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β-adrenergic signalling and novel effects in skeletal muscle
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Skeletal muscles have, due to their large mass, a big impact on the whole body metabolism. There are many signals that can regulate the functions of skeletal muscles and one such signal is activation of α- and β-adrenoceptors (α- and β-ARs) by epinephrine and norepinephrine. This activation leads to several effects which are examined in this thesis.

 

Stimulation of β-AR on muscle cells induces glucose uptake, an event that both provides the muscle with energy and lowers the blood glucose levels. We discovered two key components in the β-ARs signal to glucose uptake: the transporter protein GLUT4 and the kinase mTOR, a molecule involved in several metabolic processes but not previously known to be activated by β-ARs.

 

The classical second messenger downstream of β-ARs, cAMP, was surprisingly found to be only partly involved in the β-adrenergic glucose uptake. We also found that a molecule called GRK2 is very important for this glucose uptake.

 

A novel effect of β-AR stimulation presented in this thesis is the inhibition of myosin II-dependent contractility in skeletal muscle cells. The intracellular pathway regulating this event was different from that regulating glucose uptake and involved both classical and novel molecules in the β-AR pathway.

 

Another stimulus that we found to activate insulin-independent glucose uptake in skeletal muscle cells was the natural compound Shikonin. Shikonin increased glucose uptake in skeletal muscle cells via a calcium- and GLUT4-dependent mechanism and improved glucose homeostasis in diabetic rats.

 

Taken together, we have identified new key molecules in the adrenergic signaling pathway as well as novel downstream effects. We conclude that glucose uptake in muscles can be activated by β-adrenergic stimulation or by Shikonin and that both treatments improves glucose homeostasis in diabetic animals. This knowledge can hopefully be used in the search for new drugs to combat type II diabetes.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2013. , 61 p.
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-87205ISBN: 978-91-7447-624-8 (print)OAI: oai:DiVA.org:su-87205DiVA: diva2:601671
Public defence
2013-03-08, hörsalen, Frescati backe, Svante Arrhenius väg 21 A, Stokcholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of doctoral defence the following papers were unpublished and had a status as follows. Paper 1: Manuscript; Paper 3: Manuscript

Available from: 2013-02-14 Created: 2013-01-29 Last updated: 2013-02-05Bibliographically approved
List of papers
1. An insulin-independent pathway including β-adrenoceptors and mTORC2 that translocates GLUT4 and increases glucose uptake in skeletal muscle
Open this publication in new window or tab >>An insulin-independent pathway including β-adrenoceptors and mTORC2 that translocates GLUT4 and increases glucose uptake in skeletal muscle
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-87232 (URN)
Available from: 2013-01-30 Created: 2013-01-30 Last updated: 2013-01-30
2. beta-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells
Open this publication in new window or tab >>beta-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e22304- p.Article in journal (Refereed) Published
Abstract [en]

The beta-adrenoceptors (beta-ARs) control many cellular processes. Here, we show that beta-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin-and ROCK-dependent contractility. The beta-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the beta(2)-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the beta(2)-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of beta(2)-AR activation. In conclusion, we present a novel finding that beta(2)-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-66565 (URN)10.1371/journal.pone.0022304 (DOI)000293284600009 ()
Note
authorCount :3Available from: 2011-12-22 Created: 2011-12-20 Last updated: 2017-12-08Bibliographically approved
3. Glucose uptake in skeletal muscle can be fully induced via the β2-adrenoceptor and GRK2 without cAMP-production
Open this publication in new window or tab >>Glucose uptake in skeletal muscle can be fully induced via the β2-adrenoceptor and GRK2 without cAMP-production
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-87234 (URN)
Available from: 2013-01-30 Created: 2013-01-30 Last updated: 2013-01-30
4. Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats
Open this publication in new window or tab >>Shikonin Increases Glucose Uptake in Skeletal Muscle Cells and Improves Plasma Glucose Levels in Diabetic Goto-Kakizaki Rats
Show others...
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e22510- p.Article in journal (Refereed) Published
Abstract [en]

Background: There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells. Methodology/Principal Findings: Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. Conclusions/Significance: Shikonin increases glucose uptake in skeletal muscle cells via an insulin-independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-66594 (URN)10.1371/journal.pone.0022510 (DOI)000293175100029 ()
Note
authorCount :9Available from: 2011-12-21 Created: 2011-12-20 Last updated: 2017-12-08Bibliographically approved

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