At high altitudes, the hypoxic atmosphere decreases the oxygen partial pressure in the body, inducing several metabolic changes in tissues and cells. Furthermore, it exerts potent anorectic effects, thus causing an energy deficit. Two decades ago, a marked increase in the resting level of plasma cholecystokinin (CCK) was observed in humans at the Mt. Kanchenjunga basecamp, located at 5100 m above the sea level, compared to sea-level control values. Interestingly, acute exercise also raises plasma CCK and exerts potent anorectic effects under normoxic conditions. However, the transcriptional regulations of Cck gene underlying these effects have not yet been established. Here, we employed acute electrical pulse stimulation (EPS) followed by microarray analysis to discover novel myokines in 3D-engineered muscle. Acute EPS affects the contractile function, inducing a decline in the contractile force. Surprisingly, microarray analysis revealed an EPS-induced activation of cholecystokinin receptor (CCKR)-mediated signaling. Furthermore, Cck was constitutively upregulated in 3D-engineered muscle, and its expression increased under hypoxic conditions. Notably, a hypoxia-responsive element was detected in the Cck promoters of mice and humans. Our results suggested that hypoxia transactivated Cck expression in 3D-engineered muscle. Furthermore, the elevation in plasma CCK levels following acute exercise or at high altitude might be partly attributed to myogenic cells.

在高海拔地区，低氧气氛会降低体内氧分压，从而导致组织和细胞发生多种代谢变化。此外，它发挥强大的厌食作用，从而导致能量不足。二十年前，在 Mt. 人类中观察到血浆胆囊收缩素 (CCK) 的静息水平显着增加。与海平面控制值相比，位于海拔 5100 m 的干城章嘉峰大本营。有趣的是，急性运动也会提高血浆 CCK 并在常氧条件下发挥有效的厌食作用。然而，Cck的转录调控这些影响背后的基因尚未确定。在这里，我们采用了急性电脉冲刺激 (EPS)，然后进行了微阵列分析，以发现 3D 工程肌肉中的新型肌细胞因子。急性 EPS 影响收缩功能，导致收缩力下降。令人惊讶的是，微阵列分析揭示了 EPS 诱导的胆囊收缩素受体 (CCKR) 介导的信号激活。此外，Cck在 3D 工程肌肉中组成性上调，其表达在缺氧条件下增加。值得注意的是，在小鼠和人类的Cck启动子中检测到缺氧反应元件。我们的结果表明缺氧激活Cck在 3D 工程肌肉中表达。此外，急性运动或高海拔地区血浆 CCK 水平的升高可能部分归因于肌细胞。