Sympathetic Innervation Regulates Metabolic Flexibility of Skeletal Muscle Restricted; Files & ToC

Abstract

The sympathetic nervous system (SNS) is a complex part of the autonomic nervous system that governs involuntary bodily actions. It has long been recognized for its role in physiological regulation of organs and recently has emerged as a key player in skeletal muscle metabolic and neuromuscular junction (NMJ) health. However, the mechanism through which SNS signaling influences skeletal muscle function and adaptation to exercise remains unclear. In this dissertation, I use a mouse model of surgical sympathectomy (sympx) to test the role of sympathetic innervation to skeletal muscle in response to exercise. Using molecular, electrophysiological, immunohistochemical, and high-resolution respirometry techniques, I found that sympathetic denervation disrupts the NMJ, reducing motor and sympathetic receptor expression, with concomitant deficits in skeletal muscle function. Mechanistically, these deficits are linked to diminished CPT1 enzyme activity, which impairs long-chain fatty acid-mediated oxidation in skeletal muscle mitochondria. We then tested our findings in response to spinal cord injury (SCI), which results in overactive sympathetic signaling. We used high-resolution respirometry techniques in a mouse model of SCI to evaluate the role of SNS signaling in a muscle wasting model. We found that as in our sympx model, SCI muscles both above and below the level of lesion present with reduced long-chain fatty acid-mediated oxidation. This deficit was driven, in part, by diminished CPT1 and β-HAD enzyme activity. Altogether these findings reveal a key role for sympathetic innervation in maintaining mitochondrial metabolic function and by extension, skeletal muscle performance, offering novel insight into the interplay between the SNS, exercise, and muscle mitochondria.   

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Molecular Biology, Genetics Biology, Neuroscience
Keyword	CPT1 Sympathetic nervous system B2-adrenergic receptor mitochondria skeletal muscle
Committee Chair / Thesis Advisor	Jill Ward, Emory University
Committee Members	Jie Jiang, Emory University Guy Benian, Emory University Victor Faundez, Emory University Tamara Caspary, Emory University Bing Yao, Emory University

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