Dissertation
IMPAIRED DEVELOPMENTAL AND METABOLIC PROCESSES WITHIN THE SKELETAL MUSCLE IN RESPONSE TO HIGH-FAT-DIET
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000005405
Handle:
https://hdl.handle.net/2376/119021
Abstract
Obesity has become a major health concern due to its close associations with the development of multiple metabolic syndromes. Disruption of the skeletal muscle under the challenge of obesity has severe adverse outcomes on the systematic metabolism. Obesity during the pregnancy impairs the developmental progress in the offspring which predisposes the risks of metabolic disorders later in life. A better understanding of the impairments caused by obesity to the skeletal muscle and the underlying mechanism are urgently needed to help with the prevention of obesity-associated metabolic dysfunctions. In this dissertation, the impairments of obesity to the skeletal muscle were examined both at the embryonic and adult stages. (1) Using single-cell transcriptomic analysis, we found that maternal obesity enhanced a hypoxic state in the mouse embryos at embryonic 9.5 day, accompanied by increased glycolysis, decreased oxidative phosphorylation and elevated oxidative stress. The bone morphogen protein signaling transduction within the dermomyotome was enhanced by maternal obesity, which attenuated the myogenic differentiation by suppressing the expression of an important myogenic regulator, Mef2c. The myogenic inhibitory function of the hypoxia regulator, HIF1A, was achieved through up-regulation of the down-stream effector of Notch signaling, Hes1. Maternal obesity-attenuated myogenic differentiation at the embryonic stage may account for the impairments in muscle growth and function at later lives. (2) Retinoic acid signaling in fibro/adipogenic progenitors was found to facilitate the myofiber regeneration after injury as well as to suppress their ectopic differentiation into adipocytes. Decreased retinoic acid signaling in the skeletal muscle caused by obesity disrupted the physiological functions of fibro/adipogenic progenitors, which resulted in failed muscle repair with enhanced lipid and fibrosis accumulation. (3) AMPKα1 was identified as an important mediator for the beneficial effects of raspberry supplementation on alleviating inflammatory responses and promoting insulin sensitivity in skeletal muscle of obese mice. Taken together, our studies provide us with a better understanding of obesity-induced impairments to the skeletal muscle at both the embryonic and adult stages. Signaling mechanisms identified in these studies provide theoretic supports to the therapeutic treatments of obesity and associated metabolic syndromes.
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Details
- Title
- IMPAIRED DEVELOPMENTAL AND METABOLIC PROCESSES WITHIN THE SKELETAL MUSCLE IN RESPONSE TO HIGH-FAT-DIET
- Creators
- Liang Zhao
- Contributors
- Min Du (Advisor)James Pru (Committee Member)Jennifer Watts (Committee Member)Nathan Law (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Animal Sciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 247
- Identifiers
- 99900592360901842
- Language
- English
- Resource Type
- Dissertation