Inhibition of ADAM10 in satellite cells accelerates muscle regeneration following muscle injury

Abstract

Muscle injury is one of the most common orthopedic and sports disorders. For severe cases, surgical repair may be indicated; however, other than immobilization and the administration of anti-inflammatory drugs there is currently no effective conservative treatment for this condition. Satellite cells (SCs) are muscle-specific stem cells and are indispensable for muscle regeneration after muscle injury. SCs are activated upon muscle injury to proliferate and differentiate into myoblasts, which subsequently fuse into myofibers and regenerate the damaged muscle. We have previously shown that ADAM10, a membrane-anchored proteolytic enzyme, is essential for the maintenance of SC quiescence by activating the Notch signaling pathway in SCs. Because suppression of ADAM10 activity in SCs can activate SC differentiation, we asked whether inactivation of ADAM10 in SCs after muscle injury could enhance muscle regeneration. Using Adam10 conditional knockout mice, in which ADAM10 activity can specifically be suppressed in SCs, we found that partial inactivation of ADAM10 accelerates muscle regeneration after muscle injury. Nearly identical results were obtained by the administration of GI254023X, a selective ADAM10 inhibitor. The findings of the present study thus indicate that transient enhancement of SC differentiation after muscle injury expedites muscle regeneration and that ADAM10 can be a potential molecular target in treating muscle injuries. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

“…There are few reports on ADAMs in muscle tissue; however, two studies clearly showed that ADAM10 is expressed on muscle cells [ 92 , 93 ]. In order to repair muscle damage caused by excessive exercise or trauma, the proliferation of muscle-specific satellite cells in the muscle fibers and then differentiation are required.…”

“…In order to repair muscle damage caused by excessive exercise or trauma, the proliferation of muscle-specific satellite cells in the muscle fibers and then differentiation are required. ADAM10 in muscle satellite cells maintains the satellite cell pool; therefore, the inhibition of ADAM10 activity accelerates satellite cell differentiation [ 93 ]. The expression of ADAM17 in muscle tissue was confirmed and seems to be related to hypoxia [ 94 ].…”

Tspan15‐ADAM10 signalling enhances cancer stem cell‐like properties and induces chemoresistance via Notch1 activation in ICC

“…Therefore, we employed GI254023X, a selective ADAM10 inhibitor that down‐regulates its expression on the surface of the cell membrane 40 . No clinical trials have been conducted to date; however, several animal studies have suggested that GI254023X safely inhibits tumour progression in several malignancies 41–44 . In the present study, GI254023X mimicked the effects of Tspan15 knockdown in HuCCT1 cells with high Tspan15 expression, as GI254023X treatment decreased the expression of surface m‐ADAM10, inhibited Notch1 activation, and suppressed the development of CSC‐like properties and EMT, which inhibited cell invasiveness and chemoresistance against GemCis.…”

Pharmacologic Inhibition of ADAM10 Attenuates Brain Tissue Loss, Axonal Injury and Pro-inflammatory Gene Expression Following Traumatic Brain Injury in Mice

“…GI254023X has been applied in various animal disease models. Beneficial effects were found in a mouse model of muscle injury and regeneration in which both genetic inhibition of ADAM10 and its pharmacological inhibition by GI254023X accelerated regeneration (Mizuno et al, 2018). In a bacterial sepsis model, GI254023X reduced vascular injury, vascular endothelial (VE) cadherin cleavage and concomitant loss of endothelial barrier function (Powers et al, 2012).…”