Stretching the story of titin and muscle function

The discovery of the giant protein titin, also known as connectin, dates almost half a century back. In this review, I recapitulate major advances in the discovery of the titin filaments and the recognition of their properties and function until today. I briefly discuss how our understanding of the layout and interactions of titin in muscle sarcomeres has evolved and review key facts about the titin sequence at the gene (TTN) and protein levels. I also touch upon properties of titin important for the stability of the contractile units and the assembly and maintenance of sarcomeric proteins. The greater part of my discussion centers around the mechanical function of titin in skeletal muscle. I cover milestones of research on titin’s role in stretch-dependent passive tension development, recollect the reasons behind the enormous elastic diversity of titin, and provide an update on the molecular mechanisms of titin elasticity, details of which are emerging even now. I reflect on current knowledge of how muscle fibers behave mechanically if titin stiffness is removed and how titin stiffness can be dynamically regulated, such as by posttranslational modifications or calcium binding. Finally, I highlight novel and exciting, but still controversially discussed, insight into the role titin plays in active tension development, such as length-dependent activation and contraction from longer muscle lengths.