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 had yet to be investigated. Here, we show that Panx1 levels increase during skeletal muscle development becoming highly expressed together with Panx3 in adult skeletal muscle. In adult mice, Panx1 and Panx3 were differentially expressed in fast- and slow-twitch muscles. We also report that Panx1/PANX1 and Panx3/PANX3 are co-expressed in mouse and human satellite cells, which play crucial roles in skeletal muscle regeneration. Interestingly, Panx1 and Panx3 levels were modulated in muscle degeneration/regeneration, similar to the pattern seen during skeletal muscle development. As Duchenne muscular dystrophy is characterized by skeletal muscle degeneration and impaired regeneration, we next used mild and severe mouse models of this disease and found a significant dysregulation of Panx1 and Panx3 levels in dystrophic skeletal muscles. Together, our results are the first demonstration that Panx1 and Panx3 are differentially expressed amongst skeletal muscle types with their levels being highly modulated during skeletal muscle development, regeneration, and dystrophy. These findings suggest that Panx1 and Panx3 channels may play important and distinct roles in healthy and diseased skeletal muscles.

Rhabdomyosarcoma (RMS) is a skeletal muscle-derived soft tissue sarcoma for which a novel therapeutic strategy is greatly needed. RMS cells have lost the ability to terminally differentiate thus proliferating indefinitely. Promoting their redifferentiation to skeletal muscle tissue is thus a promising therapeutic approach. We have recently shown that levels of Pannexin 1 (Panx1) are below detectable limits in undifferentiated myoblasts, but become highly upregulated during their differentiation and indeed promote this process. We thus hypothesize that the levels of Panx1 are deregulated in RMS and that restoration of Panx1 levels may induce differentiation of RMS cells thereby alleviating their malignant properties. Briefly, our results demonstrate that both Panx1 transcript and protein are at very low levels in, both embryonal and alveolar RMS tumor specimens and patient-derived cell lines similar to that seen in fetal skeletal muscle tissue and undifferentiated myoblasts, respectively. In vitro functional analyses have revealed that while re-introduction of Panx1 in RMS cell lines led to their partial differentiation, it significantly inhibited their rate of proliferation and migration. Moreover, re-expression of Panx1 in RMS cell lines prevented both spheroid formation and growth, and induced RMS cell apoptosis. Based on this in vitro data, pre-clinical orthotopic xenograft studies are currently underway to assess the ability of Panx1 to inhibit tumor onset and growth, and induce tumor regression in vivo. Our preliminary results thus far have shown that Panx1 over-expression significantly suppresses RMS xenograft tumor growth. Taken together, these results indicate that restoration of Panx1 levels in RMS reduces its malignant properties. This, together with further investigation into the tumor-suppressive mechanism by which Panx1 mediates its effects, will establish Panx1 as a novel therapeutic target for RMS. Citation Format: Xiao Xiang, Stephanie Langlois, Marie-Eve St-Pierre, Jessica Barre, Tammy Le Pham, Kyle N. Cowan. Pannexin 1 regulates rhabdomyosarcoma tumor growth: a potential novel therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1276.

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