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Updated: Sep 3, 2025
In Vitro Bioluminescence Assay to Characterize Circadian Rhythm in Mammary Epithelial Cells
Published on: September 28, 2017
ISX-9 potentiates CaMKIIδ-mediated BMAL1 activation to enhance circadian amplitude
Huilin Li1, Jiali Ou1, Yaqun Li1
1CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Abstract:
Circadian dysregulation associates with numerous diseases including metabolic dysfunction, sleep disorder, depression and aging. Given that declined circadian amplitude is a trait commonly found with compromised health, interventions that design in precluding circadian amplitude from dampening will aid to mitigate complex, circadian-related diseases. Here we identify a neurogenic small molecule ISX-9 that is able to support persistent and higher amplitude of circadian oscillations. ISX-9 improves diurnal metabolic rhythms in middle-aged mice. Moreover, the ISX-9-treated mice show better sleep homeostasis with increased delta power during the day time and higher locomotive activity in the dark period. ISX-9 augments CaMKIIδ expression and increases BMAL1 activity via eliciting CaMKIIδ-mediated phosphorylation on BMAL1 residues S513/S515/S516, accordingly composes a positive feedback effect on enhancing circadian amplitude. CaMKIIδ-targeting, and the use of ISX-9 may serve as decent choices for treating circadian-related disorders.
Insights
A new molecule, ISX-9, helps maintain strong circadian rhythms, improving metabolism and sleep in mice. This discovery offers potential new treatments for circadian rhythm disorders and related health issues.
Area of Science:
- Chronobiology
- Neuroscience
- Molecular Biology
Background:
- Circadian rhythm disruption is linked to various diseases like metabolic dysfunction, sleep disorders, depression, and aging.
- Declined circadian amplitude is a common indicator of compromised health.
Purpose of the Study:
- To identify interventions that prevent circadian amplitude decline.
- To investigate the effects of the neurogenic small molecule ISX-9 on circadian oscillations and related physiological functions.
Main Methods:
- Administration of ISX-9 to middle-aged mice.
- Assessment of diurnal metabolic rhythms, sleep homeostasis (including delta power), and locomotive activity.
- Analysis of CaMKIIδ expression and BMAL1 activity, including phosphorylation sites.
Main Results:
- ISX-9 supports persistent and higher amplitude circadian oscillations.
- ISX-9 treatment improved diurnal metabolic rhythms and sleep homeostasis in mice.
- ISX-9 augments CaMKIIδ expression and enhances BMAL1 activity through specific phosphorylation events, creating a positive feedback loop.
Conclusions:
- ISX-9 effectively enhances circadian amplitude and improves health-related rhythms.
- Targeting CaMKIIδ and utilizing ISX-9 show promise for treating circadian rhythm disorders.
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