Titin Regulation of Active and Passive Force in Skeletal Muscle
Date
2015-09-01
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Abstract
History dependent properties of muscle contraction such as force enhancement and force depression are not readily explainable by contemporary theories describing how muscles function. The lack of clear mechanistic understanding makes these phenomena difficult to reconcile within the current muscle framework of the sliding filament and crossbridge theories. Experimental evidence has been mounting however, to overturn this antiquated two filament (actin and myosin) based paradigm for one that incorporates a third filament called titin which may serve to explain history dependence. Evidence now suggests that titin can increase its stiffness in response to contractile conditions, thus being critically involved in both passive (low calcium) and active (high calcium) muscle function. The mechanisms behind this are still debated, but two potential ideas for titin based force regulation during active stretch are: (A) an increase in the inherent stiffness of the molecular chain through calcium binding to titin immunoglobulin (Ig) domains or (B) a decrease in titin’s elastic length via transient attachment to actin. Our Ig domain work indicated that calcium had a biochemical effect that further manifested in a mechanical stiffening when Ig domains were stretched with an atomic force microscope in the presence of calcium. The magnitude of this calcium stiffening was about 20 % which lends support to this titin-based stiffening being important for active muscle contraction. Titin-actin interaction was investigated by fluorescently labeling sites on titin within muscle myofibrils where this interaction was speculated to occur. Upon muscle activation, no titin-actin interaction was seen, but rather unexpectedly a titin myosin interaction consistently developed. This led to the formulation of our Titin Entanglement Hypothesis based on observations of entangled I-band titin segments with myosin crossbridges during periods of spatial overlap between the two. This rendered the spring abbreviated and thus able to generate more force upon active stretch, until a release threshold was reached. This entanglement mechanism along with calcium stiffening of Ig domains has the potential to explain the history dependent properties mentioned above, and may serve to help understand the role of titin in active muscle contraction.
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Engineering--Biomedical
Citation
DuVall, M. (2015). Titin Regulation of Active and Passive Force in Skeletal Muscle (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28459