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Author ORCID Identifier


Open Access Dissertation

Document Type


Degree Name

Doctor of Philosophy (PhD)

Degree Program


Year Degree Awarded


Month Degree Awarded


First Advisor

Edward Debold

Second Advisor

Sam Walcott

Third Advisor

Shuang Zhou

Fourth Advisor

Wouter Hoogkamer

Subject Categories

Atomic, Molecular and Optical Physics | Biological and Chemical Physics


In response to repeated intense contractile activity, a muscle’s ability to generate force decreases due to the created state of muscular fatigue. This compromised force production state is dependent on changes within the microenvironment of muscle thought to alter the function of the force generating, contractile protein myosin. For example, phosphate (Pi), elevated during fatigue, has been suggested to alter how myosin generates force. However, the effects of Pi are not straightforward, as muscle fiber data suggest that Pi's interaction with myosin may be force-dependent. In particular, Pi has no effect on maximal shortening velocity, but dramatically decreases isometric force development. These effects of Pi on muscle force development occur in a concentration dependent manner, but the mechanism underlying its effects on myosin has not been resolved. In fact, there are two competing explanations for how Pi reduces the force generating capacity of myosin. Each explanation generates different predictions of how Pi affects myosin. Therefore, to understand the mechanism underlying Pi effects on the crossbridge, we aimed to 1) characterize the force-dependent mechanism of Pi-rebinding in skeletal myosin and 2) identify a structural element coordinating this process. Our work has a) explained the force-dependent effect of Pi on skeletal muscle myosin’s force generating capacity, b) characterized a force sensitive region within the active site that mediates Pi-rebinding, and c) improved our understanding of the mechanisms of muscular fatigue at the crossbridge level.


Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.