Loss of LAP2 alpha delays satellite cell differentiation and affects postnatal fiber-type determination.
Lamina-associated polypeptide 2 alpha (LAP2 alpha) is a nucleoplasmic protein implicated in cell cycle regulation through its interaction with A-type lamins and the retinoblastoma protein. Mutations in lamin A/C and LAP2 alpha cause late onset striated muscle diseases, but the molecular mechanisms are poorly understood. To study the role of LAP2 alpha in skeletal muscle function and postnatal tissue homeostasis, we generated complete and muscle-specific LAP2 alpha knockout mice. Whereas overall muscle morphology, function, and regeneration were not detectably affected, the myofiber-associated muscle stem cell pool was increased in complete LAP2 alpha knockout animals. At molecular level, the absence of LAP2 alpha preserved the stem cell-like phenotype of Lap2 alpha(-/-) primary myoblasts and delayed their in vitro differentiation. In addition, loss of LAP2 alpha shifted the myofiber-type ratios of adult slow muscles toward fast fiber types. Conditional Cre-mediated late muscle-specific ablation of LAP2 alpha affected early stages of in vitro myoblast differentiation, and also fiber-type determination, but did not change myofiber-associated stem cell numbers in vivo. Our data demonstrate multiple and distinct functions of LAP2 alpha in muscle stem cell maintenance, early phases of myogenic differentiation, and muscle remodeling.
Gotic
Ivana
I
Department of Medical Biochemistry, Max F. Perutz Laboratories, Center of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Schmidt
Wolfgang M
WM
Biadasiewicz
Katarzyna
K
Leschnik
Michael
M
Spilka
Rita
R
Braun
Juliane
J
Stewart
Colin L
CL
Foisner
Roland
R
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D010641:Phenotype; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C093413:lamina-associated polypeptide 2