Oxidative stress in muscle progenitor cell function Open Access

Lee, Sukkyoo (2008)

Permanent URL: https://etd.library.emory.edu/concern/etds/dr26xz11x?locale=en
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Abstract

Abstract
Oxidative stress in muscle progenitor cell function
By Sukkyoo Lee
Muscle progenitor cells are essential for muscle development, growth and
regeneration. Differentiation of muscle progenitor cells accompanies the complex
molecular change and muscle progenitor cells are exposed to oxidative stress
throughout the life span in vivo. In this dissertation, I investigated the effect of
oxidative stress on muscle progenitor cells using primary myoblast cells isolated
from transgenic mice. Gpx1-null myoblasts are globally defective in proliferation,
differentiation and apoptosis during differentiation in vitro. In addition, oxidative
stress increased by Gpx1 deletion in muscle tissue induced early senescence. I
have also studied the role of mitochondrial SOD2 in muscle progenitor cells
during aging. Sod2 overexpression preserves the function and relative
abundance of mitochondria, but not muscle mass with aging in myoblasts. Data
also suggest that the PI3K/Akt pathway is redox-regulated by oxidative stress.
The fusion defect of Sod2+/- (young) during differentiation might result in part from
this altered PI3K/Akt signaling pathway. In addition, the haplo-deficiency of
SOD1 (Sod1+/-) in myoblasts has the significantly decreased myotube formation
compared to wild-type with the altered expression of HIF-1α and myogenin.
Overall, the work characterizes the effect of oxidative stress in muscle progenitor
cell function, and highlights the importance of oxidative stress during muscle
differentiation.

Table of Contents

Table of Contents

Chapter 1: Introduction……............................................................ 1
An introduction to reactive oxygen species (ROS) …............................2
Free radical theory of aging ............................................................2
Major antioxidant defense mechanism and implications in pathology ........5
Roles of ROS during aging ..............................................................10
Skeletal muscle development and regeneration ..................................12
The source of ROS and its generation in myoblasts …......................... 17
Signaling pathways that participate in muscle differentiation and
regeneration and their possible redox regulation ................................ 20
IGF-1/PI3kinase/Akt .....................................................................20
MAPK cascade ............................................................................ 27
NF-κB ..........................................................................................31
HIF1 ......................................................................................... 35
The crosstalk between redox-regulated signaling pathways ..................38
The regulation of mitochodria in muscle differentiation .........................38
Oxidative stress in muscle during aging .............................................40
Protein degradation in muscle atrophy; Ubiquitin ligases .......................41
Signaling pathway for protein degradation .........................................44
Autophagy of muscle during aging ....................................................47
Apoptosis of muscle during aging .....................................................48
Mitochondria of skeletal muscle during aging ......................................51
Aging markers of muscle ................................................................53

Chapter 2: Materials and Methods .................................................. 62

Chapter 3: Glutathione peroxidase-1 null myoblasts are globally
defective ................................................................................... 78
Introduction ................................................................................79
Results .......................................................................................80
Discussion .................................................................................104

Chapter 4: Sod2 overexpression preserves myoblast mitochondrial
mass and function, but not muscle mass with aging .......................... 109
Introduction .............................................................................. 110
Results ......................................................................................112
Discussion ..................................................................................133

Chapter 5: Aberrant HIF-1α expression in response to oxygen in
Sod1 heterozygote myoblasts ....................................................... 138
Introduction ...............................................................................139
Results ......................................................................................140
Discussion ..................................................................................148

Chapter 6: Discussion .................................................................. 151

References ................................................................................ 163

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