Natasa Nikolic

• Mengeste, Abel Mulu; Nikolic, Natasa; Dalmao Fernandez, Andrea; 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. ISSN 1664-042X. 13. doi: 10.3389/fphys.2022.928195. 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.

• Fraser, David A.; Wang, Xiaoyu; Lund, Jenny; Nikolic, Natasa; Iruarrizaga-Lejarreta, Marta & Skjaeret, Tore [Show all 11 contributors for this article] (2022). A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH. Journal of Hepatology. ISSN 0168-8278. 76(4), p. 800–811. doi: 10.1016/j.jhep.2021.12.004.
• Vid, Jan; Mis, Katarina; Nikolic, Natasa; Dolinar, Klemen; Petric, Metka & Bone, Andraz [Show all 11 contributors for this article] (2021). Effect of differentiation, de novo innervation, and electrical pulse stimulation on mRNA and protein expression of Na+,K+-ATPase, FXYD1, and FXYD5 in cultured human skeletal muscle cells. PLOS ONE. ISSN 1932-6203. doi: 10.1371/journal.pone.0247377. Full text in Research Archive
• Mars, Tomaz; Mis, Katarina; Meznaric, Marija; Mihevc, Sonja Prpar; Vid, Jan & Haugen, Fred [Show all 11 contributors for this article] (2020). Innervation and electrical pulse stimulation – in vitro effects on human skeletal muscle cells. Applied Physiology, Nutrition and Metabolism. ISSN 1715-5312. doi: 10.1139/apnm-2019-0575. Show summary

  Contraction-induced adaptations in skeletal muscles are well characterized in vivo, but the underlying cellular mechanisms are still not completely understood. Cultured human myotubes represent an essential model system for human skeletal muscle which can be modulated ex vivo, but they are quiescent and do not contract unless being stimulated. Stimulation can be achieved by innervation of human myotubes in vitro by co-culturing with embryonic rat spinal cord, or by replacing motor neuron activation by electrical pulse stimulation (EPS). Effects of these two in vitro approaches, innervation and EPS, were characterized with respects to the expression of myosin heavy chains (MyHCs) and metabolism of glucose and oleic acid in cultured human myotubes. Adherent human myotubes were either innervated with rat spinal-cord segments or exposed to EPS. The expression pattern of MyHCs was assessed by qPCR, immunoblotting, and immunofluorescence, while the metabolism of glucose and oleic acid were studied using radiolabeled substrates. Innervation and EPS promoted differentiation towards different fiber types in human myotubes. Expression of the slow MyHC-1 isoform was reduced in innervated myotubes, whereas it remained unaltered in EPS-treated cells. Expression of both fast isoforms (MyHC-2A and MyHC-2X) tended to decrease in EPS-treated cells. Both approaches induced a more oxidative phenotype, reflected in increased CO2 production from both glucose and oleic acid. Novelty: • Innervation and EPS favour differentiation into different fiber types in human myotubes. • Both innervation and EPS promote a metabolically more oxidative phenotype in human myotubes.

• Løvsletten, Nils Gunnar; Rustan, Arild; Laurens, Claire; Thoresen, G. Hege; Moro, Cedric & Nikolic, Natasa (2019). Primary defects in lipid handling and resistance to exercise in myotubes from obese donors with and without type 2 diabetes. Applied Physiology, Nutrition and Metabolism. ISSN 1715-5312. doi: 10.1139/apnm-2019-0265.
• Nikolic, Natasa & Aas, Vigdis (2019). Electrical pulse stimulation of primary human skeletal muscle cells. Methods in molecular biology. ISSN 1064-3745. 1889, p. 17–24. doi: 10.1007/978-1-4939-8897-6_2.
• Lund, Jenny; Aas, Vigdis; Tingstad, Ragna Husby; Van Hees, Alfons & Nikolic, Natasa (2018). Utilization of lactic acid in human myotubes and interplay with glucose and fatty acid metabolism. Scientific Reports. ISSN 2045-2322. 8. doi: 10.1038/s41598-018-28249-5. Full text in Research Archive
• Nikolic, Natasa; Görgens, Sven W.; Thoresen, G. Hege; Aas, Vigdis; Eckel, Jürgen & Eckardt, Kristin (2016). Electrical pulse stimulation of cultured skeletal muscle cells as a model for in vitro exercise - possibilities and limitations. Acta Physiologica. ISSN 1748-1708. 220(3), p. 310–331. doi: 10.1111/apha.12830.
• 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. ISSN 1932-6203. 10(3). doi: 10.1371/journal.pone.0119556. 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. ISSN 0363-6143. 308(7), p. C548–C556. doi: 10.1152/ajpcell.00314.2014.
• 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.
• 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. ISSN 1932-6203. 8(4). doi: 10.1371/journal.pone.0059972. Full text in Research Archive
• Nikolic, Natasa; Rhedin, M; Rustan, Arild; Storlien, Len H.; Thoresen, G. Hege & Strømstedt, Maria (2012). Overexpression of PGC-1α Increases Fatty Acid Oxidative Capacity of Human Skeletal Muscle Cells. Biochemistry Research International. ISSN 2090-2247. 2012. doi: 10.1155/2012/714074.
• Bakke, Siril Skaret; Moro, Cedric; Nikolic, Natasa; Hessvik, Nina Pettersen; Badin, Pierre-Marie & Lauvhaug, Line [Show all 13 contributors for this article] (2012). Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1821(10), p. 1323–1333. doi: 10.1016/j.bbalip.2012.07.001.
• 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. 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. ISSN 1932-6203. 7(3). doi: 10.1371/journal.pone.0033203. Full text in Research Archive
• Fraser, David; Hessvik, Nina Pettersen; Nikolic, Natasa; Aas, Vigdis; Hanssen, Kristian Folkvord & Bøhn, Siv Kjølsrud [Show all 8 contributors for this article] (2012). Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations. Genes & Nutrition. ISSN 1555-8932. doi: 10.1007/s12263-011-0252-8. Full text in Research Archive
• Ciocoiu, Calin Constantin; Nikolic, Natasa; Nguyen, Hoa Huyen; Thoresen, G. Hege; Hansen, Trond Vidar & Aasen, Arne Jørgen (2010). Synthesis and dual PPAR alpha/delta agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516. European Journal of Medicinal Chemistry. ISSN 0223-5234. 45(7), p. 3047–3055. doi: 10.1016/j.ejmech.2010.03.035.

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• Nikolic, Natasa; Nilson, Roger; Briggs, Spike; Fimbault, Jean Cristophe; Auffray, Jean Pierre & Le Gac, Jean Marc [Show all 8 contributors for this article] (2018). A medical support in offshore racing - workshop on medical kit inventory in offshore yacht racing, 12-13 May 2017, Lorient, France. International Maritime Health. ISSN 1641-9251. 69(3), p. 214–222. doi: 10.5603/IMH.2018.0035.
• Aas, Vigdis; Bakke, Siril Skaret; Nikolic, Natasa; Hjelmesæth, Jøran; Thoresen, G. Hege & Rustan, Arild (2012). Altered energy metabolism in skeletal muscle cells derived from morbidly obese subjects.
• Bakke, Siril Skaret; Nikolic, Natasa; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis (2012). ALTERED ENERGY METABOLISM IN SKELETAL MUSCLE CELLS DERIVED FROM MORBIDLY OBESE INDIVIDUALS. Show summary

  Introduction: Obesity is strongly associated with insulin resistance and type 2 diabetes (T2D). It has been revealed that less than 1 out of 3 morbidly obese subjects have T2D (Obes Surg 2010; 20:302-7), indicating that many morbidly obese subjects possess certain characteristics that protect them against developing T2D. Skeletal muscle is an important organ involved in fatty acid and glucose metabolism and therefore one of the organs where insulin resistance is most prominent. Metabolic flexibility is defined as the muscle’s ability to change energy metabolism between fed and fasted conditions, and this ability is reduced in insulin resistance and T2D. Methods: We examined fatty acid and glucose metabolism as well as metabolic flexibility in human skeletal muscle cells using radiolabeled precursors. The cells were derived from lean healthy subjects (BMI 23±0.9 kg/m2), morbidly obese with normal glucose tolerance (BMI 44±2.0 kg/m2) and morbidly obese subjects with T2D (BMI 43±1.5 kg/m2). Results: A 2-fold increase in fatty acid metabolism was observed in cells established from morbidly obese subjects (measured as accumulation and oxidation of oleic acid) and a approximately 40% lower metabolic flexibility (measured as the ability to switch from fatty acid to glucose oxidation) compared to cells from lean subjects. Triacylglycerol lipolysis was 30% higher for obese T2D subjects compared to the other groups. Conclusion: Muscle cells derived from morbidly obese showed increased lipid metabolism, but had a lower metabolic flexibility than cells from lean. Obese subjects with T2D had increased lipolysis, which may be important for development of T2D. Conflict of Interest None disclosed Funding Norwegian Research Council, Norwegian Diabetes Foundation, Freia Chocolade Fabriks Medical Foundation and Anders Jahre’s Foundation.

• Bakke, Siril Skaret; Nikolic, Natasa; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis (2012). Altered energy metabolism in skeletal muscle cells derived from morbidly obese donors.
• Bakke, Siril Skaret; Nikolic, Natasa; Moro, Cedric; Lauvhaug, Line; Hessvik, Nina Pettersen & Thoresen, G. Hege [Show all 7 contributors for this article] (2011). DIFFERENT HANDLING OF PALMITIC ACID AND OLEIC ACID IN HUMAN SKELETAL MUSCLE CELLS.
• Bakke, Siril Skaret; Nikolic, Natasa; Moro, Cedric; Lauvhaug, Line; Hessvik, Nina Pettersen & Thoresen, G. Hege [Show all 7 contributors for this article] (2011). Different handling of palmitic acid and oleic acid in human skeletal muscle cells.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Chronic electrical pulse stimulation of cultured human skeletal muscle cells as an in vitro model of exercise.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Energimetabolismen i humane skjelettmuskelceller - Utvikling av in vitro treningsmodell.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Chronic electrical pulse stimulation of cultured human skeletal muscle cells as an in vitro model of exercise.

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