycolysis, catalyzed by the skeletal muscle isoform of hexokinase (HK2), decreased -1.9 fold (Fig 2A, S3 Table). This may be related to the observation that muscle hexokinase, HK2, is expressed at higher levels in slower compared to more glycolytic fibers, e.g.: [57]. Notably, muscle hexokinase activity is also depressed in insulin resistance and diabetes [58, 59]. Therefore changes in HK2 are also consistent with the concept of a slow to fast twitch fiber type transition and olanzapine’s effect on (Fig 3). FG fibers are more likely to convert pyruvate from glycolysis to lactate and export the lactate rather than oxidizing the pyruvate in mitochondria. Thus consistent with a fiber type transition being underway, olanzapine increased the expression of Ldha and Slc16a3 normally involved in non-oxidative glucose metabolism and cellular lactate efflux, and decreased expression of the genes coding isoforms of lactate dehydrogenase and lactate transporter that have been associated with increased lactate influx and metabolism, Ldhb and Slc16a1 (also called MCT1, see Fig 2A) [60]. Creatine kinase gene expression (CKM) was also increased by olanzapine (S1 Table and S2 Table), this too is associated with fiber type switching and anaerobic ATP formation in T2D [61].

Bottom Line: Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America.

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.

Show MeSH
Related in: MedlinePlus