Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2&#945;.

Cohen, Tatiana V; Gnocchi, Viola F; Cohen, Jonathan E; Phadke, Aditi; Liu, Henry; Ellis, Juliet A; Foisner, Roland; Stewart, Colin L; Zammit, Peter S; Partridge, Terence A

Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2α.

Cohen, Tatiana V; Gnocchi, Viola F; Cohen, Jonathan E; Phadke, Aditi; Liu, Henry; Ellis, Juliet A; Foisner, Roland; Stewart, Colin L; Zammit, Peter S; Partridge, Terence A.

Afiliación

Cohen TV; Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. cohenta@kennedykrieger.org

Hum Mol Genet ; 22(14): 2852-69, 2013 Jul 15.

Article en En | MEDLINE | ID: mdl-23535822

RESUMEN

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 (Lap2α) and the retinoblastoma gene product, pRb, to regulate cell cycle exit. We found Lap2α to be upregulated in Lmna(-/-) myoblasts (MBs). To specifically test the contribution of elevated Lap2α to the phenotype of Lmna(-/-) mice, we generated Lmna(-/-)Lap2α(-/-) mice. Lifespan and body mass were increased in Lmna(-/-)Lap2α(-/-) 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 TGFß1 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 Lap2α/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.

Asunto(s)

Proteínas de Unión al ADN/deficiencia; Lamina Tipo A/deficiencia; Proteínas de la Membrana/deficiencia; Músculo Esquelético/crecimiento & desarrollo; Distrofia Muscular de Emery-Dreifuss/metabolismo; Animales; Proliferación Celular; Proteínas de Unión al ADN/genética; Humanos; Lamina Tipo A/genética; Proteínas de la Membrana/genética; Ratones; Ratones Noqueados; Músculo Esquelético/metabolismo; Distrofia Muscular de Emery-Dreifuss/genética; Distrofia Muscular de Emery-Dreifuss/fisiopatología; Mioblastos/metabolismo; Células Satélite del Músculo Esquelético/citología; Células Satélite del Músculo Esquelético/metabolismo; Proteína Smad2/metabolismo; Proteína smad3/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Músculo Esquelético / Distrofia Muscular de Emery-Dreifuss / Lamina Tipo A / Proteínas de Unión al ADN / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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