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Characterization of a transgenic mouse overexpressing SRP-35 in their skeletal muscle

Ruiz Velez, Alexis Jesus. Characterization of a transgenic mouse overexpressing SRP-35 in their skeletal muscle. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12716

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Abstract

Skeletal muscle is the largest body organ comprising approximately 40% of total body weight under normal conditions; it is not only important for movement and posture but also for thermogenesis and metabolism. In fact this organ is also responsible for 70–75% of the insulin stimulated glucose uptake; part of the energy obtained from glucose is used to fuel muscles and the remaining is stored as glycogen. The effect of vitamin A metabolites including all trans retinoic acid (atRA), have been shown to be involved not only in skeletal muscle differentiation, but also in the skeletal muscle metabolism, enhancing glucose uptake, increasing lipid oxidation capacity and activating of PI3K-AKT pathway. However, the specific signaling pathway involved in retinoic acid signaling is still not completely understood.
SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C dehydrogenase/ reductase family 7, which use retinol as substrate to produce all-trans-retinaldehyde. In my thesis I will show that the over-expression of SRP-35 enzyme in mouse skeletal muscles enhances muscle performance in vivo; this effect is not related to alterations in excitation-contraction coupling but rather is linked to enhanced glucose metabolism. Over-expression of this enzyme causes increased phosphorylation of AKTS473, triggering translocation of Glut4 to the sarcolemma and higher glucose uptake into the muscles. I will also demonstrate that pharmacological application of atRA, a downstream product of the enzymatic activity of SRP-35, to intact muscles from WT mice, mimics the stimulation of AKTS473 phosphorylation observed in SRP35TG muscles, while inhibitors of the Retinoic Acid Receptor (RAR) α and RARγ nuclear receptors inhibit AKTS473 phosphorylation in muscles from WT mice treated with pharmacological concentrations of atRA. These results indicate that SRP-35 signaling involves non-genomic effects of RARα and RARγ. My results also demonstrate that RA signaling affects the activation of PI3K. Skeletal muscles from SRP35TG mice showed a 14 fold increase of PIP3 content, indicating the evolvement of Phosphoinositide 3-kinase (PI3K) and Mammalian target of rapamycin complex 2 (mTORC2). Additionally, the skeletal muscles obtained from SRP35TG mice kept under Low vitamin A diet (LVAD) for two generations show higher fatigue resistance and larger glycogen stores compared to those of WT littermates fed with the same diet. These results indicate that SRP-35 affects skeletal muscle metabolism and fatigue performance, which may represent an important target for the treatment of metabolic diseases.
Advisors:Treves, Susan and Martin, Ivan
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Treves, Susan and Martin, Ivan
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12716
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (127 Seiten)
Language:English
Identification Number:
Last Modified:06 Sep 2018 04:30
Deposited On:05 Sep 2018 09:45

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