| First Author | Lamar KM | Year | 2016 |
| Journal | PLoS Genet | Volume | 12 |
| Issue | 5 | Pages | e1006019 |
| PubMed ID | 27148972 | Mgi Jnum | J:232558 |
| Mgi Id | MGI:5779571 | Doi | 10.1371/journal.pgen.1006019 |
| Citation | Lamar KM, et al. (2016) Overexpression of Latent TGFbeta Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFbeta. PLoS Genet 12(5):e1006019 |
| abstractText | Latent TGFbeta binding proteins (LTBPs) regulate the extracellular availability of latent TGFbeta. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFbeta family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFbeta and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFbeta family ligand binding protein with the capacity to modify muscle disease through overexpression. |
