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Pirkmajer, Sergej; Garcia-Roves, Pablo M.; Rustan, Arild Christian & Chibalin, Alexander V.
(2022).
Editorial: Untangling energy metabolism in skeletal muscle: From physiology to pharmacology.
Frontiers in Physiology.
ISSN 1664-042X.
13.
doi:
10.3389/fphys.2022.1113860.
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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.
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Feng, Yuan Zeng; knabenes, Irlin Knivsland; Bakke, Siril S.; Lund, Jenny; Lee, Y.K. & kimmel, Alan
[Show all 9 contributors for this article]
(2015).
Increased lipid oxidation and decreased lipid storage in myotubes lacking the lipid droplet binding protein perilipin2.
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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.
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Feng, Yuan Zeng; knabenes, Irlin Knivsland; Lund, Jenny; Lee, Y.K.; kimmel, Alan & Thoresen, G. Hege
[Show all 8 contributors for this article]
(2014).
Increased lipid oxidation and decreased lipid storage in myotubes lacking perilipin2.
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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.
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Smith, Robert; Johansen, Harald Thidemann; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild & Thoresen, G. Hege
[Show all 7 contributors for this article]
(2013).
Simvastatin inhibits legumain activity and processing in human myotubes.
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Covington, Jeffrey D.; Galgani, Jose E.; Rustan, Arild; Zhang, Zhengyu; Moro, Cedric & Smith, Steven R.
[Show all 8 contributors for this article]
(2013).
Muscle perilipin 3 is reduced using in vitro and in vivo exercise models and negatively associated with exercise lipid oxidation.
The FASEB Journal.
ISSN 0892-6638.
27.
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Bakke, Siril Skaret; Feng, Yuan Zeng; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis
(2012).
Lower lipolysis to counteract the development of type 2 diabetes mellitus - evidence from myotubes established from extremely obese subjects.
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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.
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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.
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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.
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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.
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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.
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Lauvhaug, Line; Bakke, Siril Skaret; Thoresen, G. Hege & Rustan, Arild
(2011).
Different handling of oleic, palmitic, linoleic and eicosapentaenoic acids in cultured human skeletal muscle cells.
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Halle, Ingeborg F.; Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis
(2011).
Electrical pulse stimulation of cultured human skeletal muscle cells as a model of exercise in vitro.
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Dembinska-Kiec, A.; Knapp, A.; Kiec-Wilk, B.; Sliwa, A.; Czech, U. & Korczynska, M.
[Show all 7 contributors for this article]
(2010).
Metabolism of endothelial and adipose stromal vascular (SVF) fraction in the presence of fatty acids.
European Journal of Clinical Investigation.
ISSN 0014-2972.
40,
p. 78–79.
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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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Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis
(2010).
Energimetabolismen i humane skjelettmuskelceller - Utvikling av in vitro treningsmodell.
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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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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.
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.
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Bakke, Siril Skaret; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild
(2010).
The impact of the n-3 fatty acid eicosapentaenoic acid (EPA) on metabolic switching in human skeletal muscle cells.
Show summary
Our recent studies with differentiated human skeletal muscle cells (myotubes) suggests a positive role for the n-3 fatty acid eicosapentaenoic acid (EPA) compared to the other monounsaturated and saturated fatty acids (FAs) in improving overall metabolic switching in skeletal muscle in vitro. This might contribute to the beneficial health effects of dietary intake of very long-chain n-3 fatty acids.
In a study using myotubes established from lean healthy donors we showed that incubation of EPA for one day increased suppressibility, the ability of acute glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition (“fed”) to a high fatty acid, low glucose (“fasted”) condition, was also increased by EPA. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with several FAs (EPA, linoleic acid (LA) and palmitic acid (PA)). EPA present in the cell after one day was significantly less than the other FAs, probably due to a higher oxidation rate. Yet, EPA, LA and oleic acid (OA) treatment increased the number of lipid droplets (LDs) in myotubes. LD volume and intensity, as well as mitochondrial mass were independent of FA pretreatment. Microarray and PCR analysis showed that EPA regulated more genes than the other FAs, and that specific pathways involved in carbohydrate metabolism were induced only by EPA.
The present study suggests a favorable effect of EPA on skeletal muscle metabolic switching. Additional experiments with ALA (α-linolenic acid) and DHA (docosahexaenoic acid) indicated that the metabolic effects could be due to a general quality of n-3 FAs. Based on findings from this study we also suggest the use of three parameters called suppressibility, adaptability and substrate-regulated flexibility in functional studies of fuel selection and energy metabolism in cell cultures.
References:
Hessvik NP, Bakke SS et al, “Metabolic switching of human myotubes is improved by n-3 fatty acids.”, J Lipid Res. 2010 Aug;51(8):2090-104.
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Bakke, Siril Skaret; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild
(2010).
HANDLING OF PALMITIC ACID AND OLEIC ACID IN HUMAN SKELETAL MUSCLE CELLS.
Show summary
Obesity seems to be associated with type of dietary fat, and a positive association with saturated fatty acids (SFA) and a negative association with monounsaturated fatty acids (MUFA) have been found. In human skeletal muscle cells, SFA is reported to preferentially accumulate as diacylglycerol (DAG) and ceramides, while MUFA is reported to preferentially accumulate as triacylglyserol (TAG). In accordance to this, we have previously shown that the number of lipid droplets (LDs) is two-fold higher after pretreatment with oleic acid (OA) than palmitic acid (PA). PA has also been found to be more oxidized than OA. We wanted to study the handling of OA and PA in human myotubes, regarding uptake, oxidation and storage.
Satellite cells were isolated from biopsy samples from M. obliquus internus abdominis and differentiated into multinucleated myotubes. Myotubes were pretreated for 24 h with 100 μM OA/PA, and the metabolism of [14C] OA/PA was studied. For imaging with fluorescence microscope, myotubes were stained with Bodipy and Hoescht, and LDs and nuclei were counted.
Our results show that in human myotubes more OA than PA was stored, while PA was oxidized to a higher degree than OA. OA was stored mostly as TAG, while more PA than OA was stored in phospholipids. When long fatty acyl CoA synthetase was inhibited by Triacsin C, the storage of OA in TAG and DAG was reduced, but storage of PA remained unchanged. More OA than PA was subject to lipolysis; however the lipolysis seemed to parallel the storage in LDs. Thus, lipolysis might not be dependent on saturation of fatty acids stored but on the amount of lipids stored.
In conclusion, our results indicate that PA has a higher turnover and is more available for oxidation than OA. This might be of importance in further studies of the link between intracellular lipids and the development of insulin resistance.
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Aas, Vigdis; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild
(2010).
Chronic hyperglycemia impairs mitochondrial function in human myotubes.
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Rustan, Arild
(2010).
The impact of eicosapentaenoic acid (EPA) on regulation of fatty acid metabolism, metabolic flexibility and gene expression in human skeletal muscle cells.
Show summary
Our recent studies with differentiated human skeletal muscle cells (myotubes) suggests a positive role for eicosapentaenoic acid (EPA) compared to the other fatty acids (FAs) in improving overall energy metabolism and metabolic switching in skeletal muscle, which may contribute to the beneficial effects of dietary intake of very long-chain n-3 fatty acids.
In a study using myotubes established from lean donors we showed that EPA increased suppressibility, the ability of acute glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition (“fed”) to a high fatty acid, low glucose (“fasted”) condition, was increased by EPA. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). EPA per se accumulated less in the cells, however, EPA, LA and oleic acid (OA) treatment increased the number of lipid droplets (LDs) in myotubes. LD volume and intensity, as well as mitochondrial mass were independent of FA pretreatment. Microarray and PCR analysis showed that EPA regulated more genes than the other FAs and specific pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggest a favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Additional experiments with ALA and DHA indicated that the metabolic effects could be due to a general quality of n-3 FAs. Based on finding from this study we also suggest the use of three parameters called suppressibility, adaptability and substrate-regulated flexibility in functional studies of fuel selection and energy metabolism in cell cultures.
In another study we wanted to identify the potential effects of EPA and a synthetic fatty acid derivative (TTA) on energy metabolism, insulin resistance and gene expression (PCR). Here we compared the effects of EPA, TTA, and OA in myotubes established from obese individuals with type 2 diabetes and obese healthy control subjects. Our results suggest that 1) mitochondrial dysfunction in diabetic myotubes was caused by disturbances downstream of fatty acid β-oxidation; 2) EPA promoted accumulation of triacylglycerol (TAG), enhanced β-oxidation, and increased glucose oxidation; and 3) TTA improved complete palmitic acid oxidation in diabetic myotubes, opposed increased lipid accumulation, and increased glucose oxidation.
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Rustan, Arild Chr.; Wettergreen, Marianne; Hessvik, Nina; Thoresen, G. Hege & Aas, Vigdis
(2010).
Chronic hyperglycaemia impairs metabolic switching of human myotubes.
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Aas, Vigdis; Hessvik, Nina; Thoresen, Hege & Rustan, Arild Chr.
(2010).
Chronic hyperglycaemia impairs mitochondrial function in human myotubes.
