Li, Yizhi
(2024)
Synaptic Changes in Structure and Function at the Aging Mouse Neuromuscular Junction and the Evaluation of Candidate Mechanisms for Age-Induced Weakness.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Dynapenia (age-induced loss of muscle strength) remains to be a major obstacle in efforts to maintain neuromuscular function in the aged population. Weakening of neurotransmission from the motor nerve can significantly debilitate the innervated muscle fibers. In this dissertation, I have focused on the neuromuscular junction (NMJ), which serves as a bridge of communication between the end of the motor nerve terminal and the muscle fibers, to demonstrate age-related changes to this structure and its function.
The second chapter of this dissertation describes a cross-sectional characterization showing that the neurotransmission at the male mouse NMJ to be biphasic: an early increase followed by a later decrease. These functional changes were accompanied by structural alterations at the NMJ. Using the average strength of the neurotransmission, we separated animals from 3-30 months into four age groups termed Young Adult (3-6 months), Adult (7-18 months), Early Aged (19-24 months), and Later Aged (25-30 months). The age-induced deficits in the later aging stage were rescued by acutely applying a novel candidate therapeutic, GV-58.
The third chapter explores several potential mechanisms behind changes in presynaptic neurotransmitter release during neuromuscular aging. I found that the active zone density was significantly reduced in NMJs with low synaptic strength at 26 months of age. I also found that these NMJs with low synaptic strength showed facilitation during a train stimulation, hinting at a significantly lower probability of release at each active zone. Surprisingly, these low synaptic strength NMJs at 26 months also showed significantly increased readily releasable pool. Together, I found that some of the release properties on the weak NMJs have their functions reduced in the later stage of aging, and the readily releasable pool was increased to potentially compensate for the reduced neurotransmission.
These findings shed light on the mechanisms behind age-induced changes at the NMJ. For the first time, we demonstrate that NMJs from the same muscle adopt different “paces of aging”. Understanding these processes that lead to reduction in neurotransmission will guide future research efforts on developing novel therapeutics for neuromuscular aging.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
27 August 2024 |
| Date Type: |
Publication |
| Defense Date: |
25 April 2024 |
| Approval Date: |
27 August 2024 |
| Submission Date: |
6 May 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
182 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Neuromuscular junction aging |
| Date Deposited: |
27 Aug 2024 14:32 |
| Last Modified: |
27 Aug 2024 14:32 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46388 |
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