Division of Human Sciences, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan.
Graduate Course in Applied Chemistry, Environmental and Biomedical Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan.
J Biosci Bioeng. 2021 Jul;132(1):64-70. doi: 10.1016/j.jbiosc.2021.03.006. Epub 2021 Apr 8.
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，缺氧的大气会降低体内的氧气分压，导致组织和细胞发生多种代谢变化。此外，它还会产生强烈的厌食作用，从而导致能量不足。二十年前，人们在海拔 5100 米的珠穆朗玛峰大本营发现，与海平面对照值相比，人体在高海拔时的血浆胆囊收缩素（CCK）静息水平明显升高。有趣的是，在正常氧条件下，急性运动也会升高血浆 CCK，并产生强烈的厌食作用。然而，这些作用背后的 Cck 基因转录调控尚未确定。在这里，我们采用急性电脉冲刺激（EPS）后进行微阵列分析，在 3D 工程肌肉中发现新的肌肉因子。急性 EPS 会影响收缩功能，导致收缩力下降。令人惊讶的是，微阵列分析显示 EPS 诱导了胆囊收缩素受体（CCKR）介导的信号转导的激活。此外，CCK 在 3D 工程肌肉中被持续上调，并且在缺氧条件下其表达增加。值得注意的是，在小鼠和人类的 Cck 启动子中检测到了一个缺氧反应元件。我们的结果表明，缺氧会使 3D 工程肌肉中的 Cck 表达发生反式激活。此外，急性运动或高海拔后血浆 CCK 水平的升高可能部分归因于肌源性细胞。
