Adult stem cells are defined by their capacity to differentiate into a specific tissue type while maintaining their own population through a 'self-renewal'process. A precise balance of the cell fate choice between self-renewal and differentiation is critical for stem cell function, tissue homeostasis and prevention of tumor formation. However, the molecular mechanisms regulating this process are unclear. Satellite cells in the skeletal muscle represent one of the few systems in which stem self- renewal and differentiation can be elegantly dissected. Specifically, satellite cells can asymmetrically generate self-renewal and committed daughter cells upon apical-basal, but not planar, oriented cell divisions. Our long-term goal is to understand how signals within the muscle regulate satellite cell self-renewal and differentiation, and utilize this knowledge to enhance satellite cell function and improve the repair of diseased muscles. Here, we aim to investigate the role of 'Notch'signaling in the regulation of muscle stem cell fate. The Notch signaling will be visualized using a transgenic mouse in which Notch-activated cells exhibit green fluorescence. We will then examine whether Notch signaling regulates stem cell fate and self-renewal in undamaged and regenerating muscles, respectively. We will further genetically activate or inactivate key components of the Notch signaling pathway and ask how this perturbation shifts the balance between stem cell self-renewal and differentiation. Finally, we will investigate the molecular regulation of Notch signaling in satellite cells. These studies may lead to development of novel therapeutic approaches to improve muscle repair in the aged and diseased muscles that are characterized by loss of stem cells.

Public Health Relevance

Understanding how the developmental fate of muscle stem cells is regulated may lead to potential therapeutic approaches to enhance stem cell function and restore degenerated muscles caused by aging and muscle diseases, conditions that affect a quarter of Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060652-04
Application #
8500212
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$312,930
Indirect Cost
$107,730
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Shan, Tizhong; Zhang, Pengpeng; Liang, Xinrong et al. (2014) Lkb1 is indispensable for skeletal muscle development, regeneration, and satellite cell homeostasis. Stem Cells 32:2893-907
Jiang, Chunhui; Wen, Yefei; Kuroda, Kazuki et al. (2014) Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy. Dis Model Mech 7:997-1004
Bi, Pengpeng; Shan, Tizhong; Liu, Weiyi et al. (2014) Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat Med 20:911-8
Zhang, Pengpeng; Shan, Tizhong; Liang, Xinrong et al. (2014) Mammalian target of rapamycin is essential for cardiomyocyte survival and heart development in mice. Biochem Biophys Res Commun 452:53-9
Yu, Hui; Waddell, Jolena N; Kuang, Shihuan et al. (2014) Park7 expression influences myotube size and myosin expression in muscle. PLoS One 9:e92030
Shan, Tizhong; Liu, Weiyi; Kuang, Shihuan (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27:277-87
Kuroda, Kazuki; Kuang, Shihuan; Taketo, Makoto M et al. (2013) Canonical Wnt signaling induces BMP-4 to specify slow myofibrogenesis of fetal myoblasts. Skelet Muscle 3:5
Shan, Tizhong; Liang, Xinrong; Bi, Pengpeng et al. (2013) Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1ýý-Fndc5 pathway in muscle. FASEB J 27:1981-9
Liu, Weiyi; Bi, Pengpeng; Shan, Tizhong et al. (2013) miR-133a regulates adipocyte browning in vivo. PLoS Genet 9:e1003626
Song, Bing; Liu, X Shawn; Rice, Steven J et al. (2013) Plk1 phosphorylation of orc2 and hbo1 contributes to gemcitabine resistance in pancreatic cancer. Mol Cancer Ther 12:58-68

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