The sliding filament theory is widely accepted as a useful model of muscle contraction in isolated preparations. However, the theory fails to account for critically important characteristics of muscle function. Despite decades of work, a predictive model of muscle force during natural movements remains elusive. The researchers will test the hypothesis that important properties of muscle can be explained by the winding filament hypothesis. The proposed work has significant potential to inform our understanding of how neural activation and applied forces together determine in vivo muscle force. Results from the research will be integrated into graduate and/or undergraduate courses at Denison University (RUI-eligible), Northwestern University, and Northern Arizona University. In addition, the research team will leverage programs at Denison University and Northern Arizona University for recruiting under-represented participants in research. Results will be disseminated to broad audiences through standard mechanisms of publication and diverse public media, as well as participation in interdisciplinary conferences in the areas of engineering, biomechanics, and physiology.
The researchers will use the mdm mouse to test predictions of the winding filament hypothesis. The winding hypothesis claims that, in addition to the thin filaments, titin is activated by Ca2+, and that cross-bridges not only translate but also rotate the thin filaments, storing elastic energy in PEVK titin during isometric force development. Due to constraints of sarcomere geometry on titin activation and winding, the hypothesis makes unique quantitative predictions about the effects of stimulation and length changes on muscle force. By including different muscles in the proposed studies, the researchers can determine whether naturally occurring variation in titin structure and function contributes to activation- and length-dependent muscle properties (e.g., doublet potentiation and force depression/enhancement). The experiments will test whether titin activation and winding, alone or in combination, can account for observed muscle forces by comparing experimental results to model predictions.
