Hb-EGF directs systemic muscle repair.

Regenerative capacity varies between tissues, species and stages of the life cycle. Regenerative capacity also varies with the magnitude of the injury, even within a single tissue. Vertebrate skeletal muscle fully regenerates in response to small-scale injuries, but large-scale injuries often lead to incomplete repair and debilitating loss of muscle use. To understand if small- and large-scale muscle injuries activate distinct regenerative programs, we developed a systemic muscle injury model in zebrafish. Transcriptomic analysis of muscle and non-muscle tissues revealed that systemic and local muscle injuries elicit distinct molecular responses, both quantitatively and qualitatively. We found that systemic muscle injury activates the expression of heparin-binding epidermal-like growth factor (Hb-EGF) in the epidermis and that Hb-EGF is necessary for systemic muscle repair. Conversely, local muscle injury did not induce Hb-EGF expression and Hb-EGF was not required for local muscle repair. These studies suggest that large- and small-scale muscle injuries activate different regenerative programs, resulting in either systemic or local repair.