Eili Tranheim Kase

• Dalmao-Fernandez, Andrea; Katare, Parmeshwar Bajirao; Bakke, Hege Gilbø; Hamarsland, Håvard; Ellefsen, Stian & Singh, Sachin [Show all 10 contributors for this article] (2025). The use of three-dimensional primary human myospheres to explore skeletal muscle effects of in vivo krill oil supplementation. In vitro models. ISSN 2731-3433. 4(2), p. 145–155. doi: 10.1007/s44164-025-00087-6. Full text in Research Archive Show summary

  Supplementation with krill oil has shown effects on whole-body lipid and glucose metabolism, as well as on skeletal muscle strength and function. We previously showed that krill oil intervention in vivo promoted fatty acid metabolism and protein synthesis in cultured human myotubes in a two-dimensional (2D) model. The aim of this study was to explore the effects of krill oil supplementation in vivo in a 3D myosphere model, and to compare a the human skeletal muscle 3D cell model to a 2D model. Myospheres were formed from myoblasts obtained before and after 7 weeks of in vivo krill oil intervention. Glucose and oleic acid metabolism were assessed, and transcriptomic and proteomic analyses were performed. In vivo intervention with krill oil increased glucose metabolism in myospheres, while no effect was observed on fatty acid metabolism. Transcriptomic analyses of myospheres after krill oil intervention showed increased expression of genes involved in pathways like motor proteins and hypertrophy, as well as in calcium signaling, of which motor proteins and hypertrophy pathways have not been described in 2D myotube cultures. Proteomic analyses after krill oil intervention showed increased expression of proteins in glycolysis/gluconeogenesis and fatty acid degradation. Comparison of proteins expressed in the 3D myosphere model and the 2D myotube model at the basal level showed that in myospheres, mitochondrial gene expression and translation dominated, while in 2D cultures, mitochondrial organization and response to oxidative stress were more important. These findings suggest that in vivo krill oil intervention induces different metabolic effects when comparing 3D and 2D cultures. In contrast to the 2D model, data obtained with the 3D model showed gene expression changes that are more compatible with previously observed results in vivo concerning skeletal muscle motoric function. Hence, the 3D cell model might better reflect krill oil-induced modifications in skeletal muscle performance in vivo than the 2D model.

• Skagen, Christine; Stevanovic, Stanislava; Bakke, Hege Gilbø; Nyman, Tuula Anneli; Stensland, Maria & Kase, Eili Tranheim [Show all 9 contributors for this article] (2025). Reduced lipid and glucose oxidation and reduced lipid synthesis in AMPKα2/ myotubes. Archives of Physiology and Biochemistry. ISSN 1381-3455. 131(3), p. 483–492. doi: 10.1080/13813455.2024.2449409. Full text in Research Archive Show summary

  Adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in regulation ofmetabolic homeostasis. To understand the role of the catalytic α2 subunit of AMPK in skeletal muscleenergy metabolism, myotube cultures were established from AMPKα2+/+ and AMPKα2-/- mice. Myotubesfrom AMPKα2-/- mice had lower basal oleic acid and glucose oxidation compared to myotubes fromAMPKα2+/+ mice. However, the relative response to mitochondrial uncoupling was increased for oleicacid oxidation. Incorporation of acetate into lipids was also lower in myotubes from AMPKα2-/- mice.Proteomics analysis revealed that AMPKα2-/- myotubes had upregulated pathways related to mitochondrialfunction and fatty acid oxidation, and decreased pathways related to fatty acid biosynthesis. Inconclusion, ablation of AMPKα2 catalytic subunit in skeletal muscle cells resulted in reduced basaloxidation of glucose and fatty acids, however upregulated pathways related to mitochondrial functionand fatty acid oxidation and reduced lipid formation

• Katare, Parmeshwar Bajirao; Dalmao-Fernandez, Andrea; Mengeste, Abel Mulu; Navabakbar, Farnaz; Hamarsland, Håvard & Ellefsen, Stian [Show all 12 contributors for this article] (2024). Krill oil supplementation in vivo promotes increased fuel metabolism and protein synthesis in cultured human skeletal muscle cells. Frontiers in Nutrition. 11:1452768, p. 1–14. doi: 10.3389/fnut.2024.1452768. Full text in Research Archive Show summary

  Introduction: Krill oil is a dietary supplement derived from Antarctic krill; a small crustacean found in the ocean. Krill oil is a rich source of omega-3 fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid, as well as the antioxidant astaxanthin. The aim of this study was to investigate the effects of krill oil supplementation, compared to placebo oil (high oleic sunflower oil added astaxanthin), in vivo on energy metabolism and substrate turnover in human skeletal muscle cells. Methods: Skeletal muscle cells (myotubes) were obtained before and after a 7-week krill oil or placebo oil intervention, and glucose and oleic acid metabolism and leucine accumulation, as well as effects of different stimuli in vitro, were studied in the myotubes. The functional data were combined with proteomic and transcriptomic analyses. Results: In vivo intervention with krill oil increased oleic acid oxidation and leucine accumulation in skeletal muscle cells, however no effects were observed on glucose metabolism. The krill oil-intervention-induced increase in oleic acid oxidation correlated negatively with changes in serum low-density lipoprotein (LDL) concentration. In addition, myotubes were also exposed to krill oil in vitro. The in vitro study revealed that 24 h of krill oil treatment increased both glucose and oleic acid metabolism in myotubes, enhancing energy substrate utilization. Transcriptomic analysis comparing myotubes obtained before and after krill oil supplementation identified differentially expressed genes associated with e.g., glycolysis/gluconeogenesis, metabolic pathways and calcium signaling pathway, while proteomic analysis demonstrated upregulation of e.g., LDL-receptor in myotubes obtained after the krill oil intervention. Conclusion: These findings suggest that krill oil intervention promotes increased fuel metabolism and protein synthesis in human skeletal muscle cells, with potential implications for metabolic health.

• Stevanovic, Stanislava; Dalmao-Fernandez, Andrea; Mohamed, Derya; Nyman, Tuula Anneli; Kostovski, Emil & Iversen, Per Ole [Show all 11 contributors for this article] (2024). Time-dependent reduction in oxidative capacity among cultured myotubes from spinal cord injured individuals. Acta Physiologica. ISSN 1748-1708. 240:e14156(7), p. 1–15. doi: 10.1111/apha.14156. Full text in Research Archive Show summary

  Background Skeletal muscle adapts in reaction to contractile activity to efficiently utilize energy substrates, primarily glucose and free fatty acids (FA). Inactivity leads to atrophy and a change in energy utilization in individuals with spinal cord injury (SCI). The present study aimed to characterize possible inactivity-related differences in the energy metabolism between skeletal muscle cells cultured from satellite cells isolated 1- and 12-months post-SCI. Methods To characterize inactivity-related disturbances in spinal cord injury, we studied skeletal muscle cells isolated from SCI subjects. Cell cultures were established from biopsy samples from musculus vastus lateralis from subjects with SCI 1 and 12 months after the injury. The myoblasts were proliferated and differentiated into myotubes before fatty acid and glucose metabolism were assessed and gene and protein expressions were measured. Results The results showed that glucose uptake was increased, while oleic acid oxidation was reduced at 12 months compared to 1 month. mRNA expressions of PPARGC1α, the master regulator of mitochondrial biogenesis, and MYH2, a determinant of muscle fiber type, were significantly reduced at 12 months. Proteomic analysis showed reduced expression of several mitochondrial proteins. Conclusion In conclusion, skeletal muscle cells isolated from immobilized subjects 12 months compared to 1 month after SCI showed reduced fatty acid metabolism and reduced expression of mitochondrial proteins, indicating an increased loss of oxidative capacity with time after injury.

• Krapf, Solveig; Lund, Jenny; Bakke, Hege Gilbø; Nyman, Tuula Anneli; Bartesaghi, Stefano & Peng, Xiao-Rong [Show all 9 contributors for this article] (2023). SENP2 knockdown in human adipocytes reduces glucose metabolism and lipid accumulation, while increases lipid oxidation. Metabolism Open. 18. doi: 10.1016/j.metop.2023.100234. Full text in Research Archive Show summary

  Adipose tissue is one of the main regulative sites for energy metabolism. Excess lipid storage and expansion of white adipose tissue (WAT) is the primary contributor to obesity, a strong predisposing factor for development of insulin resistance. Sentrin-specific protease (SENP) 2 has been shown to play a role in metabolism in murine fat and skeletal muscle cells, and we have previously demonstrated its role in energy metabolism of human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism in primary human fat cells by using cultured primary human adipocytes to knock down the SENP2 gene. Glucose uptake and oxidation, as well as accumulation and distribution of oleic acid into complex lipids were decreased, while oleic acid oxidation was increased in SENP2-knockdown cells compared to control adipocytes. Furthermore, lipogenesis was reduced by SENP2-knockdown in adipocytes. Although TAG accumulation relative to total uptake was unchanged, there was increased mRNA expression of metabolically relevant genes such as UCP1 and PPARGC1A and mRNA and proteomic data revealed increased levels of mRNA and proteins related to mitochondrial function by SENP2-knockdown. In conclusion, SENP2 is an important regulator of energy metabolism in primary human adipocytes and its knockdown reduce glucose metabolism and lipid accumulation, while increasing lipid oxidation in human adipocytes.

• Dalmao-Fernandez, Andrea; Aizenshtadt, Aleksandra; Bakke, Hege Gilbø; Krauss, Stefan Johannes Karl; Rustan, Arild Christian & Thoresen, G. Hege [Show all 7 contributors for this article] (2023). Development of three-dimensional primary human myospheres as culture model of skeletal muscle cells for metabolic studies. Frontiers in Bioengineering and Biotechnology. 11, p. 1–13. doi: 10.3389/fbioe.2023.1130693. Full text in Research Archive Show summary

  Introduction: Skeletal muscle is a major contributor to whole-body energy homeostasis and the utilization of fatty acids and glucose. At present, 2D cell models have been the most used cellular models to study skeletal muscle energy metabolism. However, the transferability of the results to in vivo might be limited. This project aimed to develop and characterize a skeletal muscle 3D cell model (myospheres) as an easy and low-cost tool to study molecular mechanisms of energy metabolism. Methods and results: We demonstrated that human primary myoblasts form myospheres without external matrix support and carry structural and molecular characteristics of mature skeletal muscle after 10 days of differentiation. We found significant metabolic differences between the 2D myotubes model and myospheres. In particular, myospheres showed increased lipid oxidative metabolism than the 2D myotubes model, which oxidized relatively more glucose and accumulated more oleic acid. Discussion and conclusion: These analyses demonstrate model differences that can have an impact and should be taken into consideration for studying energy metabolism and metabolic disorders in skeletal muscle.

• Krapf, Solveig; Lund, Jenny; Saqib, Awais Ur Rehman; Bakke, Hege Gilbø; Rustan, Arild Christian & Thoresen, G. Hege [Show all 7 contributors for this article] (2022). Pancreatic Cancer Cell-Conditioned, Human-Derived Primary Myotubes Display Increased Leucine Turnover, Increased Lipid Accumulation, and Reduced Glucose Uptake. Metabolites. 12(11). doi: 10.3390/metabo12111095. Full text in Research Archive Show summary

  Metabolic alterations occurring in cancer cells have been seen to also occur in other tissues than cancerous tissue. For instance, cachexia, peripheral insulin resistance, or both are commonly seen in patients with cancer. We explored differences in substrate use in myotubes conditioned with the medium from a pancreatic cancer cell line, PANC-1, or primary human pancreatic cells, hPECs. Protein turnover was assessed using scintillation proximity assay, glucose and oleic acid handling were analyzed by substrate oxidation assay. We performed qPCR to study gene expression and immunoblotting and proteomic analyses to study protein expression. PANC-1-conditioned myotubes had an imbalance in protein turnover with decreased accumulation, increased decay, and decreased MYH2 gene expression. Glucose uptake decreased despite increased insulin-stimulated Akt phosphorylation. Fatty acid uptake increased, whereas fatty acid oxidation was unchanged, leading to accumulation of intracellular lipids (TAG) in PANC-1-conditioned myotubes. Secretome analyses revealed increased release of growth factors and growth factor receptor from PANC-1 cells, potentially affecting muscle cell metabolism. Myotubes exposed to pancreatic cancer cell medium displayed altered energy metabolism with increased protein/leucine turnover and lipid accumulation, while glucose uptake and oxidation reduced. This indicates production and release of substances from pancreatic cancer cells affecting skeletal muscle.

• Mengeste, Abel Mulu; Nikolic, Natasa; Fernandez, Andrea Dalmao; Feng, Yuan Zeng; Nyman, Tuula Anneli & Kersten, Sander [Show all 11 contributors for this article] (2022). Insight Into the Metabolic Adaptations of Electrically Pulse-Stimulated Human Myotubes Using Global Analysis of the Transcriptome and Proteome. Frontiers in Physiology. 13. doi: 10.3389/fphys.2022.928195. Full text in Research Archive Show summary

  Electrical pulse stimulation (EPS) has proven to be a useful tool to interrogate cell-specific responses to muscle contraction. In the present study, we aimed to uncover networks of signaling pathways and regulatory molecules responsible for the metabolic effects of exercise in human skeletal muscle cells exposed to chronic EPS. Differentiated myotubes from young male subjects were exposed to EPS protocol 1 (i.e. 2 ms, 10 V, and 0.1 Hz for 24 h), whereas myotubes from middle-aged women and men were exposed to protocol 2 (i.e. 2 ms, 30 V, and 1 Hz for 48 h). Fuel handling as well as the transcriptome, cellular proteome, and secreted proteins of EPS-treated myotubes from young male subjects were analyzed using a combination of high-throughput RNA sequencing, high-resolution liquid chromatography-tandem mass spectrometry, oxidation assay, and immunoblotting. The data showed that oxidative metabolism was enhanced in EPS-exposed myotubes from young male subjects. Moreover, a total of 81 differentially regulated proteins and 952 differentially expressed genes (DEGs) were observed in these cells after EPS protocol 1. We also found 61 overlapping genes while comparing the DEGs to mRNA expression in myotubes from the middle-aged group exposed to protocol 2, assessed by microarray. Gene ontology (GO) analysis indicated that significantly regulated proteins and genes were enriched in biological processes related to glycolytic pathways, positive regulation of fatty acid oxidation, and oxidative phosphorylation, as well as muscle contraction, autophagy/mitophagy, and oxidative stress. Additionally, proteomic identification of secreted proteins revealed extracellular levels of 137 proteins were changed in myotubes from young male subjects exposed to EPS protocol 1. Selected putative myokines were measured using ELISA or multiplex assay to validate the results. Collectively, our data provides new insight into the transcriptome, proteome and secreted proteins alterations following in vitro exercise and is a valuable resource for understanding the molecular mechanisms and regulatory molecules mediating the beneficial metabolic effects of exercise.

• Katare, Parmeshwar Bajirao; Fernandez, Andrea Dalmao; Mengeste, Abel Mulu; Hamarsland, Håvard; Ellefsen, Stian & Bakke, Hege Gilbø [Show all 9 contributors for this article] (2022). Energy metabolism in skeletal muscle cells from donors with different body mass index. Frontiers in Physiology. 13. doi: 10.3389/fphys.2022.982842. Full text in Research Archive
• Mengeste, Abel Mulu; Katare, Parmeshwar Bajirao; Fernandez, Andrea Dalmao; Lund, Jenny; Bakke, Hege Gilbø & Baker, David [Show all 11 contributors for this article] (2022). Knockdown of sarcolipin (SLN) impairs substrate utilization in human skeletal muscle cells. Molecular Biology Reports. ISSN 0301-4851. p. 6005–6017. doi: 10.1007/s11033-022-07387-0. Full text in Research Archive Show summary

  Abstract Background Recent studies have highlighted that uncoupling of sarco-/endoplasmic reticulum Ca 2+ -ATPase (SERCA) by sarcolipin (SLN) increases ATP consumption and contributes to heat liberation. Exploiting this thermogenic mechanism in skeletal muscle may provide an attractive strategy to counteract obesity and associated metabolic disorders. In the present study, we have investigated the role of SLN on substrate metabolism in human skeletal muscle cells. Methods and results After generation of skeletal muscle cells with stable SLN knockdown (SLN-KD), cell viability, glucose and oleic acid (OA) metabolism, mitochondrial function, as well as gene expressions were determined. Depletion of SLN did not influence cell viability. However, glucose and OA oxidation were diminished in SLN-KD cells compared to control myotubes. Basal respiration measured by respirometry was also observed to be reduced in cells with SLN-KD. The metabolic perturbation in SLN-KD cells was reflected by reduced gene expression levels of peroxisome proliferator-activated receptor γ coactivator 1α ( PGC1α ) and forkhead box O1 ( FOXO1 ). Furthermore, accumulation of OA was increased in cells with SLN-KD compared to control cells. These effects were accompanied by increased lipid formation and incorporation of OA into complex lipids. Additionally, formation of complex lipids and free fatty acid from de novo lipogenesis with acetate as substrate was enhanced in SLN-KD cells. Detection of lipid droplets using Oil red O staining also showed increased lipid accumulation in SLN-KD cells. Conclusions Overall, our study sheds light on the importance of SLN in maintaining metabolic homeostasis in human skeletal muscle. Findings from the current study suggest that therapeutic strategies involving SLN-mediated futile cycling of SERCA might have significant implications in the treatment of obesity and associated metabolic disorders. Graphical abstract

• Krapf, Solveig Astrid; Schjølberg, Tiril; Asoawe, Lucia; Honkanen, Susanna Kyllikki; Kase, Eili Tranheim & Thoresen, G. Hege [Show all 7 contributors for this article] (2021). Novel methods for cold exposure of skeletal muscle in vivo and in vitro show temperature-dependent myokine production. Journal of Thermal Biology. ISSN 0306-4565. 98. doi: 10.1016/j.jtherbio.2021.102930. Full text in Research Archive Show summary

  Proteins secreted from skeletal muscle serving a signalling role have been termed myokines. Many of the myokines are exercise factors, produced and released in response to muscle activity. Cold exposures affecting muscle may occur in recreational, occupational and therapeutic settings. Whether muscle temperature independently affects myokine profile, is still to be elucidated. We hypothesized that manipulating muscle temperature by means of external cooling would change myokine production and release. In the present study we have established new models for cold exposure of muscle in vivo and in vitro where rat hind limb or cultured human myotubes were cooled to 18 °C. After a recovery period, muscle tissue, cells and culture media were harvested for further analysis by qPCR and immunoassays. Expression of several myokine genes were significantly increased after cold exposure in both models: in rat muscle, mRNA levels of CCL2 (p = 0.04), VEGFA (p = 0.02), CXCL1 (p = 0.02) and RBM3 (p = 0.02) increased while mRNA levels of IL-6 (p = 0.03) were decreased; in human myotubes, mRNA levels of IL6 (p = 0.01), CXCL8 (p = 0.04), VEGFA (p = 0.03) and CXCL1 (p < 0.01) were significantly increased, as well as intracellular protein levels of IL-8 (CXCL8 gene product; p < 0.01). The corresponding effect on myokine secretion was not observed, on the contrary, IL-8 (p = 0.02) and VEGF (VEGFA gene product) p < 0.01) concentrations in culture media were reduced after cold exposure in vitro. In conclusion, cold exposure of muscle in vivo and in vitro had an effect on the production and release of several known exercise-related myokines. Myokine expression at the level of mRNA and protein was increased by cold exposure, whereas secretion tended to be decreased.

• Skagen, Christine; Nyman, Tuula Anneli; Xiao-Rong, Peng; O'Mahony, Sven; Kase, Eili Tranheim & Rustan, Arild Christian [Show all 7 contributors for this article] (2021). Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes. Current Research in Pharmacology and Drug Discovery (CRPHAR). 2, p. 1–11. doi: 10.1016/j.crphar.2021.100039. Full text in Research Archive
• Mengeste, Abel Mulu; Lund, Jenny; Katare, Parmeshwar Bajirao; Ghobadi, Roya; Bakke, Hege Gilbø & Lunde, Per Kristian [Show all 13 contributors for this article] (2021). The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells. Current Research in Pharmacology and Drug Discovery (CRPHAR). 2, p. 1–12. doi: 10.1016/j.crphar.2021.100060. Full text in Research Archive
• Lund, Jenny; Krapf, Solveig Astrid; Sistek, Medina; Bakke, Hege Gilbø; Bartesagi, Stefano & Xiao-Rong, Peng [Show all 9 contributors for this article] (2021). SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells. Current Research in Pharmacology and Drug Discovery (CRPHAR). 2, p. 1–10. doi: 10.1016/j.crphar.2021.100061. Full text in Research Archive
• Krapf, Solveig Astrid; Lund, Jenny; Lundkvist, Malin; Dale, Marianne Grebstad; Nyman, Tuula Anneli & Thoresen, G. Hege [Show all 7 contributors for this article] (2020). Pancreatic cancer cells show lower oleic acid oxidation and their conditioned medium inhibits oleic acid oxidation in human myotubes. Pancreatology (Print). ISSN 1424-3903. 20(4), p. 676–682. doi: 10.1016/j.pan.2020.04.014. Full text in Research Archive
• Løvsletten, Nils Gunnar; Vu, Helene Loang Ngo; Skagen, Christine; Lund, Jenny; Kase, Eili Tranheim & Thoresen, G. Hege [Show all 8 contributors for this article] (2020). Treatment of human skeletal muscle cells with inhibitors of diacylglycerol acyltransferases 1 and 2 to explore isozyme-specific roles on lipid metabolism. Scientific Reports. 10:238, p. 1–13. doi: 10.1038/s41598-019-57157-5. Full text in Research Archive Show summary

  Diacylglycerol acyltransferases (DGAT) 1 and 2 catalyse the final step in triacylglycerol (TAG) synthesis, the esterification of fatty acyl-CoA to diacylglycerol. Despite catalysing the same reaction and being present in the same cell types, they exhibit different functions on lipid metabolism in various tissues. Yet, their roles in skeletal muscle remain poorly defined. In this study, we investigated how selective inhibitors of DGAT1 and DGAT2 affected lipid metabolism in human primary skeletal muscle cells. The results showed that DGAT1 was dominant in human skeletal muscle cells utilizing fatty acids (FAs) derived from various sources, both exogenously supplied FA, de novo synthesised FA, or FA derived from lipolysis, to generate TAG, as well as being involved in de novo synthesis of TAG. On the other hand, DGAT2 seemed to be specialised for de novo synthesis of TAG from glycerol-3-posphate only. Interestingly, DGAT activities were also important for regulating FA oxidation, indicating a key role in balancing FAs between storage in TAG and efficient utilization through oxidation. Finally, we observed that inhibition of DGAT enzymes could potentially alter glucose–FA interactions in skeletal muscle. In summary, treatment with DGAT1 or DGAT2 specific inhibitors resulted in different responses on lipid metabolism in human myotubes, indicating that the two enzymes play distinct roles in TAG metabolism in skeletal muscle.

• Løvsletten, Nils Gunnar; Bakke, Siril Skaret; Kase, Eili Tranheim; Ouwens, D. Margriet; Thoresen, G. Hege & Rustan, Arild (2018). Increased triacylglycerol - Fatty acid substrate cycling in human skeletal muscle cells exposed to eicosapentaenoic acid. PLOS ONE. 13:e0208048(11), p. 1–15. doi: 10.1371/journal.pone.0208048. Full text in Research Archive Show summary

  It has previously been shown that pretreatment of differentiated human skeletal muscle cells (myotubes) with eicosapentaenoic acid (EPA) promoted increased uptake of fatty acids and increased triacylglycerol accumulation, compared to pretreatment with oleic acid (OA) and palmitic acid (PA). The aim of the present study was to examine whether EPA could affect substrate cycling in human skeletal muscle cells by altering lipolysis rate of intracellular TAG and re-esterification of fatty acids. Fatty acid metabolism was studied in human myotubes using a mixture of fatty acids, consisting of radiolabelled oleic acid as tracer (14C-OA) together with EPA or PA. Co-incubation of myotubes with EPA increased cell-accumulation and incomplete fatty acid oxidation of 14C-OA compared to co-incubation with PA. Lipid distribution showed higher incorporation of 14C-OA into all cellular lipids after co-incubation with EPA relative to PA, with most markedly increases (3 to 4-fold) for diacylglycerol and triacylglycerol. Further, the increases in cellular lipids after co-incubation with EPA were accompanied by higher lipolysis and fatty acid re-esterification rate. Correspondingly, basal respiration, proton leak and maximal respiration were significantly increased in cells exposed to EPA compared to PA. Microarray and Gene Ontology (GO) enrichment analysis showed that EPA, related to PA, significantly changed i.e. the GO terms “Neutral lipid metabolic process” and “Regulation of lipid storage”. Finally, an inhibitor of diacylglycerol acyltransferase 1 decreased the effect of EPA to promote fatty acid accumulation. In conclusion, incubation of human myotubes with EPA, compared to PA, increased processes of fatty acid turnover and oxidation suggesting that EPA may activate futile substrate cycling of fatty acids in human myotubes. Increased TAG—FA cycling may be involved in the potentially favourable effects of long-chain polyunsaturated n-3 fatty acids on skeletal muscle and whole-body energy metabolism.

• Lund, Jenny; Helle, Siw A; Li, Yuchuan; Løvsletten, Nils Gunnar; Stadheim, Hans Kristian & Jensen, Jørgen [Show all 9 contributors for this article] (2018). Higher lipid turnover and oxidation in cultured human myotubes from athletic versus sedentary young male subjects. Scientific Reports. 8(1). doi: 10.1038/s41598-018-35715-7. Full text in Research Archive Show summary

  In this study we compared fatty acid (FA) metabolism in myotubes established from athletic and sedentary young subjects. Six healthy sedentary (maximal oxygen uptake (VO2max)≤ 46 ml/kg/min) and six healthy athletic (VO2max> 60 ml/kg/min) young men were included. Myoblasts were cultured and diferentiated to myotubes from satellite cells isolated from biopsy of musculus vastus lateralis. FA metabolism was studied in myotubes using [14C]oleic acid. Lipid distribution was assessed by thin layer chromatography, and FA accumulation, lipolysis and re-esterifcation were measured by scintillation proximity assay.Gene and protein expressions were studied. Myotubes from athletic subjects showed lower FA accumulation, lower incorporation of FA into total lipids, triacylglycerol (TAG), diacylglycerol and cholesteryl ester, higherTAG-related lipolysis and re-esterifcation, and higher complete oxidation and incomplete β-oxidation of FA compared to myotubes from sedentary subjects. mRNA expression of the mitochondrial electron transport chain complex III gene UQCRB was higher in cells from athletic compared to sedentary. Myotubes established from athletic subjects have higher lipid turnover and oxidation compared to myotubes from sedentary subjects.Our fndings suggestthat cultured myotubes retain some of the phenotypic traits of their donors.

• Lund, Jenny; Rustan, Arild; Løvsletten, Nils Gunnar; Mudry, Jonathan M.; Langleite, Torgrim Mikal & Feng, Yuan Zeng [Show all 19 contributors for this article] (2017). Exercise in vivo marks human myotubes in vitro: Training-induced increase in lipid metabolism. PLOS ONE. 12:e0175441(4), p. 1–24. doi: 10.1371/journal.pone.0175441. Full text in Research Archive Show summary

  Background and aims: Physical activity has preventive as well as therapeutic benefits for overweight subjects. In this study we aimed to examine effects of in vivo exercise on in vitro metabolic adaptations by studying energy metabolism in cultured myotubes isolated from biopsies taken before and after 12 weeks of extensive endurance and strength training, from healthy sedentary normal weight and overweight men. Methods: Healthy sedentary men, aged 40–62 years, with normal weight (body mass index (BMI) < 25 kg/m2) or overweight (BMI ≥ 25 kg/m2) were included. Fatty acid and glucose metabolism were studied in myotubes using [14C]oleic acid and [14C]glucose, respectively. Gene and protein expressions, as well as DNA methylation were measured for selected genes. Results: The 12-week training intervention improved endurance, strength and insulin sensitivity in vivo, and reduced the participants’ body weight. Biopsy-derived cultured human myotubes after exercise showed increased total cellular oleic acid uptake (30%), oxidation (46%) and lipid accumulation (34%), as well as increased fractional glucose oxidation (14%) compared to cultures established prior to exercise. Most of these exercise-induced increases were significant in the overweight group, whereas the normal weight group showed no change in oleic acid or glucose metabolism. Conclusions: 12 weeks of combined endurance and strength training promoted increased lipid and glucose metabolism in biopsy-derived cultured human myotubes, showing that training in vivo are able to induce changes in human myotubes that are discernible in vitro.

• Ho, Giang Thanh Thi; Nguyen, Thi Kim Yen; Kase, Eili Tranheim; Tadesse, Margey; Barsett, Hilde & Wangensteen, Helle (2017). Enhanced glucose uptake in human liver cells and inhibition of carbohydrate hydrolyzing enzymes by nordic berry extracts. Molecules. ISSN 1431-5157. 22(10). doi: 10.3390/molecules22101806. Full text in Research Archive Show summary

  A Western lifestyle with low physical activity and a diet rich in sugar, fat and processed food contribute to higher incidences of diabetes and obesity. Enhanced glucose uptake in human liver cells was observed after treatment with phenolic extracts from different Nordic berries. All berry extracts showed higher inhibition against α-amylase and α-glucosidase than the anti-diabetic agent acarbose. Total phenolic content and phenolic profiles in addition to antioxidant activities, were also investigated. The berries were extracted with 80% methanol on an accelerated solvent extraction system (ASE) and then purified by C-18 solid phase extraction (SPE). Among the ASE methanol extracts, black chokeberry, crowberry and elderberry extracts showed high stimulation of glucose uptake in HepG2 cells and also considerable inhibitory effect towards carbohydrate hydrolyzing enzymes. SPE extracts with higher concentrations of phenolics, resulted in increased glucose uptake and enhanced inhibition of α-amylase and α-glucosidase compared to the ASE extracts. Crowberry and cloudberry were the most potent 15-lipoxygenase inhibitors, while bog whortleberry and lingonberry were the most active xanthine oxidase inhibitors. These results increase the value of these berries as a component of a healthy Nordic diet and have a potential benefit against diabetes.

• Åstrand, Ove Alexander Høgmoen; Viktorsson, Elvar Örn; Kristensen, Aleksander Lim; Ekeberg, Dag; Røberg-Larsen, Hanne & Wilson, Steven Ray Haakon [Show all 12 contributors for this article] (2017). Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 165, p. 323–330. doi: 10.1016/j.jsbmb.2016.07.010. Full text in Research Archive Show summary

  Liver X Receptor (LXR) modulators have shown potential as drugs since they target genes affecting metabolism and fatty acid synthesis. LXR antagonists are of particular interest since they are able to reduce the synthesis of complex fatty acids and glucose uptake. Based on molecular modeling, five new cholesterol mimics were synthesized, where four contained a hydroxyl group in the 22-S-position. The new compounds were screened in vitro against several genes affecting lipid metabolism. The compound that performed best in vitro was a dimethylamide derivative of 22(S)-hydroxycholesterol and it was chosen for in vivo testing. However, the blood plasma analysis from the in vivo tests revealed a concentration lower than needed to give any response, indicating either rapid metabolism or low bioavailability.

• Lund, Jenny; Tangen, Daniel S.; Wiig, Håvard; Stadheim, Hans Kristian; Siw, Anette Helle & Birk, Jesper B. [Show all 12 contributors for this article] (2017). Glucose metabolism and metabolic flexibility in cultured skeletal muscle cells is related to exercise status in young male subjects. Archives of Physiology and Biochemistry. ISSN 1381-3455. 124(2), p. 119–130. doi: 10.1080/13813455.2017.1369547. Full text in Research Archive Show summary

  We hypothesised that skeletal muscles of healthy young people have a large variation in oxidative capacity and fibre-type composition, and aimed therefore to investigate glucose metabolism in biopsies and myotubes isolated from musculus vastus lateralis from healthy males with varying degrees of maximal oxygen uptake. Trained and intermediary trained subjects showed higher carbohydrate oxidation in vivo. Fibre-type distribution in biopsies and myotubes did not differ between groups. There was no correlation between fibre-type I expression in biopsies and myotubes. Myotubes from trained had higher deoxyglucose accumulation and fractional glucose oxidation (glucose oxidation relative to glucose uptake), and were also more sensitive to the suppressive action of acutely added oleic acid to the cells. Despite lack of correlation of fibre types between skeletal muscle biopsies and cultured cells, myotubes from trained subjects retained some of their phenotypes in vitro with respect to enhanced glucose metabolism and metabolic flexibility.

• Viktorsson, Elvar Örn; Gabrielsen, Mari; Kumarachandran, Nugalya; Sylte, Ingebrigt; Rongved, Pål & Åstrand, Ove Alexander Høgmoen [Show all 7 contributors for this article] (2017). Regulation of liver X receptor target genes by 22-functionalized oxysterols. Synthesis, in silico and in vitro evaluations. Steroids. ISSN 0039-128X. 118, p. 119–127. doi: 10.1016/j.steroids.2016.12.003. Full text in Research Archive
• Ho, Giang Thanh Thi; Kase, Eili Tranheim; Wangensteen, Helle & Barsett, Hilde (2017). Effect of phenolic compounds from elderflowers on glucose- and fatty acid uptake in human myotubes and HepG2-Cells. Molecules. ISSN 1431-5157. 22(90), p. 1–15. doi: 10.3390/molecules22010090. Full text in Research Archive Show summary

  Type 2 diabetes (T2D) is manifested by progressive metabolic impairments in tissues such as skeletal muscle and liver, and these tissues become less responsive to insulin, leading to hyperglycemia. In the present study, stimulation of glucose and oleic acid uptake by elderflower extracts, constituents and metabolites were tested in vitro using the HepG2 hepatocellular liver carcinoma cell line and human skeletal muscle cells. Among the crude extracts, the 96% EtOH extract showed the highest increase in glucose and oleic acid uptake in human skeletal muscle cells and HepG2-cells. The flavonoids and phenolic acids contained therein were potent stimulators of glucose and fatty acid uptake in a dose-dependent manner. Most of the phenolic constituents and several of the metabolites showed high antioxidant activity and showed considerably higher α-amylase and α-glucosidase inhibition than acarbose. Elderflower might therefore be valuable as a functional food against diabetes.

• Feng, Yuan Zeng; Lund, Jenny; Li, Yuchuan; Knabenes, Irlin; Bakke, Siril Skaret & Kase, Eili Tranheim [Show all 11 contributors for this article] (2017). Loss of perilipin 2 in cultured myotubes enhances lipolysis and redirects the metabolic energy balance from glucose oxidation towards fatty acid oxidation. Journal of Lipid Research. ISSN 0022-2275. 58(11), p. 2147–2161. doi: 10.1194/jlr.M079764. Full text in Research Archive Show summary

  Lipid droplet (LD) coating proteins are essential for the formation and stability of intracellular LDs. Plin2 is an abundant LD coating protein in skeletal muscle, but its importance for muscle function is unclear. We show that myotubes established from Plin2−/− mice contain reduced content of LDs and accumulate less oleic acid (OA) in triacylglycerol (TAG) due to elevated LD hydrolysis in comparison with Plin2+/+ myotubes. The reduced ability to store TAG in LDs in Plin2−/− myotubes is accompanied by a shift in energy metabolism. Plin2−/− myotubes are characterized by increased oxidation of OA, lower glycogen synthesis, and reduced glucose oxidation in comparison with Plin2+/+ myotubes, perhaps reflecting competition between FAs and glucose as part of the Randle cycle. In accord with these metabolic changes, Plin2−/− myotubes have elevated expression of Ppara and Ppargc1a, transcription factors that stimulate expression of genes important for FA oxidation, whereas genes involved in glucose uptake and oxidation are suppressed. Loss of Plin2 had no impact on insulin-stimulated Akt phosphorylation. Our results suggest that Plin2 is essential for protecting the pool of skeletal muscle LDs to avoid an uncontrolled hydrolysis of stored TAG and to balance skeletal muscle energy metabolism. This article was originally published in the Journal of Lipid Research. © 2017 American Society for Biochemistry and Molecular Biology

• Ho, Giang Thanh Thi; Kase, Eili Tranheim; Wangensteen, Helle & Barsett, Hilde (2017). Phenolic Elderberry Extracts, Anthocyanins, Procyanidins, and Metabolites Influence Glucose and Fatty Acid Uptake in Human Skeletal Muscle Cells. Journal of Agricultural and Food Chemistry. ISSN 0021-8561. 65(13), p. 2677–2685. doi: 10.1021/acs.jafc.6b05582. Full text in Research Archive
• Kong, Xiang Yi; Feng, Yuan Zeng; Eftestøl, Einar; Kase, Eili Tranheim; Haugum, Hanne & Eskild, Winnie [Show all 8 contributors for this article] (2016). Increased glucose utilization and decreased fatty acid metabolism in myotubes from Glmpgt/gt mice. Archives of Physiology and Biochemistry. ISSN 1381-3455. 122(1), p. 36–45. doi: 10.3109/13813455.2015.1120752. Full text in Research Archive
• Kaupang, Åsmund; Kase, Eili Tranheim; Vo, Cecilie Xuan Trang; Amundsen, Marthe; Vik, Anders & Hansen, Trond Vidar (2016). Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 24(2), p. 247–260. doi: 10.1016/j.bmc.2015.12.012. Full text in Research Archive
• Kase, Eili Tranheim; Feng, Yuan Zeng; Badin, Pierre-Marie; Bakke, Siril Skaret; Laurens, C & Coue, M [Show all 11 contributors for this article] (2015). Primary defects in lipolysis and insulin action in skeletal muscle cells from type 2 diabetic individuals. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1851(9), p. 1194–1201. doi: 10.1016/j.bbalip.2015.03.005. Full text in Research Archive
• Feng, Yuan Zeng; Nikolic, Natasa; Bakke, Siril Skaret; Kase, Eili Tranheim; Guderud, Kari & Hjelmesæth, Jøran [Show all 9 contributors for this article] (2015). Myotubes from lean and severely obese subjects with and without type 2 diabetes respond differently to an in vitro model of exercise. American Journal of Physiology - Cell Physiology. 308(7), p. C548–C556. doi: 10.1152/ajpcell.00314.2014. Full text in Research Archive
• Aas, Vigdis; Lund, Jenny; Kase, Eili Tranheim; Feng, Yuan Zeng; Rustan, Arild & Thoresen, G. Hege (2015). Blodglukosesenkende legemidler ved type 2-diabetes. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 123(5), p. 20–24. Full text in Research Archive
• Kong, Xiang Yi; Kase, Eili Tranheim; Herskedal, Anette; Schjalm, Camilla; Damme, Markus & Nesset, Cecilie Kåsi [Show all 9 contributors for this article] (2015). Lack of the lysosomal membrane protein, GLMP, in mice results in metabolic dysregulation in liver. PLOS ONE. 10(6). doi: 10.1371/journal.pone.0129402. Full text in Research Archive Show summary

  Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1) has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmpgt/gt mice (formerly known as Ncu-g1gt/gtmice) were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmpgt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmpgt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmpgt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmpgt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmpgt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmpgt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmpgt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.

• Bakke, Siril Skaret; Feng, Yuan Zeng; Nikolic, Natasa; Kase, Eili Tranheim; Moro, Cedric & Stensrud, Camilla [Show all 14 contributors for this article] (2015). Myotubes from Severely Obese Type 2 Diabetic Subjects Accumulate Less Lipids and Show Higher Lipolytic Rate than Myotubes from Severely Obese Non-Diabetic Subjects. PLOS ONE. 10(3). doi: 10.1371/journal.pone.0119556. Full text in Research Archive Show summary

  About 80% of patients with type 2 diabetes are classified as overweight. However, only about 1/3 of severely obese subjects have type 2 diabetes. This indicates that several se- verely obese individuals may possess certain characteristics that protect them against type 2 diabetes. We therefore hypothesized that this apparent paradox could be related to funda- mental differences in skeletal muscle lipid handling. Energy metabolism and metabolic flexi- bility were examined in human myotubes derived from severely obese subjects without (BMI 44 ± 7 kg/m 2 ) and with type 2 diabetes (BMI 43 ± 6 kg/m 2 ). Lower insulin sensitivity was observed in myotubes from severely obese subjects with type 2 diabetes. Lipolysis rate was higher, and oleic acid accumulation, triacylglycerol content, and fatty acid adaptability were lower in myotubes from severely obese subjects with type 2 diabetes compared to se- verely obese non-diabetic subjects. There were no differences in lipid distribution and mRNA and protein expression of the lipases HSL and ATGL, the lipase cofactor CGI-58, or the lipid droplet proteins PLIN2 and PLIN3. Glucose and oleic acid oxidation were also simi- lar in cells from the two groups. In conclusion, myotubes established from severely obese donors with established type 2 diabetes had lower ability for lipid accumulation and higher li- polysis rate than myotubes from severely obese donors without diabetes. This indicates that a difference in intramyocellular lipid turnover might be fundamental in evolving type 2 diabetes.

• Åstrand, Ove Alexander Høgmoen; Sandberg, Marcel; Sylte, Ingebrigt; Gorbitz, Carl Henrik; Thoresen, G. Hege & Kase, Eili Tranheim [Show all 7 contributors for this article] (2014). Synthesis and initial biological evaluation of new mimics of the LXR-modulator 22(S)-hydroxycholesterol. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 22(1), p. 643–650. doi: 10.1016/j.bmc.2013.10.024. Full text in Research Archive
• Feng, Yuan Zeng; Nikolic, Natasa; Bakke, Siril Skaret; Boekschoten, Mark V.; Kersten, Sander & Kase, Eili Tranheim [Show all 8 contributors for this article] (2014). PPARδ activation in human myotubes increases mitochondrial fatty acid oxidative capacity and reduces glucose utilization by a switch in substrate preference. Archives of Physiology and Biochemistry. ISSN 1381-3455. 120(1), p. 12–21. doi: 10.3109/13813455.2013.829105. Full text in Research Archive
• Åstrand, Ove Alexander Høgmoen; Gikling, Ingveig; Sylte, Ingebrigt; Rustan, Arild; Thoresen, G. Hege & Rongved, Pål [Show all 7 contributors for this article] (2014). Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models. European Journal of Medicinal Chemistry. ISSN 0223-5234. 74, p. 258–263. doi: 10.1016/j.ejmech.2014.01.003. Full text in Research Archive
• Gondcaille, Catherine; Genin, Emmanuelle C.; Lopez, Tatiana E.; Dias, Alexandre M.M.; Geillon, Flore & Andreoletti, Pierre [Show all 14 contributors for this article] (2014). LXR antagonists induce ABCD2 expression. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1841(2), p. 259–266. doi: 10.1016/j.bbalip.2013.11.003. Full text in Research Archive
• Kong, Xiang Yi; Nesset, Cecilie Kåsi; Damme, Markus; Løberg, Else Marit; Lübke, Torben & Mæhlen, Jan [Show all 13 contributors for this article] (2014). Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells. Disease Models and Mechanisms. ISSN 1754-8403. 7(3), p. 351–362. doi: 10.1242/dmm.014050. Full text in Research Archive Show summary

  Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

• Åstrand, Ove Alexander; Iqbal, Zeshan; Sandberg, Marcel; Kase, Eili Tranheim; Gorbitz, Carl Henrik & Rongved, Pål (2013). (2S,3S)-2,6-Dimethylheptane-1,3-diol, the oxygenated side chain of 22(S)-hydroxycholestrol, and its synthetic precursor (R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,6-dimethylheptanoyl]-1,3-oxazolidin-2-one. Acta Crystallographica Section C: Crystal Structure Communications. ISSN 0108-2701. 69, p. 647–+. doi: 10.1107/S0108270113011852. Full text in Research Archive
• Aas, Vigdis; Bakke, Siril Skaret; Feng, Yuan Zeng; Kase, Eili Tranheim; Jensen, Jørgen & Bajpeyi, Sudip [Show all 8 contributors for this article] (2013). Are cultured human myotubes far from home? Cell and Tissue Research. ISSN 0302-766X. 354(3), p. 671–682. doi: 10.1007/s00441-013-1655-1. Full text in Research Archive Show summary

  Satellite cells can be isolated from skeletal muscle biopsies, activated to proliferating myoblasts and differentiated into multinuclear myotubes in culture. These cell cultures represent a model system for intact human skeletal muscle and can be modulated ex vivo. The advantages of this system are that the most relevant genetic background is available for the investigation of human disease (as opposed to rodent cell cultures), the extracellular environment can be precisely controlled and the cells are not immortalized, thereby offering the possibility of studying innate characteristics of the donor. Limitations in differentiation status (fiber type) of the cells and energy metabolism can be improved by proper treatment, such as electrical pulse stimulation to mimic exercise. This review focuses on the way that human myotubes can be employed as a tool for studying metabolism in skeletal muscles, with special attention to changes in muscle energy metabolism in obesity and type 2 diabetes.

• Kase, Eili Tranheim; Nikolic, Natasa; Bakke, Siril Skaret; Bogen, Kaja Kamilla; Aas, Vigdis & Thoresen, G. Hege [Show all 7 contributors for this article] (2013). Remodelling of oxidative energy metabolism by galactose improves glucose handling and metabolic switching in human skeletal muscle cells. PLOS ONE. 8(4). doi: 10.1371/journal.pone.0059972. Full text in Research Archive Show summary

  Cultured human myotubes have a low mitochondrial oxidative potential. This study aims to remodel energy metabolism in myotubes by replacing glucose with galactose during growth and differentiation to ultimately examine the consequences for fatty acid and glucose metabolism. Exposure to galactose showed an increased [14C]oleic acid oxidation, whereas cellular uptake of oleic acid uptake was unchanged. On the other hand, both cellular uptake and oxidation of [14C]glucose increased in myotubes exposed to galactose. In the presence of the mitochondrial uncoupler carbonylcyanide p-trifluormethoxy-phenylhydrazone (FCCP) the reserve capacity for glucose oxidation was increased in cells grown with galactose. Staining and live imaging of the cells showed that myotubes exposed to galactose had a significant increase in mitochondrial and neutral lipid content. Suppressibility of fatty acid oxidation by acute addition of glucose was increased compared to cells grown in presence of glucose. In summary, we show that cells grown in galactose were more oxidative, had increased oxidative capacity and higher mitochondrial content, and showed an increased glucose handling. Interestingly, cells exposed to galactose showed an increased suppressibility of fatty acid metabolism. Thus, galactose improved glucose metabolism and metabolic switching of myotubes, representing a cell model that may be valuable for metabolic studies related to insulin resistance and disorders involving mitochondrial impairments.

• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Smith, Robert; Ravna, aina westrheim; Sylte, Ingebrigt & Rustan, Arild [Show all 8 contributors for this article] (2012). The liver X receptor modulator 22(S)-hydroxycholesterol exerts cell-type specific effects on lipid and glucose metabolism. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 128, p. 154–164. doi: 10.1016/j.jsbmb.2011.10.006. Full text in Research Archive
• Kase, Eili Tranheim; Nikolic, Natasa; Hessvik, Nina Pettersen; Fjeldheim, Åse-Karine; Jensen, Jørgen & Thoresen, G. Hege [Show all 7 contributors for this article] (2012). Dietary supplementation with 22-S-hydroxycholesterol to rats reduces body weight gain and the accumulation of liver triacylglycerol. Lipids. ISSN 0024-4201. 47(5), p. 483–493. doi: 10.1007/s11745-012-3663-4. Full text in Research Archive Show summary

  This study explores the pharmacokinetics of 22-S-hydroxycholesterol (22SHC) in vivo in rats. We also carried out a metabolic study to explore whether the beneficial effects observed of 22SHC on glucose and lipid metabolism in vitro could be seen in vivo in rats. In the pharmacokinetic study, rats were given 50 mg/kg of [3H]22-S-hydroxycholesterol before absorption, distribution and excretion were monitored. In the metabolic study, the effect of 22SHC (30 mg/kg/day for 3 weeks) in rats on body weight gain [chow and high-fat diet (HFD)], serum lipids triacylglycerol (TAG) content and gene expression in liver and skeletal muscle were examined. Results showed that 22SHC was well absorbed after oral administration and distributed to most organs and mainly excreted in feces. Rats receiving 22SHC gained less body weight than their controls regardless whether the animals received chow diet or HFD. Moreover, we observed that animals receiving HFD had elevated levels of serum TAG while this was not observed for animals on HFD supplemented with 22SHC. The amount of TAG in liver was reduced after 22SHC treatment in animals receiving either chow diet or HFD. Gene expression analysis revealed that two genes (carnitine palmitoyltransferase 2 and uncoupling protein 3) involved in fatty acid oxidation and energy dissipation were increased in liver. Ucp3 expression (both protein and mRNA level) was increased in skeletal muscle, but insulin-stimulated glucose uptake and TAG content were unchanged. In conclusion, 22SHC seems to be an interesting model substance in the search of treatments for disorders involving aberrations in lipid metabolism.

• Nikolic, Natasa; Bakke, Siril Skaret; Kase, Eili Tranheim; Rudberg, Ida; Halle, Ingeborg Flo & Rustan, Arild [Show all 8 contributors for this article] (2012). Electrical Pulse Stimulation of Cultured Human Skeletal Muscle Cells as an In Vitro Model of Exercise. PLOS ONE. 7(3). doi: 10.1371/journal.pone.0033203. Full text in Research Archive Show summary

  Background and Aims Physical exercise leads to substantial adaptive responses in skeletal muscles and plays a central role in a healthy life style. Since exercise induces major systemic responses, underlying cellular mechanisms are difficult to study in vivo. It was therefore desirable to develop an in vitro model that would resemble training in cultured human myotubes. Methods Electrical pulse stimulation (EPS) was applied to adherent human myotubes. Cellular contents of ATP, phosphocreatine (PCr) and lactate were determined. Glucose and oleic acid metabolism were studied using radio-labeled substrates, and gene expression was analyzed using real-time RT-PCR. Mitochondrial content and function were measured by live imaging and determination of citrate synthase activity, respectively. Protein expression was assessed by electrophoresis and immunoblotting. Results High-frequency, acute EPS increased deoxyglucose uptake and lactate production, while cell contents of both ATP and PCr decreased. Chronic, low-frequency EPS increased oxidative capacity of cultured myotubes by increasing glucose metabolism (uptake and oxidation) and complete fatty acid oxidation. mRNA expression level of pyruvate dehydrogenase complex 4 (PDK4) was significantly increased in EPS-treated cells, while mRNA expressions of interleukin 6 (IL-6), cytochrome C and carnitin palmitoyl transferase b (CPT1b) also tended to increase. Intensity of MitoTracker®Red FM was doubled after 48 h of chronic, low-frequency EPS. Protein expression of a slow fiber type marker (MHCI) was increased in EPS-treated cells. Conclusions Our results imply that in vitro EPS (acute, high-frequent as well as chronic, low-frequent) of human myotubes may be used to study effects of exercise.

• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Fredriksson, K; Boekschoten, MV; Fjørkenstad, Anne & Koster, Gerbrand [Show all 11 contributors for this article] (2010). Metabolic switching of human myotubes is improved by n-3 fatty acids. Journal of Lipid Research. ISSN 0022-2275. 51(8), p. 2090–2104. doi: 10.1194/jlr.M003319. Full text in Research Archive
• Kase, Eili Tranheim & Birkeland, Kåre I. (2008). Antidiabetika som påvirker inkretinsystemet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 128, p. 440–442. Full text in Research Archive
• Kase, Eili Tranheim; Thoresen, G. Hege; Westerlund, S; Højlund, K; Rustan, Arild & Gaster, M (2007). Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals. Diabetologia. ISSN 0012-186X. 50, p. 2171–2180. doi: 10.1007/s00125-007-0760-7. Full text in Research Archive
• Kase, Eili Tranheim; Andersen, Bård; Nebb, Hilde Irene; Rustan, Arild & Thoresen, G. Hege (2006). 22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1761, p. 1515–1522. Full text in Research Archive
• Hermann, Monica; Kase, Eili Tranheim; Molden, Espen & Christensen, Hege Staaland (2006). Evaluation of microsomal incubation conditions on CYP3A4-mediated metabolism of cyclosporine A by a statistical experimental design. Current drug metabolism. ISSN 1389-2002. 7, p. 265–271. Full text in Research Archive
• Aas, Vigdis; Rokling-Andersen, Merethe; Kase, Eili Tranheim; Thoresen, G. Hege; Thoresen, G. Hege & Rustan, Arild Chr. (2006). Eicosapentaenoic acid (20 : 5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells. Journal of Lipid Research. ISSN 0022-2275. 47. Full text in Research Archive
• Solberg, Rigmor; Aas, Vigdis; Thoresen, G. Hege; Kase, Eili Tranheim; Drevon, Christian A. & Rustan, Arild Chr. [Show all 7 contributors for this article] (2005). Leptin Expression in Human Primary Skeletal Muscle Cells Is Reduced During Differentiation. Journal of Cellular Biochemistry. ISSN 0730-2312. 96, p. 89–96. Full text in Research Archive
• Aas, Vigdis; Rokling-Andersen, Merete; Wensaas, Andreas Johansen; Thoresen, G. Hege; Kase, Eili Tranheim & Rustan, Arild (2005). Lipid metabolism in human skeletal muscle cells: effects of palmitate and chronic hyperglycaemia. Acta Physiologica Scandinavica. ISSN 0001-6772. 1, p. 31–41. Full text in Research Archive
• Aas, Vigdis; Rokling-Andersen, Merethe; Wensaas, Andreas J.; Thoresen, G. Hege; Kase, Eili Tranheim & Rustan, Arild Chr. (2005). Lipid metabolism in human skeletal muscle cells: effects of palmitic acid and chronic hyperglycaemia. Acta Physiologica Scandinavica. ISSN 0001-6772. 183, p. 31–41. Full text in Research Archive
• Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Højlund, Kurt; Levin, Klaus & Thoresen, G. Hege [Show all 9 contributors for this article] (2005). Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes. ISSN 0012-1797. 54, p. 1108–1115. Full text in Research Archive
• Solberg, Rigmor; Aas, Vigdis; Thoresen, G. Hege; Kase, Eili Tranheim; Drevon, Christian A & Rustan, Arild [Show all 7 contributors for this article] (2005). Leptin expression in human primary skeletal muscle cells is reduced during differentiation. Journal of Cellular Biochemistry. ISSN 0730-2312. 96(1), p. 89–96. Full text in Research Archive
• Kase, Eili Tranheim; Wensaas, Andreas Johansen; Aas, Vigdis; Højlund, K; Levin, K & Thoresen, G. Hege [Show all 9 contributors for this article] (2005). Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes. ISSN 0012-1797. 54, p. 1108–1115. Full text in Research Archive
• Aas, Vigdis; Kase, Eili Tranheim; Solberg, Rigmor; Jensen, Jørgen & Rustan, Arild Chr. (2004). Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia. ISSN 0012-186X. 47(8), p. 1452–1461. doi: 10.1007/s00125-004-1465-9. Full text in Research Archive Show summary

  Aims/hypothesis The present study was conducted to evaluate the effect of hyperglycaemia in itself on glucose and lipid metabolism in human skeletal muscle cells. Methods Satellite cells were isolated from biopsy samples from the vastus lateralis muscle and differentiated into multinucleated myotubes in cultures. Metabolism studies were performed using isotopes ([3H]deoxyglucose, [14C]glucose, [14C]oleic acid and [14C]palmitic acid), and mRNA and protein levels were analysed by real-time RT-PCR and western blotting respectively. Results Exposure of myotubes to 20 mmol/l glucose for 4 days reduced insulin-stimulated glucose uptake and glycogen synthesis to 57±5% (p<0.0001) and 56±5% (p<0.0001) of normoglycaemic (5.5 mmol/l glucose) controls respectively. Basal glucose uptake and glycogen synthesis were both reduced, whereas glucose oxidation was unaltered. Total cell content of glycogen and expression of GLUT1 and GLUT4 mRNA were not affected. There was a significant increase in the incorporation of glucose into cellular NEFA (88±17% increase, p=0.006), triacylglycerol (44±21% increase, p=0.04) and cholesterol ester (89±36% increase, p=0.02) in hyperglycaemic myotubes compared with controls. Diacylglycerol tended to be increased though not significantly, and phospholipid formation were unchanged. Relative to controls, total cell content of triacylglycerol was increased by 25±7% (p=0.02) and acyl-CoA:1,2-diacylglycerol acyltransferase 1 activity was increased by 34±4% (p=0.004), whereas acyl-CoA:1,2-diacylglycerol acyltransferase 1 mRNA expression was unchanged. Total cellular uptake of palmitic acid was reduced by 18±3% (p=0.006) in hyperglycaemic cells compared with controls, while uptake of oleic acid was unchanged. Oxidation of palmitic acid or oleic acid was not affected by hyperglycaemia. Conclusions/interpretation Chronic hyperglycaemia increased triacylglycerol accumulation and the incorporation of carbohydrate into triacylglycerol (i.e. de novo lipogenesis) concomitantly with a reduced insulin-stimulated glucose uptake and glycogen synthesis. Enhanced acyl-CoA:1,2-diacylglycerol acyltransferase 1 activity supported the increased triacylglycerol synthesis during hyperglycaemia.

• Aas, Vigdis; Kase, Eili Tranheim; Solberg, Rigmor; Jensen, Jørgen & Rustan, Arild (2004). Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia. ISSN 0012-186X. 47, p. 1452–1461. Full text in Research Archive

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• Thoresen, G. Hege; Simonsen, terje; Christensen, Hege; Johansen, Harald Thidemann; Kase, Eili Tranheim & Robertsen, Ida [Show all 9 contributors for this article] (2021). Basal farmakologi. Fagbokforlaget. ISBN 9788245033557. 405 p. Full text in Research Archive
• Thoresen, G. Hege; Solberg, Rigmor; Johansen, Harald Thidemann; Kase, Eili Tranheim; Rustan, Arild Christian & Christensen, Hege [Show all 7 contributors for this article] (2020). Illustrert farmakologi. Fagbokforlaget. ISBN 9788245033564. 392 p. Full text in Research Archive

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• Viktorsson, Elvar Örn; Åstrand, Ove Alexander Høgmoen; Rustan, Arild; Thoresen, G. Hege; Kase, Eili Tranheim & Rongved, Pål (2015). Analogs of 22-S-hydroxycholesterol as potential Liver X Receptor-modulators: Synthesis and biological evaluation. Full text in Research Archive
• Kong, Xiang Yi; Nesset, Cecilie Kåsi; Schjalm, Camilla; Løberg, Else Marit; Rustan, Arild & Thoresen, G. Hege [Show all 8 contributors for this article] (2014). NCU-G1GT/GT MICE: A LONG-LIVED MODEL FOR LIVER FIBROSIS. Full text in Research Archive
• Kase, Eili Tranheim; Lund, Jenny; Feng, Yuan Zeng; Langleite, Torgrim Mikal; Aas, Vigdis & Jensen, Jan S. [Show all 11 contributors for this article] (2013). Effect of exercise on fatty acid and glucose metabolism in cultured human myotubes. Diabetologia. ISSN 0012-186X. 56, p. S250–S250. Full text in Research Archive
• Kong, Xiang Yi; Kasi, C; Schjalm, C.; Loberg, EM; Rustan, A.C. & Thoresen, G. Hege [Show all 8 contributors for this article] (2012). NCU-G1 knock-out mice: a potential new model for liver fibrosis. The FEBS Journal. ISSN 1742-464X. 279, p. 573–573. Full text in Research Archive
• Bakke, Siril Skaret & Kase, Eili Tranheim (2012). Energimetabolisme i skjelettmuskelceller relatert til insulinresistens og type 2-diabetes. BestPractice Diabetes. p. 23–25. Full text in Research Archive
• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Kase, Eili Tranheim (2010). Effects of 22-S-hydroxycholesterol (a liver X receptor modulator) on Lipid Metabolism. Full text in Research Archive Show summary

  Liver X receptors (LXRs) play a crucial role in regulation of cholesterol, lipid and carbohydrate metabolism. 22-S-hydroxycholesterol (22-S-HC) has been shown to act as an LXR antagonist and to reduce de novo lipogenesis and lipid accumulation, as well as to increase glucose uptake in human skeletal muscle cells (myotubes). The aim of the present study was to further investigate the effects of 22-S-HC on lipid and glucose metabolism in human-derived cell lines from metabolic active tissues important for development of obesity and type 2 diabetes. We also wanted to explore the effects of 22-S-HC on plasma lipids in vivo in rats. The results show that de novo lipogenesis from [14C]acetate was decreased by 22-S-HC in myotubes and HepG2 (liver) cells, whereas increased in SGBS cells (adipocytes) and unaffected in CaCo-2 cells (intestinal cells). This was partly reflected by regulation of the lipogenic genes, sterol regulatory element binding transcription factor 1 (SREBF1) and fatty acid synthase (FASN), as measured by RT qPCR. Live imaging showed that the number of lipid droplets (LDs) was increased in SGBS cells, decreased in HepG2 cells and unaffected in myotubes by 22-S-HC treatment. Furthermore, exposure to 22-S-HC increased and tended to increase glucose uptake in myotubes and SGBS cells, respectively. However, apoA1-dependent cholesterol efflux was unaffected by 22-S-HC. These observations show that 22-S-HC differently affect distinct LXR-regulated processes, and that 22-S-HC not solely acts as an antagonist to LXR, but also stimulate some LXR-regulated processes. Furthermore, the results suggest that 22-S-HC might reduce ectopic fat accumulation and result in a more favorable lipid distribution. To investigate the effects of 22-S-HC in vivo, high-fat fed Wistar rats were given 30 mg/kg/day of 22-S-HC for 3 weeks. The 22-S-HC treated rats showed significantly reduced body weight gain compared to the control animals and reduced plasma levels of free fatty acids and triacylglycerol. Therefore, compounds with properties similar to 22-S-HC may be of importance in search towards better treatments for obesity and type 2 diabetes.

• Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Andersen, B; Højlund, Kurt & Levin, K [Show all 11 contributors for this article] (2006). A role for LXR in lipid and glucose metabolism in human skeletal muscle. Full text in Research Archive
• Thoresen, G. Hege; Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Andersen, B & Højlund, Kurt [Show all 11 contributors for this article] (2005). A role for LXR in lipid metabolism in human skeletal muscle. Full text in Research Archive
• Aas, Vigdis; Kase, Eili Tranheim; Wensaas, Andreas J.; Gaster, Michael & Rustan, Arild Chr. (2004). Lipid metabolism in human skeletal muscle cells. Full text in Research Archive
• Aas, Vigdis; Kase, Eili Tranheim; Wensaas, Andreas J.; Thoresen, G. Hege & Rustan, Arild Chr. (2004). Lipid metabolism in human skeletal muscle cells. Full text in Research Archive
• Kase, Eili Tranheim; Hermann, Monica; Molden, Espen & Christensen, Hege Staaland (2003). Metabolism of cyclosporine A in microsomes isolated from CYP 3A4 transfected liver epithelial cells. Full text in Research Archive

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