| First Author | Cohen TV | Year | 2013 |
| Journal | Hum Mol Genet | Volume | 22 |
| Issue | 14 | Pages | 2852-69 |
| PubMed ID | 23535822 | Mgi Jnum | J:198543 |
| Mgi Id | MGI:5496988 | Doi | 10.1093/hmg/ddt135 |
| Citation | Cohen TV, et al. (2013) Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2alpha. Hum Mol Genet 22(14):2852-69 |
| abstractText | Mutations in lamin A/C result in a range of tissue-specific disorders collectively called laminopathies. Of these, Emery-Dreifuss and Limb-Girdle muscular dystrophy 1B mainly affect striated muscle. A useful model for understanding both laminopathies and lamin A/C function is the Lmna(-/-) mouse. We found that skeletal muscle growth and muscle satellite (stem) cell proliferation were both reduced in Lmna(-/-) mice. Lamins A and C associate with lamina-associated polypeptide 2 alpha (Lap2alpha) and the retinoblastoma gene product, pRb, to regulate cell cycle exit. We found Lap2alpha to be upregulated in Lmna(-/-) myoblasts (MBs). To specifically test the contribution of elevated Lap2alpha to the phenotype of Lmna(-/-) mice, we generated Lmna(-/-)Lap2alpha(-/-) mice. Lifespan and body mass were increased in Lmna(-/-)Lap2alpha(-/-) mice compared with Lmna(-/-). Importantly, the satellite cell proliferation defect was rescued, resulting in improved myogenesis. Lmna(-/-) MBs also exhibited increased levels of Smad2/3, which were abnormally distributed in the cell and failed to respond to TGFbeta1 stimulation as in control cells. However, using SIS3 to inhibit signaling via Smad3 reduced cell death and augmented MB fusion. Together, our results show that perturbed Lap2alpha/pRb and Smad2/3 signaling are important regulatory pathways mediating defective muscle growth in Lmna(-/-) mice, and that inhibition of either pathway alone or in combination can ameliorate this deleterious phenotype. |
