Zuckermann Lecture

The mechanical work of titin folding and muscle contraction

Julio Fernández

Department of Biological Sciences
Columbia University

We do not know why the mechanical stretching of muscle tissues, such as during yoga, is so beneficial for humans. Current theories of muscle contraction propose that the power stroke of a myosin motor is the sole source of mechanical energy driving the sliding filaments of a contracting muscle. Amazingly, these models exclude titin, the largest protein in the human body, which determines the passive elasticity of muscles and is mechanically unfolded by stretching. During my lecture I will provide evidence at the single molecule level, that stepwise unfolding and folding of titin Ig domains occurs in the elastic I band region of intact myofibrils at physiological sarcomere lengths and forces of 6-8 pN. Further, I will show that titin folding does mechanical work at these forces that is up to three times larger than that generated by a myosin motor. Therefore, it appears inescapable that folding of titin Ig domains is an important, but so far unrecognized contributor to the force generated by a contracting muscle. Thus, ancient wisdom was right again: recruiting titin domains to the unfolded state by stretching greatly increases the storage of elastic energy in muscle, which is an essential component of muscle contraction.