Integrated Multiomics Analysis Reveals Manual Therapy Restores Autophagic Homeostasis via the AMPK/ULK1 Axis in Chronic Low Back Pain

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BACKGROUND: Chronic low back pain (CLBP) is characterized by persistent neuroinflammation and metabolic dysregulation, extending beyond local tissue injury to central neural maladaptation. While manual therapy (MT) is a clinically validated intervention, its capacity to modulate the neuro-immune-metabolic axis remains poorly understood. METHODS: We established a complete Freund's adjuvant (CFA)-induced CLBP rat model and used a combination of in vivo behavioral and molecular techniques to study MT intervention mechanisms. The therapeutic effects were evaluated via multidimensional approaches combining behavioral assays, histology, and high-throughput dual-tissue (prefrontal cortex and multifidus muscle) proteomics and metabolomics. RESULTS: MT intervention significantly attenuated mechanical hyperalgesia and suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) in muscle tissues. Integrated omics revealed distinct reprogramming of metabolic pathways, including GABAergic synapses and oxidative phosphorylation. Crucially, the CLBP model exhibited aberrant upregulation of autophagy initiation markers (AMPK, ULK1, and LC3B) coupled with substrate accumulation (p62), indicative of pathological autophagic stress. MT partially normalized the altered expression of autophagy-related proteins. CONCLUSION: Our findings from a CFA-induced inflammatory multifidus injury rat model suggest that AMPK/ULK1-linked autophagy signaling may correlate with the therapeutic effects of MT on inflammatory muscle-type low back pain; these preclinical observations require further verification in heterogeneous clinical CLBP cohorts and multiple animal models.

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