This project proposes experiments to evaluate the effects and mechanisms by which glucocorticoid steroids alter repair and regeneration of muscle fibers in the muscular dystrophies. The muscular dystrophies are incurable, characterized by chronic sarcolemmal disruption that leads to fiber wastage and loss. In response to sarcolemma injury, a repair complex composed of many proteins including the annexins and ferlins seal the sarcolemmal damage. This process is impaired in dystrophic conditions, and is accompanied by defective regeneration. Therefore, systems that enhance endogenous sarcolemmal repair and myogenic potential are highly valuable for novel therapeutics. At present, chronic administration of glucorticoid steroids is the only pharmacological treatment to alleviate myopathic progression in Duchenne Muscular Dystrophy (DMD), although the side effects are prominent. Furthermore, the use of steroids is controversial or not recommended in other forms of muscular dystrophy. Despite this use in DMD, the mechanism by which steroids act in fiber repair and regeneration is not well understood. We developed a protocol using high-resolution confocal microscopy to induce and analyze real-time sarcolemmal injury and repair in isolated muscle fibers. Our preliminary data show a single pulse administration of glucocorticoids correlates with acutely enhanced fiber repair in both wildtype and dystrophic myofibers. Glucocorticoid exposure resulted in upregulation of annexins A1 and A6, and these data provide one mechanism by which sarcolemmal injury was more efficient. These experiments will permit a more detailed understanding of the ancillary pathways to the repair complex.
|Effective start/end date||2/1/16 → 1/31/21|
- Parent Project for Muscular Dystrophy Research, Inc. (Agreement 3/3/16)