Project 465169

While skeletal muscle has an extraordinary capacity to regenerate in healthy individuals following damage, there is a dramatic impairment in regenerative potential in Duchenne muscular dystrophy (DMD), resulting in significant muscle loss. DMD, the most common muscular dystrophy, has no effective therapy and results in the premature death of patients. Skeletal muscles regenerate through a process that requires a type of cell called a satellite cell (SC). In response to injury, SCs quickly expand and differentiate into muscle cells to restore the damaged tissue. We have recently found that the channel protein pannexin1 (Panx1) is present in skeletal muscle and its SCs. Our data revealed that mice that do not have Panx1 have less SCs and that targeting Panx1 reduces SC differentiation in culture and impairs skeletal muscle regeneration in mice. In order to clearly understand the role of Panx1 channels in skeletal muscle regeneration and in SCs, we will use mice that have been genetically engineered to lack Panx1, either in their entire body or only in their SCs, and compare them to normal mice. Using mouse models of DMD, we have previously found that, as compared to healthy muscles, dystrophic muscles have much less Panx1. Muscle cells from DMD patients also show reduced PANX1 channel activity. Here, we will specifically evaluate the role of Panx1 in DMD. We will also investigate whether increasing Panx1 levels in muscle cells from DMD patients, as well as in muscles from dystrophic mice improves muscle dystrophy. Through this research program we will understand the physiologic functions of Panx1 in skeletal muscle regeneration, its role in DMD, and examine the therapeutic potential of increasing Panx1 levels in dystrophic muscles. Ultimately, our goal is to translate this knowledge into the identification and development of new strategies to enhance skeletal muscle repair and improve the life of DMD patients.