Cigarette Smoke‐Exposed Alveolar Epithelial Cell‐Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through HDAC2 Signalling

BACKGROUND: Skeletal muscle dysfunction (SMD) is a common extrapulmonary complication of chronic obstructive pulmonary disease (COPD). Histone deacetylase 2 (HDAC2) is closely involved in the suppression of inflammatory transcription and is progressively reduced during COPD progression. Exosomes mediate intercellular communication by transferring bioactive cargos, including proteins. This study aimed to elucidate the molecular mechanism by which alveolar epithelial cell-derived exosomes regulate HDAC2 and contribute to COPD-related SMD. METHODS: Exosome inhibitor GW4869 was used to assess the role of exosomes in skeletal muscle injury induced by chronic cigarette smoke (CS) exposure. Exosomes isolated from the bronchoalveolar lavage fluid (BALF) of CS-exposed mice and from cigarette smoke extract (CSE)-exposed mouse alveolar epithelial (MLE12) cells were applied to recipient mice and/or mouse myoblast (C2C12) cells to evaluate muscle phenotypes, myogenic differentiation and cellular senescence. Rescue experiments using HDAC2 overexpression or HDAC activator ITSA1 treatment, together with proteomics and protein interaction assays, were performed to elucidate the underlying molecular mechanisms. RESULTS: , p < 0.001), along with decreased muscle atrophy and senescence markers. In vitro, exosomes derived from 8% CSE-exposed MLE12 cells (Exo-CSE) impaired myogenic differentiation, decreased myotube diameter (10.50 ± 0.74 μm vs. 29.27 ± 0.48 μm, p < 0.001) and increased the number of senescent cells (206.7 ± 5.13 vs. 9.33 ± 1.53, p < 0.001). Exo-CSE significantly reduced HDAC2 expression in C2C12 cells (0.18 ± 0.03 vs. 0.53 ± 0.04, p < 0.001), whereas HDAC2 overexpression or ITSA1 treatment rescued impaired myogenic differentiation and cellular senescence caused by Exo-CSE. Proteomic analysis identified proline/arginine-rich end leucine-rich protein (PRELP) as a key exosomal cargo, and exosomes derived from PRELP-silenced CSE-exposed MLE12 cells markedly restored HDAC2 expression in recipient C2C12 cells (0.42 ± 0.02 vs. 0.18 ± 0.03, p < 0.001). Mechanistically, PRELP disrupted the stabilizing interaction between heat shock protein family A member 5 (HSPA5) and HDAC2, accelerating HDAC2 degradation, likely through the ubiquitin-proteasome pathway. In vivo, the combination of PRELP knockdown and the HDAC activator ITSA1 synergistically alleviated CS-induced muscle atrophy and senescence. CONCLUSIONS: In COPD, CS-exposed alveolar epithelial cells release PRELP-enriched exosomes that promote SMD by disrupting HSPA5-mediated HDAC2 stabilization and accelerating HDAC2 degradation. Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD.