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Updated: Jun 2, 2026
A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice
Published on: June 14, 2024
Brain and Muscle ARNT-Like 1 Ameliorates Sepsis-Induced Acute Lung Injury by Orchestrating Endoplasmic
Jingqi Li1, Shiping Liu, Xue Zhu
1All authors: Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, China.
Objectives:
To evaluate the clinical prognostic value of the core circadian transcription factor brain and muscle ARNT-like 1 (BMAL1) in sepsis-induced acute lung injury (SI-ALI) and explore its mechanistic role in orchestrating organellar homeostasis and macrophage resilience.
Design:
Prospective clinical cohort study and randomized blinded preclinical laboratory investigation.
Setting:
ICU and research laboratory of Renmin Hospital of Wuhan University.
Subjects:
Thirty patients with SI-ALI and 12 healthy controls; adult male C57BL/6 mice and mouse alveolar macrophage cell line (MH-S) alveolar macrophages.
Interventions:
Clinical monitoring of BMAL1, clock circadian regulator (CLOCK) genes, and hormones. Murine cecal ligation and puncture models, lipopolysaccharide treated MH-S cell treated with nobiletin, small interfering RNA-mediated knockdown of BMAL1, and pharmacological modulators of endoplasmic reticulum (ER)-phagy.
Measurements And Main Results:
Patients with SI-ALI exhibited profound circadian arrhythmia with significantly reduced expression of BMAL1 and CLOCK. BMAL1 levels were significantly lower in nonsurvivors and served as a robust predictor of 28-day mortality (area under the curve = 0.8177), showing a significant negative correlation with Sequential Organ Failure Assessment scores. In preclinical models, pharmacological activation of BMAL1 via nobiletin significantly mitigated lung histopathological damage, improved 5-day survival, and enhanced macrophage phagocytic and bactericidal activity. Mechanistically, BMAL1 deficiency impaired family with sequence similarity 134, member B-mediated ER-phagy, leading to inositol-requiring enzyme 1 increased and NADH:ubiquinone oxidoreductase core subunit V1, ATP synthase F1 subunit alpha, and seahorse-derived respiration/adenosine triphosphate production decreased. Nobiletin rescued these organellar defects in a BMAL1-dependent manner.
Conclusions:
BMAL1 is a master regulator of cellular homeostasis in SI-ALI. It protects against lung injury by orchestrating a coordinated response between ER-phagy and mitochondrial metabolism. BMAL1 represents a clinically valuable prognostic biomarker and a potential therapeutic target for SI-ALI.
