PAI-1-regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy.
Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)-21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)-β in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-β with a remarkable cell proliferation-promoting potential. Age-associated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1(-/-) mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1-miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals.
Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.
Esther
E
Ardite
Eusebio
E
Perdiguero
Berta
B
Vidal
Susana
S
Gutarra
Antonio L
AL
Serrano
Pura
P
Muñoz-Cánoves
D000293:Adolescent; D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D002648:Child; D003094:Collagen / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D009136:Muscular Dystrophies / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology
C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt