The long term goal of my research program is to understand the function and design of muscular systems. This involves performing experiments that facilitate the integration of information from molecular, cellular and whole animal studies. This approach is unusual because scientists generally work on either molecules, cells or whole animals, but not on all three. However, this approach is crucial because it pinpoints the gaps in our understanding of muscle function. Vertebrate muscle must perform mechanical work to power locomotion, pump blood, and produce sound. The frequency at which work is produced varies dramatically from less than 1Hz for cardiac muscle (or slow-twitch skeletal muscle) to more than 200 Hz for super-fast sound producing muscles of toadfish. The toadfish swimbladder is the fastest vertebrate muscle known. Based on the simple assumption that for each stimulus sufficient Ca2+ is released to saturate TNC and is then resequestered prior to the next stimulus, the swimbladder's Ca2+ pumping rate that we measured was 8-fold too low for this requirement. The question arises what really is the pattern of Ca2+ release and reuptake during normal motor behavior? And what are the relative roles of parvalbumin and Ca2+ pumps in sequestering Ca2+ (swimbladder has highest the [PARV] ever measured)? Although these are fundamental questions in muscle physiology, the answers are surprisingly unknown. The swimbladder makes an excellent model. It is a pure fiber type so that we can perform experiments on the single cell level as well as on large bundles. Further, it's pattern of activation and relaxation in vivo is easily measured by simply analyzing the rate and number of sound pulses. Importantly, we have recently developed novel energetics techniques based on using BTS to block the crossbridge ATPase, which allow us for the first time to track the actual Ca2+ fluxes during normal muscle motor behavior. Ultimately, elucidation of the principles of how healthy motor systems work are useful in understanding disease of the motor and cardiovascular systems. For instance, this integrative approach on an unusual muscle enabled us to see the gaps in our understanding and to develop new technologies which are applicable to all muscle systems. Understanding Ca2+ cycling and PARV function in a normal system will likely provide some important clinical insights into skeletal muscle diseases such as Brody's diseases as well as the recent demonstration that introduction of PARV (which is not normally expressed in cardiac muscle) into pathologically slow relaxing hearts can return relaxation rate and cardiovascular parameters to normal.
| Harwood, Claire L; Young, Iain S; Tikunov, Boris A et al. (2011) Paying the piper: the cost of Ca2+ pumping during the mating call of toadfish. J Physiol 589:5467-84 |
| Kargo, William J; Ramakrishnan, Arun; Hart, Corey B et al. (2010) A simple experimentally based model using proprioceptive regulation of motor primitives captures adjusted trajectory formation in spinal frogs. J Neurophysiol 103:573-90 |
| Tikunov, Boris A; Rome, Lawrence C (2009) Is high concentration of parvalbumin a requirement for superfast relaxation? J Muscle Res Cell Motil 30:57-65 |
