Regulation of Pannexin 1 and Pannexin 3 During Skeletal Muscle Development, Regeneration and Dystrophy

Abstract

Pannexin 1 (Panx1) and Pannexin 3 (Panx3) are single membrane channels recently implicated in myogenic commitment, as well as myoblast proliferation and differentiation in vitro. However, their expression patterns during skeletal muscle development and regeneration have yet to be investigated. Here, I show that Panx1 levels increase during development, becoming highly expressed in adult skeletal muscle. A switch in Panx3 expression pattern was observed as its ~70 kDa immunoreactive species was mainly expressed in embryonal and neonatal muscles while its ~40 kDa species was the main form expressed in adult skeletal muscle. In adult mice, Panx1 and Panx3 were differentially expressed in fast- and slow-twitch muscles. Interestingly, Panx1 and Panx3 levels were modulated in muscle degeneration/regeneration, similar to the pattern seen during skeletal muscle development. Since Duchenne muscular dystrophy is characterized by skeletal muscle degeneration and impaired regeneration, I next used mild and severe mouse models of this disease and found a significant down-regulation of both Panx1 and the lower MM form of Panx3 in dystrophic skeletal muscles, with an increase in the ~70 kDa immunoreactive species of Panx3. I also found that Panx1/PANX1 and Panx3/PANX3 are co-expressed in mouse and human satellite cells, which play crucial roles in skeletal muscle regeneration. Indeed, in vitro PANX1 levels may be increasing during human primary satellite cell differentiation and blocking PANX1 channel activity with the pharmacological compounds probenecid or carbenoxolone inhibited the differentiation and fusion of these satellite cells into myotubes. In addition, satellite cell proliferation was inhibited by probenecid and carbenoxolone. These findings are the first to demonstrate that Panx1 and Panx3 are differentially expressed amongst skeletal muscle types with their levels being highly modulated during skeletal muscle development, regeneration and dystrophy. In addition to our laboratory’s previous reports, I now demonstrate that PANX1 levels may be modulated during satellite cell differentiation and that PANX1 channels regulate satellite cell differentiation and proliferation. Altogether, my studies suggest that Panx1/PANX1 and Panx3/PANX3 channels may play important and distinct roles in myoblasts and satellite cells in healthy and diseased skeletal muscles.