The S341P mutant MYOC renders the trabecular meshwork sensitive to cyclic mechanical stretch

Area of Science:

• Ophthalmology and cellular biology
• Mechanobiology
• Glaucoma research

Background:

• The trabecular meshwork (TM) regulates intraocular pressure (IOP) by controlling aqueous humor outflow.
• Mutant myocilin (MYOC) is linked to TM dysfunction and elevated IOP, a glaucoma risk factor.
• The response of TM cells with mutant MYOC to mechanical stress is not well understood.

Purpose of the Study:

• To investigate how TM cells with mutant MYOC respond to cyclic mechanical stretch (CMS).
• To compare gene expression and oxylipin profiles in TM cells with and without mutant MYOC under CMS.
• To identify molecular mechanisms underlying TM cell sensitivity to mechanical stress in MYOC-mutant backgrounds.

Main Methods:

• Applied CMS to human primary TM cells using the Flexcell system.
• Performed genome-wide transcriptome analysis and oxidized lipidomics.
• Overexpressed MYOC^S341P in TM cells for comparison with control and TM-CMS groups.

Main Results:

• TM cells overexpressing MYOC^S341P exhibited increased sensitivity to mechanical stress.
• KEGG analysis indicated downregulated genes involved in oxidative phosphorylation, suggesting mitochondrial dysfunction and oxidative stress.
• Significant alterations in oxylipin profiles were observed in MYOC^S341P-expressing cells under CMS.
• Identified potential key genes (SARM1, AHNAK2, NT5C, SOX8) involved in this sensitivity.

Conclusions:

• Mitochondrial dysfunction and oxidative stress likely contribute to TM cell damage in MYOC^S341P backgrounds under mechanical stress.
• Mutant MYOC sensitizes TM cells to mechanical forces, potentially exacerbating glaucoma pathogenesis.
• The identified genes warrant further investigation for their role in MYOC-associated glaucoma.