Project 7 - Caveolar dynamics

Principal investigators
Markus Schülke-Gerstenfeld, MD, Prof and Simone Spuler, MD, Prof 

We demonstrated an almost complete absence of caveolae due to mutations in the PTRF/Cavin gene in patients with a novel type of congenital generalized lipodystrophy (CGL4). In addition to lipodystrophy, the patients also had a striking muscle phenotype. Skeletal muscles were enlarged and showed the “rippling” phenomenon. Furthermore, gross hypertrophy of smooth muscle caused intestinal obstruction and the cardiac muscle was affected with a wide range of various arrhythmias, including long-QT syndrome, sick-sinus syndrome, ventricular, and supraventricular tachycardia. We will now investigate how caveolae are involved in the signaling transduction pathways that guarantee homeostasis and adaption of muscle mass to varying metabolic and mechanical demands. We will rely on novel life-cell-imaging experiments. In addition we will investigate how the signaling cascades are disturbed in primary myoblasts from patients with caveolin-3 and PTRF/Cavin deficiency. As several receptors (e.g. insulin and ActRIIB receptors) co-localize with caveolae, we hypothesize that caveolae might be an ideal vehicle to down- and up-regulate receptor density, simply by internalization under the sarcolemma (endocytosis) and resurfacing (exocytosis). Imaging of these dynamic processes will be accomplished with time-resolved atomic-force microscopy coupled with confocal microscopic localization of EGFP-tagged PTRF and caveolin-3 protein.

Dynamics of muscle caveolae

Dr.-Ing. Tobias Timmel

Caveolae are flask-like invaginations of the cell membrane with an average diameter of 50-100 nm. They occur in many mammalian cell types and are involved in numerous dynamic cellular processes such as signal transduction and endocytosis. The formation and regulation of these cholesterol rich structures depends on the presence of caveolin and cavin proteins, whereas Caveolin-3 and Cavin-4 are muscle specific. The lack of these proteins has been strongly linked to several diseases such as cancer, cardiovascular and muscular diseases.

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