Titin based mechanostransduction

Michael Radke, Thirupugal Govindarajan, Christopher Polack, Douaa Mugahid

Titin is a unique molecule that contains elastic spring elements and a kinase domain, as well as multiple phosphorylation sites. Therefore, it has been frequently speculated that titin and invertebrate giant titin-like molecules could act as a stretch sensor in muscle. More recently, this concept has been supported by studies on human dilative cardiomyopathies which suggest an impaired interaction of titin with its regulatory ligands Tcap/telethonin and MLP protein. However, so far it has remained unknown how the stretch signal is processed, i.e. how the mechanical stimulus stretch is converted into a biochemical signal.

To investigate the stretch signaling pathway, we apply mechanical strain in vivo (plaster cast for skeletal muscle; aortic banding for the heart) and in tissue culture (cultivation of primary cells on elastic membranes). The resulting changes in protein expression and localization in our titin kinase and spring element deficient animals are used to map the mechanotransduction pathway.