Collaborative Research: A New Twist on Muscle Contraction

Project: Research project

Project Details

Description

OVERVIEW: 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. We will test the hypothesis that important properties of muscle, which have defied explanation for decades, can be explained by the winding filament hypothesis. The 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 both EDL and soleus muscles in the proposed studies, we can ask whether naturally occurring variation in titin structure and function contributes to activation- and length-dependent muscle properties. Preliminary data support the hypothesis that activation of titin is impaired in mdm muscles. Mdm muscles show deficiencies in doublet potentiation and behave differently in isovelocity stretch and shortening tests. We will use the mdm mouse as a model system to test predictions of the winding filament hypothesis.
INTELLECTUAL MERIT: Our specific aims are: 1) to investigate the force-extension properties of distal tandem Ig and PEVK domains of titin in soleus and EDL muscles from wild type and mdm mice using immuno-gold electron transmission microscopy; 2) to investigate muscle force in doublet potentiation and isovelocity stretch and shortening experiments; and 3) to combine models of Ca2+ flux and muscle activation with a kinematic model of titin activation and winding. We will test whether titin activation and winding, alone or in combination, can account for observed muscle forces by comparing experimental results to model predictions. Decades of published work and our preliminary data suggest a role for titin in doublet potentiation and force enhancement. If the combined Ca2+-crossbridge-titin models are consistent with the results of the proposed experiments, then the proposed work will transform our understanding of the mechanism of muscle contraction. Alternatively, the proposed experiments and model predictions may refute all or parts of the winding filament theory. If titin activation and/or winding mechanisms are refuted, the antibody data will suggest alternative hypotheses, which can also be tested using the combined models.
StatusFinished
Effective start/end date8/1/157/31/19

Funding

  • National Science Foundation (IOS-1456623)

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