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    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.

    Olanzapine altered expression of out of genes. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes e. 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. Second generation antipsychotics SGAs, also called, atypical antipsychotics , like olanzapine, are used to treat schizophrenia and bipolar disorder [ 1 ].

    Owing to superior efficacy for psychiatric disorders compared to first generation drugs and a growing number of off- and on-label indications, the rate of new antipsychotic prescriptions has been growing steadily for adults and children [ 2 ].

    For example, estimates indicated 3. Unfortunately, some SGAs cause adverse metabolic side effects that can negatively impact patient compliance. These side effects include hyperglycemia, glucose intolerance, weight gain, dyslipidemia, obesity, hyperglycemia, type 2 diabetes T2D , ketoacidosis and even death [ 4 — 10 ].

    Olanzapine and clozapine are two examples that may cause average body weight gains in the range to 1 pound per week [ 11 ]. While weight gain contributes to the metabolic complications of SGAs, there is strong evidence of body weight independent metabolic effects preceding obesity and type 2 diabetes.

    For example, dyslipidemia, hyperglycemia and glucose intolerance can be observed minutes or days after SGA administration, associated with rapid changes in muscle metabolism [ 12 ]. Therefore understanding acute actions of SGAs might elucidate mechanisms contributing to these side effects. Skeletal muscle is one of the most important tissues by weight for the disposal of glucose and macronutrients.

    As a major component of whole body energy balance it has the potential to impact the acute effects of SGAs on glycemia and glucose tolerance. Chronic olanzapine treatment in rats and dogs increased adiposity but not body weight [ 17 — 19 ]. This implies that changes in lean mass could be occurring, conceivably altering muscle energy requirements, susceptibility to atrophy and glycemia.

    Such changes could facilitate the adiposity elicited by olanzapine [ 17 — 19 ]. More information on how SGAs affects skeletal muscle is needed. Skeletal muscles exhibit different fiber types with distinct features and energy requirements. While various classification schemes a simple classification is slow oxidative, SO , intermediate fast oxidative-glycolytic, FOG and fast twitch glycolytic, FG.

    SO fibers contract or twitch more slowly than other types, are more efficient using oxygen to sustain contractions owing to their higher concentration of myoglobin contributing to darker color , mitochondria and increased vascularity [ 20 , 21 ].

    They express myosin heavy chain 7 MYH7 , as found in soleus. At other end of the spectrum, FG fibers IIb containing MYH4 have a very fast twitch force and very high power, but a low capillary density and mitochondrial and myoglobin content reflected in their whiter color [ 20 — 22 ]. FOG fiber types exhibit intermediate characteristics and unique myosin heavy chains e. An important difference between slower and faster fibers, in addition to energy consumption and twitch speed, is that FG fibers are more susceptible than SO to atrophy arising from various metabolic pathologies [ 23 ].

    In obesity and T2D, skeletal muscle has been associated with either a loss of oxidative enzyme capacity irrespective of muscle fiber type [ 24 ], or a transition of muscle fiber types from more SO to the less metabolically flexible FG fibers [ 25 — 29 ]. Given the importance of skeletal muscle as a major consumer of whole body energy and macronutrients, it is important to understand how olanzapine affects this tissue before significant changes in adiposity occur. Therefore in this study we used RNA-Seq to quantify gene expression in response to continuous infusion of olanzapine for 24h using a protocol that produces a mild hyperglycemia.

    All animal living conditions are consistent with standards laid forth in the Guide for the Care and Use of Laboratory Animals , 8th edition, published by the National Research Council. A week or more after this surgery, all the experimental animals had regained their body weight trajectories.

    They continued to have free access to the same food, water and dried corncob bedding used in the home cages. The next day catheters were connected to the catheter swivel system. Control rats were infused with vehicle at the same rate and volume. At the conclusion of the infusions additional heparinized plasma and blood glucose determinations were obtained for blood glucose determination.

    While under continuous anesthesia, the animals were euthanized by cutting the diaphragm and removing the heart. Total RNA was extracted as previously described with slight modification [ 30 ]. A ratio above 1. Six libraries were pooled per HiSeq lane, followed by on-board cluster generation on a Rapid Run single-end flow cell and subsequent 50 cycles sequencing v3 sequencing kit according to the manufacturer's instructions HiSeq , Illumina.

    The uniquely mapped reads were used to calculate the normalized expression level of genes, as fragments per kilobase of exon per million fragments mapped FPKM , using Cufflinks v. The results were normalized to internal Eef2 mRNA controls.

    Functional annotation clustering, pathway analysis and gene ontology along with associated confidences indicating the strength of evidence for pathway effects were obtained using a series of tools including Ingenuity Pathway Analysis IPA, Ingenuity Systems, www. Pathway analysis was performed on genes that were statistically different based on DEGSeq analysis.

    Olanzapine rapidly elevates plasma glucocorticoids as it does glucose [ 31 ]. The potential impact of glucocorticoid changes on gene expression and needs to be considered in interpreting the findings [ 31 ]. Genes affected by this increase in corticosteroid concentrations were either identified from the above pathway analysis packages or by examining microarray time course data from muscle tissue during constant infusion of methylprednisolone in adrenalectomized rats NCBI Geo profile GDS [ 32 ].

    Rats with comparable body weights vehicle: This acute effect is consistent with previous findings in humans and animal models, however far greater rises in blood glucose can be achieved with higher doses [ 31 ]. Transcriptome sequencing of mRNA of gastrocnemius muscle from rats in the control group resulted in FPKM values expected for striated skeletal muscle tissue. For example, the top one hundred FPKM values were associated with genes that encode proteins of the skeletal muscle contractile machinery, cation transporters, glycolysis, oxidative metabolism and protein synthesis S1 Table.

    Cluster analysis indicated that the data from each rat clustered into their respective control or OLZ treatment groups not shown. Of 26, genes in the rat genome build we used, genes were determined to be significantly different due to olanzapine S1 Table and S2 Table.

    Our goal was to examine compare these two over different FKPM bin ranges e. We endeavored to have at least one OLZ and one Control value in different bins so that more bins could be evaluated. Furthermore, other studies have demonstrated that RNA-Seq is highly accurate for quantifying expression levels [ 33 ].

    Genes were selected so that different FKPM size bins 1— Lpl , Atp2a2 , Tnni1 , — Statistical significance was determined using the DEGSeq R package, which takes into consideration the variability of all of the genes analyzed.

    Bioinformatic analysis of the RNA-Seq data indicates that olanzapine is causing a muscle fiber type transition to the most glycolytic and fastest twitch fiber type IIb. Multiple lines of evidence support this. The first is an observed decrease in the genes for a number of myosin heavy chain genes and an increase in myosin heavy chain 4, Myh4 Table 1.

    The second is altered expression of other genes and isoforms that comprise fiber type specific components of the muscle sarcomere and muscle cation transporters Table 1. The categorization of these genes as slow or fast is based on literature along with annotation from the RGD and Genecard databases.

    Based on these sources, FG fibers e. M-protein; Myom2 , myozenin 1 a. Isoforms of fast and slow twitch muscle fiber genes with statistically significant changes when comparing Vehicle and Olanzapine groups are indicated by the presence of a normalized fold change value. SLIM1, Fhl1 , myoglobin MB , myosin binding protein C, slow type Mybpc1 , myosin, light chain 2, regulatory, cardiac, slow Myl2 , myosin, light chain 3, alkali; ventricular, skeletal, slow Myl3 , myomesin 3 Myom3 , myogenin Myog , myozenin 2 a.

    Olanzapine also decreased the expression of the gene coding for Muscle LIM protein CRP3 , Csrp3 which is involved in slow myosin heavy chain expression and fast to slow fiber transitions [ 55 ]. While adult rat gastrocnemius is generally considered a mixed muscle, its fiber composition already contains a majority of FG fibers [ 56 ]. That explains why the magnitude of the change in IIb-related genes was generally less than the magnitude of lowering of slower twitch fiber associated genes.

    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 This may be related to the observation that muscle hexokinase, HK2 , is expressed at higher levels in slower compared to more glycolytic fibers, e. Notably, muscle hexokinase activity is also depressed in insulin resistance and diabetes [ 58 , 59 ].

    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 ].

    The blue lines indicate the sarcolemma A or the mitochondrial membrane C. Metabolites and glycolytic intermediates are shown in black font; gene names are italicized. Colored font indicates a change predicted to oppose red or promote green the pathway. Where the abundance of two isoforms is different, the font size is smaller for the isoform where the FPKM has a lower value S3 Table.

    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: Compared to SO fibers, FG fibers have: 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. An exception was with isocitrate dehydrogenase IDH subunit genes. Idh3b , Idh3a and Idh3g showed inconsistent changes or no significant difference, whereas Idh3b , an obesity candidate gene [ 49 ], was decreased, as was another IDH Idh2 , Genes for the malate aspartate shuttle were decreased, whereas those for the glycerol phosphate shuttle were increased.

    The observed decrease in malate-aspartate shuttle is consistent with a the concept of a transition being underway to a less oxidative muscle fiber type [ 62 ]. Further consistent with a shift to a more glycolytic fiber type, sarcolemmal, cytosolic and mitochondrial genes coding for enzymes and transporters in lipid oxidation were reduced by olanzapine Table 2. For example, Lpl that encodes lipoprotein lipase was Similarly, gene expression of the sarcolemmal fat transporters, FAT Slc27a1 and fatty acid translocase Cd36 were reduced along with the cytosolic muscle fatty acid binding protein Fabp3 and enzymes that convert fatty acids to their respective acyl-CoAs were reduced, along with genes for fatty acyl-CoA mitochondrial transport and oxidation, including the rate-controlling step in muscle fatty acid oxidation Cpt1b , Table 2.

    In contradistinction, olanzapine infusion increased the expression the mitochondrial fatty acid transporter gene, UCP3 , and that of the adipose tissue specific fatty acid binding protein 4 FABP4 , also called AP2 , Table 2 and S1 Table. While we have no explanation for these changes, it is noted that increased skeletal muscle UCP3 expression occurs in T2D and during slow to fast twitch muscle fiber type transitions [ 63 , 64 ]. Further studies would be needed to examine these ideas.

    The corresponding molecular identity and database number is in S1 Table. Both of these are obesity or diabetes candidate genes [ 49 ]. These 72 genes largely comprise mitochondrial and nuclear-encoded mitochondrial genes in the oxidative phosphorylation pathway, including complexes I—V. To summarize, a third piece of evidence supporting a transition to a more glycolytic type IIb arises from the observation of a general increase in glycolytic genes and diminution in those for oxidation of glucose, lipid and branched chain amino acids, consistent with the known metabolic differences between muscle fiber types [ 56 , 59 , 66 ].

    In order to transition from one fiber type to another, the sarcomeric and non-sarcomeric components specific to the slower fiber types would have to be degraded and replaced with new components found in IIb fibers. Gene expression and pathway analyses are consistent with this idea. Pathway analysis revealed increases in the EIF2 Signaling pathway for global protein synthesis and genes involved in apoptosis and proteosomal mediated degradation.

    Ingenuity pathway analysis predicted that apoptosis was also preparing to be activated Z-score of 2. Olanzapine also up-regulated the expression of genes involved in the 20S core particle of the proteosome including: Genes from the canonical pathway from Ingenuity Pathway Analysis that were significantly affected by olanzapine treatment are shown.

    In addition to the canonical pathways mentioned earlier e. Both have been previously linked to muscle fiber transitions. Olanzapine elevates glucocorticoids [ 31 ], and we did observe a number of glucocorticoid response genes up regulated by olanzapine. However other genes that are induced by methylprednisolone in skeletal muscle during time course studies [ 32 ], were either not affected e.

    Furthermore most of the changes we observed in genes encoding proteins or enzymes of the sarcomere, glycolysis, lipid metabolism, amino acid metabolism and protein turnover could not be ascribed to this mechanism. Nevertheless, upstream pathway analysis did implicate a large set of other potential regulators S8 Table.

    The loss of genes associated with VEGF signaling is consistent with the observation that fast fibers are less vascularized as cited earlier. However, there is no known link between any of the above pathways and receptors that olanzapine is known to inhibit. MYOZ1 expression is restricted to fast skeletal muscle in contrast to myozenin-2 MYOZ2 , FatZ1 which encodes calsarcin-1, found in adult cardiac and slow-twitch skeletal muscle [ 55 ].

    Knock-out mouse studies suggest that myozenins act as a brake on calcineurin signaling which plays a critical role in the promotion of fast-twitch fibers [ 55 ]. Myoz1 KO mice have similar muscle size, lower body weight and more slow oxidative muscle fibers [ 42 ].

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