skeletal muscle repair; mechanical transduction in muscle; Insulin-like growth factor.
skeletal muscle, muscular dystrophy, IGF-I.
Description of Research
The general focus of my laboratory is skeletal muscle repair. We utilize agents which 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.
We have embarked on a new area of investigation into disorders associated with craniofacial muscles, such as temporomandibular joint (TMJ) disorders. Seed funds for this research have been provided by The Joseph and Josephine Rabinowitz Award for Excellence in Research. Pain in this joint and the associated muscles affects approximately 10 million individuals in the United States, the majority of whom are women between in childbearing years. While there has been significant effort made into understanding the cause of this disorder, it remains unclear what underlying mechanisms give rise to muscle and joint pain in the temporomandibular joint and muscles, while sparing other muscles and joints throughout the body. Our working hypothesis is that the intrinsic repair processes are impaired in craniofacial muscles compared to other muscles of the body. We propose that damage wrought by heightened activity or trauma is inefficiently repaired in TMJ muscles, thus exacerbating the intensity and duration of pain associated with muscle damage. Repair-enhancing proteins, such as insulin-like growth factor I, are being assessed in animal models for muscle repair.
A second project is developing appropriate therapeutic strategies for the treatment of the muscles affected in rotator cuff injury funded through the NIH. Shoulder injuries are one of the most common tendon disorders found in the normal healthy population. Damage to the rotator cuff tendons can occur with overuse or by direct trauma. Tendon tears not only affect the biomechanical properties of the tendon, but also lead to debilitation of the muscles attached to the tendons. The supraspinatus muscle, in particular, is most affected by rotator cuff injuries because it is the primary muscle involved with shoulder stabilization and movement. In humans, a combination of lack of muscle activity due to the pain of movement and the potential shortened state of the detached muscle fibers can lead to severe muscle atrophy and the accumulation of fat or fibrotic tissue in the areas normally occupied by healthy muscle. While tendon repair can be performed in an attempt to restore a firm connection between the bone and muscle, a delay between the time of tendon insult and surgical repair can inhibit the healing process, and can result in weak and inadequately repaired muscles. This suggests that there are additional factors which can affect the ultimate healing process of muscle and tendon after surgical repair. Interventions that aid the repair processes of muscle and tendon could improve the prognosis of successful healing. In muscle, high levels of insulin-like growth factor I (IGF-I) increase the regenerative capacity of the tissue. If increased expression of IGF-I is introduced prior to tendon repair, it is possible that the resultant enhanced regenerative capacity would lead to accelerated recovery of the muscle.
A third project examines the mechanical signal transduction properties of the dystrophin glycoprotein complex (DGC) through funding from the Muscular Dystrophy Association and American Heart Association. The DGC is a membrane-spanning complex which links 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.
-Expression profiling comparisons between craniofacial and limb muscle.
-Enhancing muscle repair in rat tenotomy model.
-Functional distinctions of Insulin-like Growth Factor I isoforms.
Jessie Feng, Research technician
Rong-Ine Ma, Research technician
Zuozhen Tian, Research technician
Charles Crowder, Master's student
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Last updated: 04/01/2013
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