Dokument: The Role of Contractile Activity in the Crosstalk between Human Skeletal Muscle Cells and Adipocytes
| Titel: | The Role of Contractile Activity in the Crosstalk between Human Skeletal Muscle Cells and Adipocytes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=26523 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20130823-083907-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dipl.Ing(FH) Raschke, Silja [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Eckel, Jürgen [Gutachter] Prof. Dr. Schmitt, Lutz [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Nowadays, the prevalence of type 2 diabetes is increasing worldwide and reaches epidemic proportions already. Obesity and inactivity are closely associated with muscle insulin resistance, which is a major risk factor for the pathogenesis of type 2 diabetes. In this context, adipocyte‐secreted factors, so-called adipokines, have been intensively studied and implicated in the negative crosstalk between adipose tissue and skeletal muscle. In contrast, regular physical activity does not only prevent obesity, but also considerably improves insulin sensitivity and skeletal muscle metabolism. While the detrimental effect of adipokines has
been intensively studied, less is known about the underlying mechanisms of the beneficial effect of muscle acitivity, partly due to the lack of suitable models. Most likely, specific myokines released from contracting muscle mediate these health promoting effects. Therefore, we thought to establish and characterise an in vitro model of human skeletal muscle contraction, with a view to directly studying the signalling pathways and mechanisms that are involved in the beneficial effects of muscle activity. In this study, contracting human skeletal myotubes were established by applying electrical pulse (EPS) stimulation. We showed that the effects of EPS on myotubes were similar to the effect of exercise on skeletal muscle in vivo in terms of de novo sarcomer formation and enhanced AMPK activation, glucose uptake, and mitochondrial biogenesis. Additionally, the secretion of myokines like IL-6 was enhanced. Most interestingly, muscle contractile activity eliminates insulin resistance, as insulin signalling was not disturbed after incubation with various adipokines and inflammatory signalling was not activated. Using the contracting myotubes, we found 44 novel contraction-regulated myokines and 52 myokines, which have not been described as myokines before. Comparing the secretome of primary human adipocytes and myotubes revealed an extensive overlap. We termed cytokines released by both cell types ‘adipo-myokines’. PEDF is a good example, since it is one of the most abundant adipokines secreted from primary human adipocytes. Nevertheless, PEDF secretion is increased by contractile activity of myotubes, while whole body PEDF serum levels of humans decrease after one acute bout of exercise. Beside PEDF, DPP4 and follistatin-like 1 have been validated as myokines within the scope of this study. Just recently, irisin, a novel contraction-regulated myokine, has drawn attention, since it was reported that the beneficial effect of exercise can partly be ascribed to irisin. In mice, viral delivery of FNDC5, the gene encoding the precursor protein of irisin, diminished dietinduced weight gain and metabolic dysfunction, since it caused a browning of subcutaneous fat. Brown adipose tissue AT is primarily a thermogenic tissue that burns fat to generate heat by uncoupling the proton electrochemical gradient. Thus, this tissue is discussed as target for novel type 2 diabetes drug therapies. However, data generated here in primary human adipocytes using recombinant irisin revealed evidence against the beneficial effect of irisin in humans. Irisin was not contraction-regulated in human myotubes and most interestingly, it had no effect on the browning of primary human adipocytes. The in vitro contraction model provided the starting point to investigate mechanisms and underlying signalling pathways that mediate the beneficial effects of muscle contraction. With this model, we found that contractile acitivity of skeletal muscle abrogates inflammatory signalling and insulin resistance. We identified 44 contraction-regulated myokines and validated PEDF, DDP4 and follistatin-like 1. In our model system irisin was not contraction-regulated and the beneficial effect could not be determined. Taken together, these findings will contribute to understand the molecular pathways of physical activity, which will help to further clarify the potential of exercise as a way of combating insulin resistance. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 23.08.2013 | |||||||
| Dateien geändert am: | 23.08.2013 | |||||||
| Promotionsantrag am: | 31.01.2013 | |||||||
| Datum der Promotion: | 19.04.2013 |
