Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Kenneth Krauter

Second Advisor

Bradley B. Olwin

Third Advisor

Kristi Anseth

Fourth Advisor

Brian DeDecker

Fifth Advisor

Rui Yi

Abstract

Sarcopenia is a geriatric syndrome characterized by loss of skeletal muscle mass, skeletal muscle function and decreased regenerative capacity. A number of skeletal muscle-specific physiological decrements may contribute to sarcopenia; among these is an age-related impairment of satellite cells, the skeletal muscle stem cells required for muscle regeneration. I find that cell-autonomous deficits underlie a loss of self-renewal in aging satellite cells. The decline in self-renewal implicates altered p38αβ mitogen-activated protein kinase (MAPK) activity, which is activated by fibroblast growth factor (FGF) signaling and involved in satellite cell activation, differentiation and self-renewal in young satellite cells. Asymmetric activation of active p38αβ MAPK produces one daughter cell committed to myogenesis and one quiescent daughter cell. In old satellite cells, elevated levels of phosphorylated p38αβ MAPK inhibit asymmetric distribution of active p38αβ MAPK thereby preventing self-renewal through asymmetric division. Partial inhibition of p38αβ MAPK rescues asymmetric distribution of active p38αβ MAPK and self-renewal in aging satellite cells. Attenuated FGF signal transduction fails to stimulate further p38αβ MAPK phosphorylation and contributes to reduced self-renewal in aging satellite cells. Constitutive activation of FGF Receptor 1 rescues the reduced FGF signaling in old satellite cells to increase Pax7 expression and self-renewal. Signaling through the FGF/p38αβ MAPK axis regulates satellite cell self-renewal and suggest therapeutic targets for treatment of age-related muscle wasting. While Wnt, Notch and now FGF signaling regulate self-renewal in the satellite cell niche, the specific molecular mechanisms driving asymmetric and symmetric division remain unclear. I develop degradable, 4-arm (poly)ethylene glycol (PEG) hydrogels as an artificial satellite cell niche to study the molecular interactions driving self-renewal. I identify heparin sequences and extracellular matrix proteins that promote satellite cell self-renewal in hydrogel culture, and I demonstrate that 4-arm PEG hydrogels are good candidates for future use in regenerative medicine.

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