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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Kinesiology

Year Degree Awarded

2015

Month Degree Awarded

May

First Advisor

Lawrence M. Schwartz

Second Advisor

Patty Freedson

Third Advisor

Sarah Witkowski

Fourth Advisor

Maria Urso

Subject Categories

Bioinformatics | Cellular and Molecular Physiology | Exercise Physiology | Exercise Science | Laboratory and Basic Science Research | Molecular Biology

Abstract

Eccentric (muscle lengthening) exercise induces temporary muscle damage that can lead to long-term muscle adaptation, a process known as the repeated bout effect where subsequent exercise results in less damage. The existence of a contralateral repeated bout effect (CRBE) has been controversial. The primary goals of this study were to: 1) validate the existence of the CRBE; and 2) define the underlying molecular mechanisms.

Thirty-six young men performed 100 maximal eccentric actions of the knee extensors using one leg (bout 1) and repeated the exercise with the contralateral leg five weeks later (bout 2). Vastus lateralis muscle biopsies were taken from eccentric-exercised (ECC) and control (CON) legs at 3 h after each bout.

The subjects experienced a reduced muscle strength loss after bout 2 versus bout 1, confirming the existence of the CRBE. Microarray analysis demonstrated that the inflammatory responses were one of the top differentially regulated biological functions and identified nuclear factor-kappa B (NF-κB) as a key signaling regulator. DNA-binding activity assays verified reduced NF-κB DNA binding activity in the contralateral leg. qRT-PCR analysis confirmed the induction of three NF-κB-related pro-inflammatory genes (ANKRD1, CRY61, and IL1R1) in response to eccentric exercise which was attenuated in the contralateral leg in bout 2 relative to bout 1. These results suggest that an attenuated inflammatory response mediated by NF-κB may contribute to the CRBE.

To evaluate ANKRD1 as a biomarker for skeletal muscle damage, seven young men performed eccentric exercise with one leg and biopsies were obtained pre-exercise from the control leg and 24 h post-exercise from the exercised leg. Cytoplasmic ANKRD1 protein levels were increased at 24 h post-eccentric exercise and ANKRD1 nuclear accumulation was positively correlated with muscle strength loss. Finally, ANKRD1 mRNA was found to be up-regulated in various muscle damage models suggesting that ANKRD1 is a potential muscle damage biomarker.

The data presented in this dissertation confirmed the existence of the CRBE and implicate reduced gene responses, most notably in inflammatory pathways. It also demonstrated that ANKRD1 may be a valuable biomarker for muscle damage. Exploiting the CRBE may have implications for human health, especially for rehabilitative therapies.

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