Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Molecular Physiology and Biophysics

First Advisor

Christopher M. Adams

Abstract

Skeletal muscle atrophy is a debilitating condition that commonly occurs as a secondary consequence of many acute and chronic medical conditions, including muscle disuse, heart and renal failure, starvation, cancer, HIV/AIDS, and aging. Though it leads to weakness, falls, and fractures, and reduces independence and quality of life for millions of Americans annually, no effective pharmacologic therapies for muscle atrophy exist. This is largely due to a poor understanding of the pathogenesis of skeletal muscle atrophy at a molecular level. In this thesis, I describe my studies into the molecular pathogenesis of skeletal muscle atrophy. Using mouse models, I showed that the gene encoding the pro-atrophy nuclear protein Gadd45a is regulated by distinct pathways after muscle denervation and fasting, and also identified a novel protein regulating skeletal muscle fiber size.

First, we demonstrated that denervation-induced muscle atrophy, unlike atrophy mediated by fasting, does not require the bZIP transcription factor ATF4. However, the lysine deacetylase HDAC4 is sufficient to induce Gadd45a mRNA and necessary for Gadd45a mRNA induction after denervation, but not after fasting. Taken together, these data show that Gadd45a is a central convergence point for muscle atrophy caused by several stimuli, and also demonstrate that distinct pathways mediate Gadd45a induction in different models of skeletal muscle atrophy.

Second, we identified spermine oxidase as a critical regulator of muscle fiber size. We observed that spermine oxidase mRNA and spermine oxidase protein were reduced by several distinct causes of muscle atrophy (i.e. immobilization, denervation, fasting, and aging). Furthermore, spermine oxidase overexpression increased muscle fiber size, while spermine oxidase knockdown caused muscle fiber atrophy. Restoring spermine oxidase expression significantly attenuated muscle atrophy after limb immobilization, denervation, and fasting. Finally, we identified p21 as a key upstream regulator of spermine oxidase expression, and spermine oxidase as a required mediator of p21-mediated skeletal muscle fiber atrophy.

Collectively, these findings greatly advance our understanding of the molecular pathogenesis of skeletal muscle atrophy. These data demonstrate that Gadd45a is a convergence point for multiple pro-atrophy pathways and identify spermine oxidase as a novel therapeutic target for the treatment of skeletal muscle atrophy. These discoveries suggest several important new areas for future research, and further our understanding of this common, debilitating condition.

Public Abstract

Skeletal muscle atrophy is a common secondary consequence of many severe acute and chronic medical conditions, including limb immobilization, muscle denervation, and starvation. Although muscle atrophy is frequently debilitating and reduces independence and quality of life for millions of Americans annually, the mediators of muscle atrophy remain poorly understood at the molecular level; this has hindered development of effective pharmacologic therapies. Here, using mouse models, we have identified novel pathways mediating skeletal muscle atrophy. First, we demonstrate that muscle atrophy caused by muscle denervation causes atrophy through a pathway involving the lysine deacetylase HDAC4, while muscle atrophy caused by fasting causes atrophy through an independent pathway involving the bZIP transcription factor ATF4; however, both pathways converge on and induce the important pro-atrophy gene Gadd45a. Second, we identify the polyamine catabolism enzyme spermine oxidase as an important factor in the maintenance of skeletal muscle fiber size, and show that it is decreased during skeletal muscle atrophy. Taken together, these data elucidate several important mechanisms and pathways mediating skeletal muscle atrophy and identify potential targets for therapeutic development to treat this common yet often serious condition.

Keywords

publicabstract, Gadd45a, HDAC4, muscle atrophy, p21, skeletal muscle, spermine oxidase

Pages

xiii, 101 pages

Bibliography

Includes bibliographical references (pages 94-101).

Copyright

Copyright 2016 Kale Stephen Bongers

Included in

Biophysics Commons

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