title: Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2α.
abstract: 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 TGFβ1 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.
authors.affiliation: Research Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. cohenta@kennedykrieger.org
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Cohen
authors.forename: Viola F
authors.initials: VF
authors.lastname: Gnocchi
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Cohen
authors.forename: Aditi
authors.initials: A
authors.lastname: Phadke
authors.forename: Henry
authors.initials: H
authors.lastname: Liu
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Roland
authors.initials: R
authors.lastname: Foisner
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
authors.forename: Terence A
authors.initials: TA
authors.lastname: Partridge
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D032446:Myoblasts / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; C440308:lamin C; C093413:lamina-associated polypeptide 2
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