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Severe thermoregulatory deficiencies in mice with a gene deletion in titin

Miyano, Carissa (2018) Severe thermoregulatory deficiencies in mice with a gene deletion in titin. Masters thesis, Northern Arizona University.

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Muscular dystrophy with myositis (mdm) mice, which carry a deletion in the muscle protein titin, shiver at a lower than expected frequency for their body size, have body temperatures that decrease below ambient temperatures of 34°C, and have reduced active muscle stiffness in vivo compared to their wild type siblings. The impairment in shivering thermogenesis could be due to the N2A deletion in the titin protein leading to more compliant muscles and lower shivering frequency. I hypothesized that the ability of mdm mice to use the other heat production mechanism, nonshivering thermogenesis (NST), may also be impaired and contribute to their hypothermic state. To assess the response to cold exposure, body temperature and metabolic rate were measured in wild type and mdm mice using open-flow respirometry at four ambient temperature ranges: 19-21°C, 23-25°C, 27-30°C, and 33-35°C. Following the temperature experiment, NST was maximally stimulated by administering 1.2 mg kg-1 of norepinephrine subcutaneously. In the temperature experiment, there was a significant interaction between genotype and temperature, with mdm mice having significantly higher metabolic rates at 27-30°C and lower metabolic rates at 23-25°C compared to wild type mice. After correcting metabolic rate for Q10 effects, mdm mice had lower metabolic rates compared to size-matched Perognathus longimembris (little pocket mouse). In addition, the capacity for NST estimated by area underneath the metabolic response curve was also reduced in mdm mice compared to wild type littermates. When comparing mdm mice to other mice with similar body mass (7g), the effects of low metabolic rate and capacity for NST were exacerbated because predicted values of metabolic rate and capacity for NST are larger for smaller animals. These results indicate that a deletion in N2A titin causes severe thermoregulatory defects at every level of thermoregulation, including NST. Direct effects of the titin mutation likely lead to the lower shivering frequency observed. Indirect effects likely lead to a lower capacity for NST and metabolism in general. Future studies should investigate effects on oxidative phosphorylation or other signaling pathways.

Item Type: Thesis (Masters)
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: metabolism; muscular dystrophy with myositis (mdm); nonshivering thermogenesis; thermoregulation; titin
Subjects: Q Science > QH Natural history > QH301 Biology
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: 24 Apr 2019 22:45
URI: http://openknowledge.nau.edu/id/eprint/5460

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