ArticleJournal of cachexia, sarcopenia and muscle2026
PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.
Article in Journal of cachexia, sarcopenia and muscle, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundSepsis-induced myopathy (SIM) is a common and life-threatening complication, but its underlying mechanisms remain poorly understood. PACS2, a key resident protein at mitochondria-associated endoplasmic reticulum membranes (MAMs), regulates ER homeostasis under various pathological conditions. However, whether sepsis disrupts PACS2-dependent MAM integrity, thereby triggering ER dysfunction and muscle wasting, remains unexplored.
methodsWe established a sepsis mouse model via cecal ligation and puncture (CLP) and assessed muscle function using compound muscle action potential (CMAP) recording and grip strength measurements. Muscle atrophy was evaluated by H&E staining and Western blotting. PACS2 expression was determined by Western blotting, immunohistochemistry and qRT-PCR. MAM integrity was assessed by immunofluorescence co-localization of IP3R and VDAC1, and ER-phagy (reticulophagy) activation was evaluated by transmission electron microscopy, Western blotting and fluorescence microscopy. To investigate the functional role of PACS2, adeno-associated virus (AAV)-mediated PACS2 overexpression was performed in mouse tibialis anterior muscle and gastrocnemius muscles, followed by RNA-sequencing analysis. The MAPK pathway proteins p-ERK, p-P38 and p-JNK levels were assessed by Western blotting, and the involvement of ERK-MAPK signalling was tested pharmacologically via intraperitoneal injection of the ERK inhibitor SCH772984.
resultsSeptic mice developed progressive skeletal muscle atrophy (p < 0.001) and dysfunction (p < 0.01), accompanied by 56% reduction in PACS2 expression at 96 h post-CLP (p < 0.01), 25% decrease in MAM integrity (p < 0.05) and subsequent activation of FAM134B-mediated ER-phagy (p < 0.01). AAV-mediated PACS2 overexpression significantly alleviated muscle atrophy by restoring MAM integrity by 28% (p < 0.01), reducing FAM134B expression by 43% (p < 0.01) and attenuating ER-phagy (p < 0.01). Co-immunoprecipitation revealed no detectable direct protein-protein interaction between PACS2 and FAM134B. Transcriptome sequencing and Western blotting analysis demonstrated that PACS2 overexpression specifically activated the ERK-MAPK signalling pathway (55% increase in p-ERK, p < 0.01) without affecting p-P38 or p-JNK levels (p>0.05), which suppressed FAM134B-mediated ER-phagy (p < 0.05) and ameliorated muscle atrophy (p < 0.05) by inhibiting nuclear translocation of TFEB (p < 0.01). Pharmacological ERK inhibition with SCH772984 abolished the protective effects of PACS2 by promoting TFEB nuclear translocation (p < 0.001) and TFEB-mediated FAM134B expression (p < 0.001).
conclusionsOur findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B-mediated ER-phagy through the ERK-MAPK-TFEB signalling axis, thereby providing novel mechanistic insights and potential therapeutic targets for SIM.
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