PAI-1-regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy

Area of Science:

• Biochemistry
• Molecular Biology
• Muscle Physiology

Background:

• Duchenne muscular dystrophy (DMD) is characterized by skeletal muscle fibrosis, a primary cause of mortality.
• The fibrotic mechanisms driving DMD progression are not fully understood.
• Extracellular matrix remodeling plays a critical role in muscle degeneration.

Purpose of the Study:

• To investigate the role of the PAI-1/uPA balance in regulating microRNA-21 (miR-21) biogenesis.
• To elucidate the mechanisms linking miR-21 to age-associated muscle fibrosis and dystrophy in DMD.
• To evaluate the therapeutic potential of targeting the PAI-1-miR-21 axis in DMD.

Main Methods:

• Utilized mdx dystrophic mouse models with genetic PAI-1 deficiency.
• Analyzed collagen metabolism, TGF-β signaling, and miR-21 expression in muscle fibroblasts.
• Interfered with miR-21 and uPA activity and assessed effects on muscle fibrosis and dystrophy.
• Examined the PAI-1-miR-21 axis in muscle tissue samples from DMD patients.

Main Results:

• Genetic loss of PAI-1 altered collagen metabolism via uPA-mediated TGF-β processing and activated miR-21 expression.
• miR-21 inhibited PTEN and enhanced AKT signaling, promoting TGF-β-induced cell proliferation.
• Interference with miR-21 or uPA reversed fibrosis and muscle deterioration in mdx mice; PAI-1 deficiency exacerbated dystrophy.
• The PAI-1-miR-21 fibrogenic axis was found to be dysregulated in DMD patient muscle.

Conclusions:

• The extracellular PAI-1/uPA balance is a key regulator of miR-21 biogenesis and muscle fibrosis in DMD.
• The PAI-1-miR-21 axis represents a potential therapeutic target for mitigating fibrosis and treating DMD.
• Targeting this pathway offers a novel strategy for individuals with currently untreatable muscular dystrophies.