AMPK/ SIRT1 signaling pathway activation acts on PGC-1α/ PPARγ to alleviate sepsis-acquired weakness.

Abstract

Intensive care unit-acquired weakness (ICU-AW) represents a critical complication that severely impairs the prognostic outcomes of patients with sepsis. This study aimed to elucidate whether the activation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) signaling pathway ameliorates sepsis-acquired weakness (SAW) via modulating the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/peroxisome proliferator-activated receptor γ (PPARγ) axis. A PGC-1α knockout mouse model was established using the cecal ligation and puncture (CLP) method to induce sepsis and subsequent SAW. Multiple histological analyses were performed to evaluate tissue pathological lesions, mitochondrial morphological and structural abnormalities, myelin injury, and skeletal muscle alterations. ELISA was utilized to quantify the expression levels of pro-inflammatory factors and neurotransmitters. Western blotting and RT-qPCR were further employed to detect the expression of mitochondrial functional proteins and downstream molecules associated with the AMPK/SIRT1 signaling pathway. Successful construction of the PGC-1α knockout CLP mouse model was confirmed via systematic verification. Functional experiments validated that AMPK/SIRT1 pathway activation exerts protective effects against SAW in CLP mice through targeting the PGC-1α/PPARγ signaling cascade. Mechanistically, AMPK/SIRT1 activation further modulates the PGC-1α/PPARγ pathway, thereby alleviating the progression of SAW. Collectively, targeted regulation of PGC-1α may serve as a promising and actionable therapeutic strategy for the clinical prevention and treatment of ICU-AW in septic patients.