Ardite et al. describe how increased production of a microRNA leads to progressive muscle deterioration in Duchenne muscular dystrophy (DMD) patients.
As DMD patients age, their damaged muscle cells are gradually replaced by collagen-rich fibrous tissue. This muscle fibrosis is partly induced by TGF-β, which is highly activated in DMD patients, though exactly how this cytokine promotes fibrogenesis is unclear. Ardite et al. examined the role of miR-21, a microRNA whose production is stimulated by TGF-β signaling.
miR-21 was upregulated in the collagen-producing fibroblasts of both DMD patients and muscular dystrophy model (mdx) mice. Inhibiting miR-21 reduced collagen levels and prevented, or even reversed, fibrogenesis in diseased animals, whereas mdx mice overexpressing the microRNA produced more collagen and developed fibrotic muscles at earlier ages.
Ardite et al. also discovered that TGF-β activity and miR-21 production were regulated by the balance of two extracellular factors: uPA—a protease that activates TGF-β—and its inhibitor PAI-1. mdx mice developed fibrotic muscles more quickly in the absence of PAI-1, but these symptoms could be reversed by inhibiting uPA with a drug or a specific siRNA. In addition to producing more collagen, PAI-1–null fibroblasts also proliferated rapidly because the extra miR-21 induced by active TGF-β inhibited the tumor-suppressive phosphatase PTEN.
TGF-β inhibitors prevent muscle fibrosis but have damaging side effects; this study suggests that uPA or miR-21 may make attractive alternative targets. Senior author Pura Muñoz-Cánoves now wants to investigate the function of miR-21 in other cell types that influence muscle homeostasis, such as the macrophages involved in tissue repair.
