Adenosine 5'-monophosphate prevents sepsis-associated muscle wasting by activating AMPK and suppressing IL-1β inflammatory cytokines.

Abstract

Background: Sepsis-associated muscle wasting (SAMW) causes long-term functional decline, even after recovery. Emerging evidence indicates that adenosine 5'-monophosphate (AMP) confers organ-protective effects in response to physiological stress or injury, potentially through the activation of AMP-activated protein kinase (AMPK) signalling pathways. In this study, we investigated the effects of AMP on SAMW to evaluate its efficacy as a therapeutic agent to alleviate SAMW.

Methods: In vivo, a mouse model of cecum ligation and puncture sepsis was established using male C57BL/6 mice, which received intraperitoneal AMP (0.5 mg/g) or saline as a control. In vitro, C2C12 myoblasts and RAW264.7 macrophages were cultured under standard conditions and treated with AMP. Forelimb grip strength, blood and muscle sampling, western blotting, AMP assays, RNA sequencing, ELISA, flow cytometry, real-time PCR, immunohistochemistry, histology, and computed tomography imaging were performed to assess molecular, cellular, and physiological responses. In addition, plasma samples from patients with sepsis were analysed to explore translational relevance.

Results: AMP suppressed sepsis-induced inflammatory cytokine production and improved muscle strength by attenuating mammalian target of rapamycin complex 1 activation and modulating AMPK signaling, thereby contributing to the preservation of muscle mass and a reduction in systemic inflammation. In vitro, AMP suppressed LPS- induced IL-1β production in RAW264.7 macrophages and attenuated LPS- or IL-1β-induced myotube atrophy in C2C12 cells and shifted the cells towards a fast-twitch phenotype. Evaluation of clinical samples revealed elevated inflammatory cytokines in patients with sepsis exhibiting muscle wasting.

Conclusions: This study demonstrates that AMP effectively mitigates SAMW by activating AMPK and suppressing IL-1β-mediated molecular pathways. These findings highlight the potential of AMP as a novel therapeutic agent for preserving skeletal muscle functionality and morphology in sepsis.