Clemens, Zachary
(2024)
Failure to communicate: Dysregulated muscle paracrine signaling due to mitochondrial dysfunction.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Muscle matters. Skeletal muscle accounts for nearly half our body mass and serves as a central endocrine and metabolic hub. Deficits in muscle health lead to declines in quality of life, reduced mobility, and poor disease outcomes. Despite its importance, skeletal muscle health receives relatively little attention in the field of environmental health. Chronic exposure to unsafe levels of arsenic via contaminated drinking water affects nearly 300 million people worldwide. While much attention has been paid to arsenic-associated cancers, less focus is given to cardiometabolic disease, and even less to skeletal muscle deficits. Arsenic-induced muscle deficits are recognized, but mechanisms for these effects remain uncertain. Mitochondrial dysfunction is a consistent observation in studies of arsenic exposure, and paracrine signaling via extracellular vesicles (EVs) is increasingly being recognized as an important factor in muscle health. The aim of this dissertation research was to investigate a link between these factors, testing the global hypothesis that arsenic exposure disrupts muscle progenitor cell-driven regeneration through mitochondrial dysregulation of EV-mediated paracrine signaling.
We first used gene delivery of the anti-geronic protein Klotho to show how mitochondrial function and muscle regeneration respond to treatment at different ages. We found that Klotho improved mitochondrial integrity in old animals, leading to healthier regeneration, but at extreme age, the effect was lost. We also found that arsenic exposure decreased MPC expression of Klotho through epigenetic regulation that could be reversed by repairing mitochondria.
We then considered the effects that arsenic has on EV signaling. Using a novel 3D skeletal muscle construct model to isolate MPC-specific effects of arsenic exposure, we found that arsenic causes MPCs to release EVs that confer deleterious effects on muscle regeneration. Finally, we investigated how mitochondrial dysfunction contributes to this effect. Using the mitochondrial protectant SS-31, we showed that aberrant EV signaling is a product of arsenic-induced mitochondrial dysfunction. Overall, these studies identified mitochondrial regulation of EV signaling as a crucial hub responsible for the perpetuation of arsenic-induced muscle dysfunction. Our findings may potentially contribute to future efforts to reverse these consequences.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 June 2024 |
| Date Type: |
Publication |
| Defense Date: |
20 June 2024 |
| Approval Date: |
26 June 2024 |
| Submission Date: |
21 June 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
189 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Environmental and Occupational Health |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Arsenic, skeletal muscle, toxicology, regeneration, extracellular vesicles, mitochondrial dysfunction, klotho |
| Date Deposited: |
27 Jun 2024 00:27 |
| Last Modified: |
27 Jun 2024 00:27 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46612 |
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