Cigarette Smoke-Exposed Alveolar Epithelial Cell-Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through...

Area of Science:

• Cell Biology
• Molecular Biology
• Pulmonary Medicine

Background:

• Skeletal muscle dysfunction (SMD) is a prevalent extrapulmonary complication in chronic obstructive pulmonary disease (COPD).
• Histone deacetylase 2 (HDAC2) levels decrease during COPD progression, impacting inflammatory transcription.
• Exosomes facilitate intercellular communication through the transfer of bioactive molecules, including proteins.

Purpose of the Study:

• To investigate the molecular mechanisms by which exosomes from alveolar epithelial cells influence HDAC2 levels.
• To determine the role of these exosomes in the development of COPD-related skeletal muscle dysfunction.

Main Methods:

• Exosome inhibitor GW4869 was used to evaluate exosome involvement in cigarette smoke (CS)-induced skeletal muscle injury.
• Exosomes from CS-exposed mice and CSE-exposed MLE12 cells were administered to mice and C2C12 cells to assess muscle phenotypes.
• Rescue experiments involved HDAC2 overexpression or HDAC activator ITSA1, alongside proteomics and protein interaction assays.

Main Results:

• Exosome inhibition ameliorated CS-induced muscle dysfunction, improving grip strength and muscle fiber size while reducing atrophy and senescence.
• Exosomes from CSE-exposed cells impaired myogenic differentiation, reduced myotube diameter, and increased cellular senescence.
• These exosomes decreased HDAC2 expression; HDAC2 overexpression or ITSA1 treatment rescued these effects.
• Proteomic analysis identified proline/arginine-rich end leucine-rich protein (PRELP) as a key exosomal cargo that disrupts HSPA5-HDAC2 interaction, accelerating HDAC2 degradation.

Conclusions:

• Alveolar epithelial cells in COPD release PRELP-enriched exosomes that drive SMD by reducing HDAC2 stability.
• Targeting the PRELP-HDAC2 axis offers a potential therapeutic strategy for COPD-related skeletal muscle dysfunction.