Department of Anatomy & Cell Biology
Dr. Barton has been a member of the Penn Dental Medicine faculty since 2003. Her research interests focus on muscle physiology, where she is studying mechanisms of skeletal muscle repair and mechanical signal transduction through membrane complexes. The ultimate goal is to develop therapies which can aid in muscle disease and enhance repair after injury. Dr. Barton is the Course Director of Physiology at Penn Dental Medicine and also teaches in Histology.
Students participating in the School’s student research program can work on the folllowing projects:
The general focus of my laboratory is skeletal muscle repair. We utilize agents that can enhance repair processes, and examine their effects at the molecular and functional levels in mouse muscle. This research has broad-reaching applications, which include rehabilitative medicine and prevention of age- and disease-associated muscle weakness. Muscle repair is a highly orchestrated process requiring the removal of damaged tissue and the subsequent reconstruction of functioning muscle fibers. Because muscle fibers are post-mitotic, repair must rely on satellite cells, a stem cell-like population residing close to muscle fibers as a source for replenishing nuclear content of the muscle. Satellite cells are normally quiescent unless triggered by signals from muscle growth or damage. Insulin-like Growth Factor-I (IGF-I) has long been recognized as one of the critical factors for regulating satellite cell actions during muscle regeneration, helping to repair damaged regions of the fibers, and to promote muscle growth.
We are developing appropriate therapeutic strategies to combat muscle weakness and fragility associated with the muscular dystrophies. We have based our therapies on the igf1 gene. While the predominant focus of research has been on physiological impact and benefit of IGF-I, there has also been a continued and growing undercurrent of studies geared toward the characterization of additional potentially active peptides produced by the igf1 gene. Alternative splicing of the gene results in multiple isoforms that retain the identical sequence for mature IGF-I, but also give rise to divergent C-terminal sequences, called the E-peptides. The E-peptides might modulate the actions, stability, or bioavailability of IGF-I, or they might have independent activity. These possibilities have gained the attention of the skeletal muscle field, where novel actions of IGF-I or the E-peptides could have significant impact on muscle mass, strength and repair. This work is funded by NIH R01 and Program project grant.
Our mechanistic studies examine the bioactivity, binding partners and signaling pathways driven by the E-peptides. Recent evidence from our lab demonstrates that the E-peptide extensions directly regulate two critical steps in muscle repair independent of IGF-I. First, the rodent EA and EB peptides stimulate proliferation of muscle cells in culture, potentially increasing the number of satellite cell available for repair. Second, the E-peptides drive increased expression of matrix metalloproteinases, specifically MMP-13. In other tissue types, MMP-13 activity is a key regulator of wound healing, bone remodeling, and tumor invasion, as well as a modulator of additional MMP activity. Therefore, MMP-13 may improve muscle repair by enhancing satellite cell migration through the extracellular matrix, and by coordinating matrix remodeling around newly formed muscle fibers. Future work in this area will address the role MMP-13 plays in skeletal muscle. This work is funded by an NIH R01.
A third project examines the mechanical signal transduction properties of the dystrophin glycoprotein complex (DGC). The DGC is a membrane-spanning complex linking the actin cytoskeleton on the inside of the cell to the extracellular matrix. Mutations in several members of this complex lead to muscular dystrophy, a degenerative disease of muscle. As the list of genetic diseases associated with this complex expands, it is becoming clear that the DGC not only maintains membrane integrity, but also contributes to the survival of the muscle in other undefined ways. These studies suggest a significant role for the DGC in sensing mechanical load in muscle. We have been able to show that a specific member of the DGC is necessary to coordinate mechanical signals. These experiments have demonstrated a novel function for this complex in muscle, and make it apparent that muscle degeneration and disease does not arise solely from membrane fragility. Previous support for this work was provided by the Muscular Dystrophy Association, and a recent award from NASA will support its continuation.