All ETDs from UAB

Advisory Committee Chair

Marcas M Bamman

Advisory Committee Members

C Scott Bickel

Lori L McMahon

Douglas R Moellering

David G Standaert

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The human neuromuscular system deteriorates progressively with age and disease. This results in denervation events and ultimately motor unit remodeling, which is revealed by abnormal “groups” of myofibers expressing the same myosin protein isoform – a phenomenon described as myofiber type grouping. Despite the acceptance of myofiber type grouping as a hallmark indicator of motor unit remodeling, traditional techniques of detecting it lack quantitative parameters and therefore comparative data in aging and disease are scarce. The purpose of this dissertation is to establish a statistically-driven, quantitative method for detecting myofiber type grouping and to use it to characterize the effects of aging, Pakinson’s disease (PD) and resistance exercise training (RT) as well as distinguish grouped and ungrouped type I myofiber phenotypes. Here we quantitatively define a heightened age- and PD-related grouping of myofibers expressing type I myosin (i.e. type I myofiber grouping). Furthermore, we demonstrate an association between high type I myofiber grouping and increased markers of neuromuscular degeneration which include expression levels of denervation-associated genes and proteins and extraneous motor unit activation (MUA) patterns during a submaximal sit-to-stand task. We also show that PD displays more severe type I myofiber grouping (group size), heightened expression of biomarkers of denervation, and abnormally higher MUA compared to age-matched Older adults. RT appears to reduce type I myofiber grouping severity (group size) in only Older and PD individuals with the highest grouping prevalence, but does not seem to modify molecular biomarkers of denervation. Lastly, we show for the first time that grouped type I myofibers in older adults phenotypically resemble myofibers expressing type II myosin isoforms and that the abundance of such myofibers increases as type I myofiber grouping increases. Altogether, these data suggest that type I myofiber grouping is a useful surrogate measure for detecting varying extents of neuromuscular degeneration. Despite a large inter-individual variability, on average it appears that PD leads to advanced neuromuscular degeneration compared to normal aging and that RT may be beneficial in the context of high type I myofiber grouping. Our findings also provide novel insight into the completeness of myofiber type switching during motor unit remodeling.

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