P1: Titin based mechanotransduction in skeletal muscle atrophy and hypertrophy
Michael Gotthardt and Norbert Huebner
Summary
We are interested in elucidating the role of titin as a mechanosensor. Our global hypothesis is that titin senses myocyte stretch and signals appropriate muscle responses, in part via its kinase domain. We will use mouse models that lack individual titin domains, which will be challenged using immobilization and exercise protocols. The molecular analysis includes expression profiling and visualization of proteins by immunofluorescence staining to monitor hypertrophy signaling. Finally, we will investigate the role of titin in muscular atrophy using both the established knockout mice and a novel model of an immobile organism that nevertheless exhibits little muscle atrophy, namely the hibernating grizzly bear.
Schematic diagram of the sarcomere (modified from Gregorio et al., Curr. Opin. Cell. Biol. 11: 18-25, 1999). Titin forms a continuous filament system along the muscle fiber in vertebrate striated muscle overlapping in the M-band and in the Z-disc. The titin kinase is found near the edge of the M-band region, while the elastic PEVK resides in the I-band. Titin interacts with a plethora of sarcomeric proteins, such as T-cap and C-protein.
