Myoferlin Regulates Cell Proliferation and Migration through the ERK and PI3K/Akt Signaling Pathways in Airway Smooth Muscle Cells.

BACKGROUND

The migration and proliferation of airway smooth muscle (ASM) cells are critical processes in the pathogenesis of asthma; however, the underlying regulatory mechanisms remain unclear. Myoferlin (MYOF), a protein known for its involvement in membrane repair, vesicle trafficking, and cancer progression, has recently been associated with enhanced cell migration and proliferation. Nevertheless, the specific role of MYOF in ASM phenotype remains unclear.

METHODS

Human airway smooth muscle cells (HASMCs) were stimulated with tumor necrosis factor-alpha (TNFα), interleukin-1 beta (IL-1β), or platelet-derived growth factor BB (PDGF-BB) to assess myoferlin expression. Genetic knockdown and the specific pharmacological inhibitor HJ445A were performed to evaluate myoferlin's role in cell proliferation (assessed via CCK-8 and proliferating cell nuclear antigen expression) and migration (evaluated by wound-healing assay). Signaling pathway activation, including MAPK and PI3K/Akt, was examined by Western blot.

RESULTS

The expression of myoferlin was markedly upregulated in airway smooth muscle cells (ASMCs) upon stimulation with tumor necrosis factor-alpha (TNF-α), interleukin- 1 beta (IL-1β), and platelet-derived growth factor BB (PDGF-BB). The knockdown or inhibition of myoferlin significantly suppressed PDGF-BB-induced proliferation and migration of ASMCs. Mechanistically, myoferlin depletion or inhibition selectively attenuated PDGF-BB-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, suggesting that these signaling pathways are potentially involved in MYOF- mediated ASMC proliferation and migration.

DISCUSSION: This study identifies myoferlin as a key contributor to PDGF-BB-induced ASMC proliferation and migration, and suggests that MYOF inhibition may have therapeutic potential in airway remodeling. However, whether MYOF directly modulates the ERK and PI3K/Akt pathways or acts indirectly through upstream receptor regulation remains to be determined and requires further investigation.

CONCLUSION

Myoferlin is upregulated in activated airway smooth muscle cells (ASMCs) and drives their proliferation and migration via activation of the ERK and PI3K/Akt signaling pathways. Targeted inhibition of myoferlin significantly suppresses these pathological processes.