Hypoxia transactivates cholecystokinin gene expression in 3D-engineered muscle

Area of Science:

• Physiology
• Molecular Biology
• Altitude Medicine

Background:

• High altitude induces hypoxia, causing metabolic changes and appetite suppression, leading to energy deficit.
• Elevated plasma cholecystokinin (CCK) levels were previously observed at high altitudes and after acute exercise.
• The transcriptional regulation of the Cck gene in response to these conditions remains unclear.

Purpose of the Study:

• To investigate the transcriptional regulation of the cholecystokinin (Cck) gene in engineered muscle under hypoxic conditions.
• To identify novel myokines involved in the response to electrical pulse stimulation (EPS) and hypoxia.

Main Methods:

• Utilized 3D-engineered muscle models stimulated by acute electrical pulse stimulation (EPS).
• Performed microarray analysis to identify gene expression changes.
• Investigated hypoxia-responsive elements in Cck gene promoters.

Main Results:

• Acute EPS led to a decline in muscle contractile force and activated cholecystokinin receptor (CCKR)-mediated signaling.
• The Cck gene was constitutively upregulated in 3D-engineered muscle, with increased expression under hypoxia.
• A hypoxia-responsive element was identified in the Cck promoters of both mice and humans.

Conclusions:

• Hypoxia transactivates Cck gene expression in 3D-engineered muscle.
• Myogenic cells may partly contribute to elevated plasma CCK levels observed during acute exercise and at high altitudes.