Author ORCID Identifier

https://orcid.org/0000-0002-3688-9716

Date Available

7-19-2021

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Health Sciences

Department/School/Program

Rehabilitation Sciences

First Advisor

Dr. Esther Dupont-Versteegden

Second Advisor

Dr. Timothy A. Butterfield

Abstract

Long term weakness and atrophy of the quadriceps muscle are a direct result of anterior cruciate ligament (ACL) injuries and persist for up to 10 years post injury. Muscle atrophy ensues regardless of ligamentous reconstruction surgery, indicating that muscle atrophy following injury is a function of the ligament rupture and not reconstruction surgery. Elucidating the mechanisms underlying quadriceps atrophy following ACL rupture is crucial for developing interventions to restore proper quadriceps size and mitigate weakness thereby allowing for improved patient function. In addition to understanding the specific mechanisms that contribute to quadriceps atrophy following ACL rupture, the timing of atrophic events that cause the decreased function of the quadriceps muscle must be elucidated to determine the best intervention strategy. Most studies involving human subjects are conducted post ACL reconstruction with limited emphasis on the cellular changes in muscle that could be responsible for the observed atrophy and weakness. Animal models involving open-knee surgery for ACL transection have been employed to investigate cellular mechanisms in muscle, but these models are not mimicking the human ACL rupture, which is a closed-knee injury. Thus, there is a need for fundamental research of the timing and underlying mechanisms of inflammation and quadriceps atrophy following ACL injury. The purpose of this dissertation is twofold: Firstly, to examine the relationship between serum and synovial joint inflammatory markers and proteomics in ACL deficient subjects; and to use those acquired data to identify potential cellular processes that may influence skeletal muscle and track those processes longitudinally in conjunction with changes in muscle size following a closed ACL injury in a rat model. The goals of these studies were to determine if a closed ACL rupture in the absence of surgical repair would induce persistent quadriceps atrophy, determine the relationship between ACL rupture and intra-articular and systemic inflammation, and investigate time-dependent cellular changes in the vastus lateralis muscle. Results indicate there is an increase in inflammatory cytokines (IL-1b (interleukin 1-beta) and IL-6(interleukin six)) in both the synovial joint fluid and systemic circulation following injury in humans. In the in vivo animal model of ACL rupture quadriceps atrophy was observed one week post injury, but muscle size unexpectedly recovered as early as 2 weeks. Gene expression of MAFbx and Murf-1 (atrophy markers) was elevated as early as 48 hours after ligament rupture. No signs of muscle damage were observed at any time point. This dissertation provides the first longitudinal investigation into the changes in muscle physiology following a closed ACL-rupture, informed by a proteomic analysis of human serum and synovial fluid after an acute clinical ACL tear. The results of these studies begin to characterize a relationship between joint inflammation and muscle atrophy in the acute time period following ACL injury.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.285

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