Mishra, Dhruv (2021) Investigating the role of titin in skeletal muscles from mdm mice with a deletion in N2A titin. Doctoral thesis, Northern Arizona University.
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Abstract
Muscle physiology is usually considered as a well-developed field which is sufficiently defined by fundamental principles from the sliding filament and swinging cross-bridge theories. However, a key muscle protein, titin, was isolated 20 years after establishment of these original theories. Even after two decades, the role of titin in active muscle function remains elusive. Titin spans from Z-line to M-line, comprising a half-sarcomere. Most previous studies focused on the I-band, where titin is elastic and serves as an attachment point between thick and thin filaments. Previous studies proposed that the compliance of titin precludes a role in active muscle contraction. However, recent studies have proposed that titin stiffness increases in skeletal muscles during active contraction. To explore the role of titin in skeletal muscles, we used mdm mice that have deletion in N2A titin, which has been proposed to bind to actin in active muscles. The main aim of this dissertation was to investigate the role of titin in mdm mice, specifically how the small deletion in the N2A region affects residual force enhancement (RFE), passive stress, and sarcomere structure during activation and stretch. Our results demonstrate that the mdm mutation decreases RFE and leads to an alternate splicing pattern in the PEVK region of mdm mice which ultimately results in higher passive stress in mdm skeletal muscles. The x-ray diffraction results suggest that I1,0 intensity, lattice spacing and thick filament periodicity are activation- and length-dependent properties of WT muscles which are absent in mdm muscles. The results of all three studies are consistent with lower the active stiffness of mdm muscles (Powers et al., 2016; Monroy et al., 2017), possibly due to lack of N2A titin-actin binding in active muscle (Dutta et al., 2018). Our research was focused on gaining a deeper insight into the function of titin in skeletal muscles from mdm mice with a small deletion in N2A titin. Results from these studies can help us to better understand the mechanisms contributing to muscle weakness in titin-related skeletal muscle diseases.
Item Type: | Thesis (Doctoral) |
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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: | Biostatistics; Muscle Physiology; Titinopathies |
Subjects: | Q Science > QM Human anatomy |
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: | 25 May 2023 22:12 |
Last Modified: | 25 May 2023 22:12 |
URI: | https://openknowledge.nau.edu/id/eprint/5906 |
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