Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave. B107, Urbana, IL, 61801, USA.
Department of Molecular Medicine, Graduate School of Medicine, Gachon University, Incheon, 406-840, Republic of Korea.
Exp Cell Res. 2020 Sep 1;394(1):112165. doi: 10.1016/j.yexcr.2020.112165. Epub 2020 Jul 6.
TNF-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells, although non-apoptotic functions have also been reported for this cytokine in various cell types. TRAIL and its receptor TRAIL-R2 are expressed in skeletal muscles, but a potential role of muscle-derived TRAIL in myogenesis has not been explored. Here we report that TRAIL is an autocrine regulator of myogenic differentiation. Knockdown of TRAIL or TRAIL-R2 enhanced C2C12 myoblast differentiation, and recombinant TRAIL inhibited expression of the cell cycle inhibitor p21, accompanied by suppression of myoblasts from exiting the cell cycle, a requisite step in the myogenic differentiation process. Blocking cell cycle progression restored differentiation from inhibition by recombinant TRAIL, supporting the notion that TRAIL exerts its effect in myogenesis through modulating cell cycle exit. We also found that TRAIL knockdown led to enhanced muscle regeneration in mice upon injury, recapitulating the in vitro observation. Additionally, inhibition of ERK activation reversed the negative effect of recombinant TRAIL on p21 expression and myoblast differentiation, suggesting that ERK signaling may be a mediator of TRAIL's function to suppress cell cycle withdrawal and inhibit differentiation. Taken together, our findings uncover a muscle cell-autonomous non-apoptotic function of TRAIL in skeletal myogenesis.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）已知可诱导癌细胞凋亡，但这种细胞因子在各种细胞类型中也具有非凋亡功能。TRAIL 和其受体 TRAIL-R2 在骨骼肌中表达，但肌肉来源的 TRAIL 在成肌中的潜在作用尚未被探索。在这里，我们报告 TRAIL 是成肌分化的自分泌调节剂。TRAIL 或 TRAIL-R2 的敲低增强了 C2C12 成肌细胞的分化，重组 TRAIL 抑制了细胞周期抑制剂 p21 的表达，同时抑制了成肌细胞退出细胞周期，这是成肌分化过程中的必需步骤。阻断细胞周期进程恢复了重组 TRAIL 抑制的分化，支持 TRAIL 通过调节细胞周期退出来发挥其在成肌中的作用的观点。我们还发现，TRAIL 敲低导致损伤后小鼠的肌肉再生增强，这再现了体外观察结果。此外，抑制 ERK 激活逆转了重组 TRAIL 对 p21 表达和成肌细胞分化的负效应，表明 ERK 信号可能是 TRAIL 抑制细胞周期退出和抑制分化功能的介质。总之，我们的发现揭示了 TRAIL 在骨骼肌成肌中的肌肉细胞自主非凋亡功能。
