Oxidative stress in muscle progenitor cell function Público

Lee, Sukkyoo (2008)

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