Author ORCID Identifier
https://orcid.org/0000-0003-4578-8463
Date Available
12-4-2026
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Health Sciences
Department/School/Program
Rehabilitation Sciences
Advisor
Dr. Christopher S. Fry
Abstract
The molecular etiology of protracted quadriceps atrophy and weakness following anterior cruciate ligament (ACL) injury remains undefined, limiting our understanding of the inceptive events underlying poor functional recovery. ACL injury reduces quadriceps satellite (muscle stem) cell abundance, but whether satellite cell loss is a consequence or causative factor to quadriceps atrophy remains unresolved. Satellite cells govern muscle plasticity and represent a promising therapeutic target to improve recovery. Myonuclear methylation status heavily dictates muscle gene expression and transcriptional regulation. In this collection of projects, satellite cell presence was shown to support muscle fiber size late, but not early post-ACL transection surgery (ACLT) in mice. A timecourse of ACLT revealed elevated myonuclear transcriptional output of fibrosis related genes 3-days post-ACLT prior to atrophy observed 7-days post-ACLT. In humans, integrated DNA methylation and gene expression revealed a persistent, myogenically repressive epigenetic signature in response to the injury that was maintained 4-months post-ACLR. In addition, GDNF promoter hypomethylation coincided with its elevated transcript abundance, a well-known feature of skeletal muscle denervation. This collection of projects describes rapid imprinting of DNA methylation following ACL injury that represses genes critical for muscle function and gives evidence of a denervation response to the injury.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.438
Funding Information
This study was supported by National Institute s of Health - National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR072061
Recommended Citation
Thomas, Nicholas, "Satellite Cell and Myonuclear Dynamics Following ACL Injury" (2024). Theses and Dissertations--Rehabilitation Sciences. 109.
https://uknowledge.uky.edu/rehabsci_etds/109
Included in
Biomedical Informatics Commons, Computational Biology Commons, Kinesiology Commons, Rehabilitation and Therapy Commons, Translational Medical Research Commons
