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The role of titin in contraction of skeletal muscle

Hessel, Anthony L (2018) The role of titin in contraction of skeletal muscle. Doctoral thesis, Northern Arizona University.

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The physiology of muscle contraction is commonly regarded as a mature field in which the fundamental principles, comprising the sliding-filament and swinging cross-bridge theories, have been adequately described. However, our current ability to predict in vivo muscle forces in humans and other animals is inadequate, indicating that our current model of muscle function is incomplete. Muscle proteins that were discovered after the establishment of these original theories were not incorporated into the early iterations of muscle theory. One such protein, titin, was discovered 20 years after muscle theory was codified, and its role in muscle function is still unclear. Titin spans the half-sarcomere, but is often studied in the I-band, where it is elastic and attaches the thick and thin filaments. Initial investigations suggested that titin was too compliant to contribute force during contraction. Recent studies, however, indicate that titin in skeletal muscle increases stiffness upon muscle activation. This “titin activation” theoretically improves our ability to predict in vivo muscle forces in computational models and thus has the potential to radically change our understanding of muscle contraction. Unfortunately, there is very little experimental evidence to complement these theoretical models. To experimentally explore the role of titin, I used muscular dystrophy with myositis (mdm) mice, which have a small deletion in titin that leads to a loss of titin activation, and compared contractile properties between mdm and wild-type muscles. The focus of this dissertation is to investigate the role of titin activation during two contraction modes: 1) cyclical contractions that produce negative work, and 2) isometric contractions at maximal and submaximal activation levels. These data show that muscle function is negatively affected by the mdm mutation, suggesting that this small deletion in titin, and subsequent loss of titin activation, plays a critical role in regulating force during contraction. Future studies will be required to identify the mechanisms by which titin activation regulates force during contraction, as well as the mechanisms that lead to an increase in titin stiffness in skeletal muscle.

Item Type: Thesis (Doctoral)
Publisher’s Statement: © Copyright is held by the author. Digital access to this material is made possible by the Cline Library, Northern Arizona University. Further transmission, reproduction or presentation of protected items is prohibited except with permission of the author.
Keywords: eccentric contractions; skeletal muscle; titin
Subjects: Q Science > QP Physiology
MeSH Subjects: A Anatomy > A02 Musculoskeletal System
NAU Depositing Author Academic Status: Student
Department/Unit: Graduate College > Theses and Dissertations
College of the Environment, Forestry, and Natural Sciences > Biological Sciences
Date Deposited: 04 May 2021 19:50
URI: http://openknowledge.nau.edu/id/eprint/5438

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