microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice
Ning Liu, Andrew H. Williams, Johanna M. Maxeiner, Svetlana Bezprozvannaya, John M. Shelton, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson
Ning Liu, Andrew H. Williams, Johanna M. Maxeiner, Svetlana Bezprozvannaya, John M. Shelton, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson
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Research Article Muscle biology

microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice

Abstract

Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle–specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy.

Authors

Ning Liu, Andrew H. Williams, Johanna M. Maxeiner, Svetlana Bezprozvannaya, John M. Shelton, James A. Richardson, Rhonda Bassel-Duby, Eric N. Olson

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Figure 4

Analysis of the more severe dystrophic phenotype of miR-206–KO;mdx mice.

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Analysis of the more severe dystrophic phenotype of miR-206–KO;mdx mice....
(A) WT, miR-206–KO, mdx, and miR-206–KO;mdx mice at 6 weeks of age. miR-206–KO;mdx mice are runted with kyphosis compared with mdx mice. Kyphosis was revealed by x-ray in miR-206–KO;mdx mice. (B) Serum CK levels of WT, miR-206–KO, mdx, and miR-206–KO;mdx mice at 4 weeks of age. 6 mice were analyzed from each genotype. ***P < 0.001. (C) Results of Evans blue dye (EBD) uptake of GP muscle, quadriceps (quad), and TA muscles of mdx and miR-206;mdx mice. Immunostaining with laminin (green) is shown in the right column. Evans blue dye is detected as a red signal under fluorescence microscopy. Scale bar: 100 μm. (D) Ten-week-old WT, miR-206–KO, mdx, and miR-206–KO;mdx mice were subjected to forced downhill running on a treadmill. Muscle performance was measured as time to exhaustion. Left panel: total running time. Right panel: total running distance. Six mice were analyzed from each genotype. **P < 0.01. (E) Immunostaining for desmin and laminin on quadriceps muscle of mdx and miR-206–KO;mdx mice at 6 weeks of age. Scale bar: 100 μm. Data are presented as mean ± SEM.