Study on the role and mechanism of AMP-activated protein kinase in regulating mitochondrial function and modulating cardiomyocyte injury in sepsis

doi:10.3969/j.issn.1006-7795.2025.02.018

Abstract

Abstract: Objective To investigate the role and mechanism of AMP-activated protein kinase (AMPK) in regulating mitochondrial function and cardiomyocyte injury in sepsis. Methods Forty Balb/c mice were randomly divided into four groups: Sham group (n=10), Sham+ 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR) group (n=10), CLP group (n=10), and CLP+AICAR group (n=10). A sepsis mouse model was established through cecal ligation and puncture (CLP). Echocardiography and histological analysis were used to assess sepsis-induced cardiac injury. Neonatal rat cardiomyocytes (NRCMs) were incubated with lipopolysaccharide (LPS) (10 μg/mL) for 24 h to induce an in vitro sepsis model, and treated with AICAR. Mitochondrial function and dynamics were assessed by using Western blotting, enzyme-linked immunosorbent assay （ELISA）, and immunofluorescence assays. Results Compared with the Sham group, AMPK expression in the myocardial tissue of CLP mice was significantly reduced (P < 0.05). Compared with the CLP group, AMPK expression in the CLP+AICAR group was significantly increased (P < 0.05). Survival analysis showed that CLP led to a high mortality rate (~60%), while AICAR treatment significantly improved the survival rate of CLP mice (P < 0.05). Compared with the Sham group, cardiac output (CO), stroke volume (SV), and left ventricular end-diastolic volume (LVEDV) were significantly decreased in the CLP group (P < 0.05), while left ventricular posterior wall systolic (LVPWs) and left ventricular posterior wall thickness (LVPWd) were significantly increased (P < 0.05). AICAR treatment alleviated the cardiac dysfunction induced by CLP. Compared with the CLP group, mitochondrial size and the number of mitochondrial cristae in the myocardial tissue of CLP+AICAR group mice were significantly increased (P < 0.05), while DHE fluorescence intensity and the number of TUNEL-positive cells were significantly reduced (P < 0.05). Compared with the LPS group, ATP production, mitochondrial respiration rate, and complex I, II, and III activities in NRCMs of the LPS+AICAR group were significantly increased (P < 0.05), while mitochondrial and cytoplasmic ROS levels were significantly reduced (P < 0.05). Compared with the control group, mitochondrial size in NRCMs of the LPS group was significantly reduced (P < 0.05), while Bax and Caspase-3 expression, as well as mitochondrial fission index, were significantly increased (P < 0.05), and these changes were mitigated by AICAR (P < 0.05). Conclusion AMPK plays a crucial role in maintaining cardiac function and mitigating septic myocardial injury by regulating mitochondrial structure and function, energy metabolism, oxidative stress, and apoptosis.

Key words: AMP-activated protein kinase, mitochondria, sepsis, cardiomyocytes, cardiac function

CLC Number:

R631

Huang Kang, Dai Yao, Wu Songbai, Lü Jianlei, Feng Jie. Study on the role and mechanism of AMP-activated protein kinase in regulating mitochondrial function and modulating cardiomyocyte injury in sepsis[J]. Journal of Capital Medical University, 2025, 46(2): 314-323.

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