Work

Effect of early intensive physical therapy on NLRP3 inflammasome activation and muscle atrophy in critical illness myopathy (PT-NLRP3-CIM): a two-centre randomized open-label study protocol

Year: 2026

Type: article

Abstract: BACKGROUND: Critical illness myopathy (CIM) is a prevalent cause of intensive care unit-acquired weakness (ICUAW). It is associated with prolonged mechanical ventilation and increased mortality and frequently evolves into postintensive care syndrome with long-term cognitive and physical impairments. Although several molecular mechanisms have been implicated in CIM, including muscle atrophy and altered contractility, its exact etiopathogenesis is not fully understood. Evidence suggests that activation of the NLRP3 inflammasome and upregulation of atrogenes significantly contribute to this condition. In murine models of sepsis and denervation, which mimic CIM, NLRP3 activation induces muscle atrophy. Physical therapy, including enhanced mobilization supported by servo-assisted devices, a nonpharmacological intervention, can regulate inflammation, reduce IL-1β and NLRP3 levels, and improve mitochondrial and autophagy processes; however, whether it reduces NLRP3 activation and alleviates atrophy in human CIM remains uncertain. METHODS: ) twice daily for 60 min over seven consecutive days. An additional ICU control group without CIM (n = 8) will be included for biomarker analyses. At baseline and on day 7, blood and vastus lateralis muscle biopsies will be obtained for histologic, molecular, and transcriptomic analyses. The primary outcomes are as follows: (1) NLRP3 inflammasome priming and activity (protein and gene expression by Western blot, RT-qPCR, and ELISA) and (2) indices of muscle atrophy (fiber diameter, atrogenes expression, the myosin/actin ratio, and sarcomere organization by immunofluorescence and transmission electron microscopy). The secondary outcomes include strength and function (MRC-SS, FSS-ICU), feasibility and safety, microarray-based transcriptomic profiling, and associations between biochemical/molecular markers and CIM diagnosis by clinical assessment and ultrasound. DISCUSSION: We hypothesize that enhanced PT (in addition to conventional care) reduces NLRP3 activation and muscle atrophy in critically ill adults. This translational trial combines clinical assessments integrating muscle biopsies and blood measures to elucidate CIM pathogenesis and assess PT intervention. These findings may identify therapeutic targets and inform early mobilization strategies in ICU practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT07017517. Registered on 26 May 2025.

Source: Trials

DOI: 10.1186/s13063-026-09536-3