Kiisa Nishikawa, CBI Director

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In my laboratory, we recently published a new model of muscle contraction that incorporates an active role for the giant, viscoelastic titin protein (Nishikawa et al. 2011). Our new “winding filament” hypothesis suggests that titin is engaged mechanically in skeletal muscles through calcium-dependent binding of the N2A region to thin filaments, after which the cross-bridges wind the PEVK region upon the thin filaments.

Current research is focused on three related projects. The first project tests predictions of the winding filament hypothesis experimentally, using the mdm mutation in mice as a model system for in vitro studies of muscle physiology and in vivo studies of movement. Ongoing projects include using active and passive load-clamp experiments on intact soleus muscles to test the hypothesis that calcium-dependent activation of titin is impaired in muscles of mdm mice. We are also using pharmacological agents, including butanedione monoxeme and dantrolene to investigate calcium-dependent activation of titin in mdm genotypes. At the whole organism-level, we are investigating breathing rates, shivering rates, locomotion and jumping ability of mdm genotypes. These studies will determine whether calcium-dependent activation of titin is impaired in skeletal muscles of mdm mice, and if so, the consequences of impairment on movement.

The second project is a multidisciplinary collaboration among biology, biochemistry and nano-engineering to investigate interactions among N2A, calcium, calcium binding proteins, and actin using techniques of molecular biology and atomic force microscopy. WE are characterizing the structure and calcium binding properties of clones of N2A and PEVK titin from mdm genotypes using a variety of biochemical techniques, including CD and NMR. We are currently developing techniques to attach individual cloned titin molecules to AFM cantilever tips to measure calcium-dependent binding to f-actin in vitro.

The third project is also multidisciplinary, combining biology and mechanical engineering to emulate biological actuation in human engineered devices, using both algorithms and robotic muscles, with applications in prosthetics, orthotics and robotics. A computer simulation of the winding filament model has been developed and the algorithm will be used to control a powered, foot-ankle prosthesis to test whether performance can be improved over control algorithms that employ conventional Hill-type muscle models. In addition, we have developed a bench-model actuator that captures the automatic, instantaneous adaptation to load perturbations exhibited by animal muscles. Together, computer simulations and the bench model are being used to develop “robotic muscles”, biomimetic actuators that function like real muscles, for a variety of applications in prosthetics, orthotics and robotics.