Defense Date


Document Type


Degree Name

Doctor of Philosophy


Biomedical Engineering

First Advisor

Dr. Michael McClure


Advanced glycation end-products (AGEs) non-enzymatically accumulate on skeletal muscle collagen in old age via the Maillard reaction, causing an increase in intramuscular collagen and a stiffening of the muscle’s microenvironment. AGEs abrogate muscle regeneration through stiffening the muscle stem cell (MuSC) microenvironment and by binding to the receptor for advanced glycation end products (RAGE). Stiffer substrates promote MuSC proliferation at the expense of differentiation, and soluble AGEs are known to abrogate myogenic differentiation. Previously our group has demonstrated that decellularized muscle matrix (DMM), a type of extracellular matrix (ECM) scaffold extracted from skeletal muscle, encourages regeneration in a challenging rat volumetric muscle loss (VML) injury. Clinically, most human tissue for organ transplantation is sourced from older donors. My dissertation addresses whether old age is an important factor for DMM, and if this concern is AGE dependent. We isolated DMM from an aged murine model, and proved that AGE cross-links are present and that they are associated with increased stiffness. Further, we demonstrate that AGE-cross-linked collagen is stiffer, and disrupts myoblasts’ proliferation and differentiation in a RAGE-dependent manner. Curiously, AGE cross-links reduced RAGE in myoblasts, and RAGE inhibition shut down late myogenesis. Impressively, when myoblasts were challenged with the RAGE agonist S100b, myofiber formation was restored. We next proved that RAGE is significantly regulated in VML injuries, and we could regulate this with adipose-derived stromal cell delivery. Interestingly, AGEs were reduced in VML injuries, most likely due to an increase in new collagen deposition. Finally, we proved that an AGE-laden DMM disrupts muscle regeneration in a VML model and promotes inflammation while downregulating ECM synthesis. This was associated with upregulations in the AGE receptors RAGE and Galectin-3. Altogether, this dissertation provides strong evidence that age matters in the clinical translation of DMM, and AGEs are a prime target for rejuvenation therapies in skeletal muscle aging. Also, future study is warranted into the role that S100b can play in countering the AGE-RAGE axis in old age.


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