Hege Gilbø Bakke

• Dalmao-Fernandez, Andrea; Katare, Parmeshwar Bajirao; Bakke, Hege Gilbø; Hamarsland, Håvard; Ellefsen, Stian & Singh, Sachin [Vis alle 10 forfattere av denne artikkelen] (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), s. 145–155. doi: 10.1007/s44164-025-00087-6. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Nundal, Camilla Hatlevoll; Lunde, Siri; Bakke, Hege Gilbø; Bohov, Pavol; Aloysius, Thomas Aquinas & Rustan, Arild Christian [Vis alle 15 forfattere av denne artikkelen] (2025). Herring oil rich in long-chain monounsaturated fatty acid (C22: 1n-11) lowers plasma lipids and modulates fatty acid composition, oxidation, and inflammation in rats. Frontiers in Nutrition. 12, s. 1–11. doi: 10.3389/fnut.2025.1611166. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Marine oils and fatty fish rich in long-chain n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (C20:5n-3, EPA) and docosahexaenoic acid (C22:6n-3, DHA), have been reported to enhance fatty acid (FA) oxidation and reduce plasma triacylglycerol and cholesterol levels. In addition to n-3 PUFAs, herring oil contains long-chain monounsaturated fatty acids (MUFAs), including cetoleic acid (C22:1n-11). This study aimed to investigate the effect of consuming CETO3® oil—derived from herring and naturally rich in n-3 PUFAs and cetoleic acid—on plasma lipid levels, FA composition, mitochondrial oxidation, and inflammation in rats. Methods: Rats were fed low-fat diets supplemented with 5% CETO3® oil (experimental) or soy oil (control) for 10 weeks. Plasma lipid profile (triglycerides (TG), total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)) and FA composition in both liver and plasma were analyzed. In vitro substrate oxidation was assessed using ¹⁴CO₂-trapping in human liver and human myotubes. Safety parameters, including blood hematology, glucose tolerance, and organ weights, were also measured. Results: CETO3® supplementation decreased plasma levels of total fat (−58%), TG (−55%), total cholesterol (−41%), and LDL cholesterol (−45%), while increasing the ratio of HDL to LDL cholesterol (46%). Supplementation also increased hepatic and plasma levels of long-chain n-3, n-9, and n-11 MUFAs, including C22:1n-11, and decreased n-6 FA accumulation. The reduction in saturated long-chain FAs in both the liver and plasma indicated increased hepatic peroxisomal and mitochondrial activity. Furthermore, increased oleic acid oxidation was observed in human myotubes in the presence of C20:1n-11 and C20:1n-9. Discussion: These findings suggest that intake of CETO3® oil lowers plasma lipids, potentially through enhanced peroxisomal and mitochondrial FA oxidation. The shift in FA composition, with reduced n-6 FAs and increased n-3 and n-11 MUFAs, indicates an anti-inflammatory effect. CETO3® oil also appears safe, as hematological parameters, glucose tolerance, and organ weights remained unaffected.

• Skagen, Christine; Stevanovic, Stanislava; Bakke, Hege Gilbø; Nyman, Tuula Anneli; Stensland, Maria & Kase, Eili Tranheim [Vis alle 9 forfattere av denne artikkelen] (2025). Reduced lipid and glucose oxidation and reduced lipid synthesis in AMPKα2/ myotubes. Archives of Physiology and Biochemistry. ISSN 1381-3455. 131(3), s. 483–492. doi: 10.1080/13813455.2024.2449409. Fulltekst i vitenarkiv Vis sammendrag

  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

• Lund, Jenny; Lähteenmäki, Emilia; Eklund, Tiia; Bakke, Hege Gilbø; Thoresen, G. Hege & Pirinen, Eija [Vis alle 9 forfattere av denne artikkelen] (2024). Human HDL subclasses modulate energy metabolism in skeletal muscle cells. Journal of Lipid Research. ISSN 0022-2275. 65:100481(1), s. 1–16. doi: 10.1016/j.jlr.2023.100481. Fulltekst i vitenarkiv Vis sammendrag

  In addition to its antiatherogenic role, HDL reportedly modulates energy metabolism at the whole-body level. HDL functionality is associated with its structure and composition, and functional activities can differ between HDL subclasses. Therefore, we studied if HDL2 and HDL3, the two major HDL subclasses, are able to modulate energy metabolism of skeletal muscle cells. Differentiated mouse and primary human skeletal muscle myotubes were used to investigate the influences of human HDL2 and HDL3 on glucose and fatty uptake and oxidation. HDL-induced changes in lipid distribution and mRNA expression of genes related to energy substrate metabolism, mitochondrial function, and HDL receptors were studied with human myotubes. Additionally, we examined the effects of apoA-I and discoidal, reconstituted HDL particles on substrate metabolism. In mouse myotubes, HDL subclasses strongly enhanced glycolysis upon high and low glucose concentrations. HDL3 caused a minor increase in ATP-linked respiration upon glucose conditioning but HDL2 improved complex I–mediated mitochondrial respiration upon fatty acid treatment. In human myotubes, glucose metabolism was attenuated but fatty acid uptake and oxidation were markedly increased by both HDL subclasses, which also increased mRNA expression of genes related to fatty acid metabolism and HDL receptors. Finally, both HDL subclasses induced incorporation of oleic acid into different lipid classes. These results, demonstrating that HDL subclasses enhance fatty acid oxidation in human myotubes but improve anaerobic metabolism in mouse myotubes, support the role of HDL as a circulating modulator of energy metabolism. Exact mechanisms and components of HDL causing the change, require further investigation.

• Katare, Parmeshwar Bajirao; Dalmao-Fernandez, Andrea; Mengeste, Abel Mulu; Navabakbar, Farnaz; Hamarsland, Håvard & Ellefsen, Stian [Vis alle 12 forfattere av denne artikkelen] (2024). Krill oil supplementation in vivo promotes increased fuel metabolism and protein synthesis in cultured human skeletal muscle cells. Frontiers in Nutrition. 11:1452768, s. 1–14. doi: 10.3389/fnut.2024.1452768. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Krapf, Solveig; Lund, Jenny; Bakke, Hege Gilbø; Nyman, Tuula Anneli; Bartesaghi, Stefano & Peng, Xiao-Rong [Vis alle 9 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 7 forfattere av denne artikkelen] (2023). Development of three-dimensional primary human myospheres as culture model of skeletal muscle cells for metabolic studies. Frontiers in Bioengineering and Biotechnology. 11, s. 1–13. doi: 10.3389/fbioe.2023.1130693. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 7 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Katare, Parmeshwar Bajirao; Fernandez, Andrea Dalmao; Mengeste, Abel Mulu; Hamarsland, Håvard; Ellefsen, Stian & Bakke, Hege Gilbø [Vis alle 9 forfattere av denne artikkelen] (2022). Energy metabolism in skeletal muscle cells from donors with different body mass index. Frontiers in Physiology. 13. doi: 10.3389/fphys.2022.982842. Fulltekst i vitenarkiv
• Mengeste, Abel Mulu; Katare, Parmeshwar Bajirao; Fernandez, Andrea Dalmao; Lund, Jenny; Bakke, Hege Gilbø & Baker, David [Vis alle 11 forfattere av denne artikkelen] (2022). Knockdown of sarcolipin (SLN) impairs substrate utilization in human skeletal muscle cells. Molecular Biology Reports. ISSN 0301-4851. s. 6005–6017. doi: 10.1007/s11033-022-07387-0. Fulltekst i vitenarkiv Vis sammendrag

  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

• Mengeste, Abel Mulu; Lund, Jenny; Katare, Parmeshwar Bajirao; Ghobadi, Roya; Bakke, Hege Gilbø & Lunde, Per Kristian [Vis alle 13 forfattere av denne artikkelen] (2021). The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells. Current Research in Pharmacology and Drug Discovery (CRPHAR). 2, s. 1–12. doi: 10.1016/j.crphar.2021.100060. Fulltekst i vitenarkiv
• Lund, Jenny; Krapf, Solveig Astrid; Sistek, Medina; Bakke, Hege Gilbø; Bartesagi, Stefano & Xiao-Rong, Peng [Vis alle 9 forfattere av denne artikkelen] (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, s. 1–10. doi: 10.1016/j.crphar.2021.100061. Fulltekst i vitenarkiv
• Lindquist, Carine; Bjørndal, Bodil; Bakke, Hege Gilbø; Slettom, Grete; Clason, Marie Karoliussen & Rustan, Arild [Vis alle 10 forfattere av denne artikkelen] (2019). A mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar rats. PLOS ONE. 14:e0222558(9), s. 1–17. doi: 10.1371/journal.pone.0222558. Fulltekst i vitenarkiv Vis sammendrag

  A fatty acid analogue, 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), was previously shown to have hypolipidemic effects in rats by targeting mitochondrial activity predominantly in liver. This study aimed to determine if 1-triple TTA could influence carbohydrate metabolism. Male Wistar rats were treated for three weeks with oral supplementation of 100 mg/kg body weight 1-triple TTA. Blood glucose and insulin levels, and liver carbohydrate metabolism gene expression and enzyme activities were determined. In addition, human myotubes and Huh7 liver cells were treated with 1-triple TTA, and glucose and fatty acid oxidation were determined. The level of plasma insulin was significantly reduced in 1-triple TTA-treated rats, resulting in a 32% reduction in the insulin/glucose ratio. The hepatic glucose and glycogen levels were lowered by 22% and 49%, respectively, compared to control. This was accompanied by lower hepatic gene expression of phosphenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, and Hnf4A, a regulator of gluconeogenesis. Gene expression of pyruvate kinase, catalysing the final step of glycolysis, was also reduced by 1-triple TTA. In addition, pyruvate dehydrogenase activity was reduced, accompanied by 10-15-fold increased gene expression of its regulator pyruvate dehydrogenase kinase 4 compared to control, suggesting reduced entry of pyruvate into the TCA cycle. Indeed, the NADPH-generating enzyme malic enzyme 1 (ME1) catalysing production of pyruvate from malate, was increased 13-fold at the gene expression level. Despite the decreased glycogen level, genes involved in glycogen synthesis were not affected in livers of 1-triple TTA treated rats. In contrast, the pentose phosphate pathway seemed to be increased as the hepatic gene expression of glucose-6-phosphate dehydrogenase (G6PD) was higher in 1-triple TTA treated rats compared to controls. In human Huh7 liver cells, but not in myotubes, 1-triple-TTA reduced glucose oxidation and induced fatty acid oxidation, in line with previous observations of increased hepatic mitochondrial palmitoyl-CoA oxidation in rats. Importantly, this work recognizes the liver as an important organ in glucose homeostasis. The mitochondrially targeted fatty acid analogue 1-triple TTA seemed to lower hepatic glucose and glycogen levels by inhibition of gluconeogenesis. This was also linked to a reduction in glucose oxidation accompanied by reduced PHD activity and stimulation of ME1 and G6PD, favouring a shift from glucose- to fatty acid oxidation. The reduced plasma insulin/glucose ratio indicate that 1-triple TTA may improve glucose tolerance in rats.

• Reppe, Sjur; Jackson, Catherine; Ringstad, Håkon; Tønseth, Kim Alexander; Bakke, Hege Gilbø & Eidet, Jon Roger [Vis alle 7 forfattere av denne artikkelen] (2018). High Throughput Screening of Additives Using Factorial Design to Promote Survival of Stored Cultured Epithelial Sheets. Stem Cells International. ISSN 1687-966X. doi: 10.1155/2018/6545876. Fulltekst i vitenarkiv Vis sammendrag

  There is a need to optimize storage conditions to preserve cell characteristics during transport of cultured cell sheets from specialized culture units to distant hospitals. In this study, we aimed to explore a method to identify additives that diminish the decrease in the viability of stored undifferentiated epidermal cells using multifactorial design and an automated screening procedure. The cultured cells were stored for 7–11 days at 12°C in media supplemented with various additives. Effects were evaluated by calcein staining of live cells as well as morphology. Twenty-six additives were tested using (1) a two-level factorial design in which 10 additives were added or omitted in 64 different combinations and (2) a mixture design with 5 additives at 5 different concentrations in a total of 64 different mixtures. Automated microscopy and cell counting with Fiji enabled efficient processing of data. Significant regression models were identified by Design-Expert software. A calculated maximum increase of live cells to 37 ± 6% was achieved upon storage of cell sheets for 11 days in the presence of 6% glycerol. The beneficial effect of glycerol was shown for epidermal cell sheets from three different donors in two different storage media and with two different factorial designs. We have thus developed a high throughput screening system enabling robust assessment of live cells and identified glycerol as a beneficial additive that has a positive effect on epidermal cell sheet upon storage at 12°C. We believe this method could be of use in other cell culture optimization strategies where a large number of conditions are compared for their effect on cell viability or other quantifiable dependent variables.

• Reppe, Sjur; Lien, Tonje Gulbrandsen; Hsu, Yi-Hsiang; Gautvik, Vigdis Teig; Olstad, Ole Kristoffer & Yu, Rona [Vis alle 11 forfattere av denne artikkelen] (2017). Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women. Epigenetics. ISSN 1559-2294. 12(8), s. 674–687. doi: 10.1080/15592294.2017.1345832. Fulltekst i vitenarkiv Vis sammendrag

  DNA methylation affects expression of associated genes and may contribute to the missing genetic effects from genome-wide association studies of osteoporosis. To improve insight into the mechanisms of postmenopausal osteoporosis, we combined transcript profiling with DNA methylation analyses in bone. RNA and DNA were isolated from 84 bone biopsies of postmenopausal donors varying markedly in bone mineral density (BMD). In all, 2529 CpGs in the top 100 genes most significantly associated with BMD were analyzed. The methylation levels at 63 CpGs differed significantly between healthy and osteoporotic women at 10% false discovery rate (FDR). Five of these CpGs at 5% FDR could explain 14% of BMD variation. To test whether blood DNA methylation reflect the situation in bone (as shown for other tissues), an independent cohort was selected and BMD association was demonstrated in blood for 13 of the 63 CpGs. Four transcripts representing inhibitors of bone metabolism—MEPE, SOST, WIF1, and DKK1—showed correlation to a high number of methylated CpGs, at 5% FDR. Our results link DNA methylation to the genetic influence modifying the skeleton, and the data suggest a complex interaction between CpG methylation and gene regulation. This is the first study in the hitherto largest number of postmenopausal women to demonstrate a strong association among bone CpG methylation, transcript levels, and BMD/fracture. This new insight may have implications for evaluation of osteoporosis stage and susceptibility. The final version of this research has been published in Epigenetics. © 2017 Taylor & Francis

• Hedfors, Ida; Bakke, Hege; Skjødt, Karsten & Grimholt, Unni (2012). Antibodies recognizing both IgM isotypes in Atlantic salmon. Fish and Shellfish Immunology. ISSN 1050-4648. 33(5), s. 1199–1206. doi: 10.1016/j.fsi.2012.09.009. Fulltekst i vitenarkiv
• Lukacs, Morten Ferenc; Harstad, Håvard; Bakke, Hege; Beetz-Sargent, M.; McKinnel, Linda & Lubieniecki, K.P. [Vis alle 8 forfattere av denne artikkelen] (2010). Comprehensive analysis of MHC class I genes from the U-, S-, and Z-lineages in Atlantic salmon. BMC Genomics. 11(154). doi: 10.1186/1471-2164-11-154. Fulltekst i vitenarkiv Vis sammendrag

  Background: We have previously sequenced more than 500 kb of the duplicated MHC class I regions in Atlantic salmon. In the IA region we identified the loci for the MHC class I gene Sasa-UBA in addition to a soluble MHC class I molecule, Sasa-ULA. A pseudolocus for Sasa-UCA was identified in the nonclassical IB region. Both regions contained genes for antigen presentation, as wells as orthologues to other genes residing in the human MHC region.

• Harstad, Håvard; Lukacs, Morten Ferenc; Bakke, Hege & Grimholt, Unni (2008). Multiple expressed MHC class II loci in salmonids; details of one non-classical region in Atlantic salmon (Salmo salar). BMC Genomics. 9, s. 193–209. doi: 10.1186/1471-2164-9-193. Fulltekst i vitenarkiv
• Kjøglum, Sissel; Larsen, Stig; Bakke, Hege & Grimholt, Unni (2008). The Effect of Specific MHC Class I and Class II Combinations on Resistance to Furunculosis in Atlantic Salmon (Salmo salar). Scandinavian Journal of Immunology. ISSN 0300-9475. 67(2), s. 160–168. doi: 10.1111/j.1365-3083.2007.02052.x. Fulltekst i vitenarkiv
• Lukacs, Morten; Harstad, Håvard; Grimholt, Unni; Beetz-Sargant, Marianne; Cooper, G.A. & Reed, Linda [Vis alle 11 forfattere av denne artikkelen] (2007). Genomic organization of duplicated Major Histocompatibility Complex class I regions in Atlantic salmon (Salmo salar). BMC Genomics. 8(251), s. 251–270. Fulltekst i vitenarkiv
• Glover, Kevin; Grimholt, Unni; Bakke, Hege G.; Nilsen, Frank; Storset, Arne & Skaala, Øystein (2007). Major histocompatibility complex (MHC) variation and susceptibility to the sea louse Lepeophtheirus salmonis in Atlantic salmon Salmo salar. Diseases of Aquatic Organisms. ISSN 0177-5103. 76(1), s. 57–65. Fulltekst i vitenarkiv
• Kjøglum, Sissel; Larsen, Stig; Bakke, Hege G. & Grimholt, Unni (2006). How specific MHC class I and class II combinations affect disease resistance against infectious salmon anaemia in Atlantic salmon (Salmo salar). Fish and Shellfish Immunology. ISSN 1050-4648. 21(4), s. 431–441. Fulltekst i vitenarkiv

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• Reppe, Sjur; Jackson, Catherine; Ringstad, Håkon; Tønseth, Kim Alexander; Bakke, Hege Gilbø & Eidet, Jon Roger [Vis alle 7 forfattere av denne artikkelen] (2018). Factorial design in regenerative medicine–high throughput screening of additives to promote survival of stored undifferentiated epidermal cells. Investigative Ophthalmology and Visual Science. ISSN 0146-0404. 59(9), s. 3865–3865. Fulltekst i vitenarkiv
• Reppe, Sjur; Jackson, Catherine; Ringstad, Håkon; Tønseth, Kim Alexander; Bakke, Hege Gilbø & Eidet, Jon Roger [Vis alle 7 forfattere av denne artikkelen] (2018). Factorial design in regenerative medicine–high throughput screening of additives to promote survival of stored undifferentiated epidermal cells. Fulltekst i vitenarkiv
• Grimholt, Unni; Nederbragt, Alexander Johan; Rounge, Trine Ballestad; Malmstrøm, Martin; Star, Bastiaan & Tooming-Klunderud, Ave [Vis alle 12 forfattere av denne artikkelen] (2009). The cod genome project. Fulltekst i vitenarkiv
• Harstad, Håvard; Bakke, Hege; Lukacs, Morten Ferenc; Kjøglum, Sissel; Storset, Arne & Moen, Thomas [Vis alle 7 forfattere av denne artikkelen] (2008). Assosiasjoner mellom MHC og resistens mot IPN i Atlantisk laks. Fulltekst i vitenarkiv
• Harstad, Håvard; Lukacs, Morten; Kjøglum, Sissel; Larsen, Stig; Bakke, Hege G. & Koop, Ben F. [Vis alle 7 forfattere av denne artikkelen] (2007). Current understanding of associations between MHC and disease resistance in Atlantic salmon. Fulltekst i vitenarkiv

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