The basis of the Frank-Starling mechanism of the heart is the increase in active 
force when muscle is stretched. Various findings have shown that muscle length, 
i.e., sarcomere length (SL), modulates activation of cardiac myofilaments at a 
given concentration of Ca2+ ([Ca2+]). This augmented Ca2+ activation with SL, 
commonly known as "length-dependent activation", is manifested as the leftward 
shift of the force-pCa (= -log [Ca2+]) relation as well as by the increase in 
maximal Ca2+ -activated force. Despite the numerous studies that have been 
undertaken, the molecular mechanism(s) of length-dependent activation is (are) 
still not fully understood. The giant sarcomere protein titin/connectin is the 
largest protein known to date. Titin/connectin is responsible for most passive 
force in vertebrate striated muscle and also functions as a molecular scaffold 
during myofibrillogenesis. Recent studies suggest that titin/connectin plays an 
important role in length-dependent activation by sensing stretch and promoting 
actomyosin interaction. Here we review and extend this previous work and focus 
on the mechanism by which titin/connectin might modulate actomyosin interaction.