Rationale: Lamina-associated polypeptide (LAP)2␣ is a mammalian chromatin-binding protein that interacts with a fraction of A-type lamins in the nuclear interior. Because mutations in lamins and LAP2␣ lead to cardiac disorders in humans, we hypothesized that these factors may play important roles in heart development and adult tissue homeostasis. Objective: We asked whether the presence of LAP2␣ was required for normal cardiac function. Methods and Results: To study the molecular mechanisms of the disease, we analyzed heart structure and function in complete and conditional Lap2␣ ؊/؊ mice as well as Lap2␣ ؊/؊ /Mdx mutants. Unlike conditional deletion of LAP2␣ in late embryonic striated muscle, its complete knockout caused systolic dysfunction in young mice, accompanied by sporadic fibrosis in old animals, as well as deregulation of major cardiac transcription factors GATA4 and myocyte enhancer factor 2c. Activation of compensatory pathways, including downregulation of -adrenergic receptor signaling, resulted in reduced responsiveness of the myocardium to chronic -adrenergic stimulation and stalled the progression of LAP2␣-deficient hearts from hypertrophy toward cardiac failure. Key Words: lamins Ⅲ LAP2␣ Ⅲ dilated cardiomyopathy Ⅲ -adrenergic receptors D ilated cardiomyopathy (DCM) is a primary myocardial disease characterized by dilation and impaired contraction of one or both heart ventricles. One of the genes most frequently involved in the development of DCM is LMNA, which encodes the nuclear intermediate filament proteins lamin A and lamin C 1 . Mutations in lamin A/C cause the most severe forms of DCM, posing a high risk of heart failure in symptomatic patients. 1 Besides heart muscle disease, mutations in LMNA cause a variety of pathological conditions in skeletal muscle, skin, nerve, bone, and adipose tissue, known as laminopathies, 2 emphasizing the importance of the search for molecular disease mechanisms. Dystrophin deficiency in anRecently, research on laminopathies has focused on lamin A/C-interacting proteins, whose mutations have been linked to a similar spectrum of human disorders. 3 One of the best studied lamin A/C-binding partners is lamina associated polypeptide (LAP)2␣, an unusual splice variant of the mammalian LAP2 gene. 4 All LAP2 proteins (␣, , ␥, ␦, , ) share a common chromatin-binding structural motif called the LEM (LAP2-emerin-MAN1) domain at their N terminus. The C terminus of most LAP2 variants comprises a transmembrane region, which targets them to the inner nuclear membrane, where they serve mainly structural roles. 5 LAP2␣ lacks the common LAP2 transmembrane domain and possesses an additional chromatin-binding region at its C-terminal end, which mediates targeting to the nuclear interior. 4 In the nucleoplasm LAP2␣ specifically interacts with a fraction of lamin A/C via its unique C-terminal tail. 6 Together, LAP2␣ and lamin A/C influence various nuclear processes, such as epigenetic chromatin regulation, gene expression, and signal transduction. 7 In particular, LAP2␣-l...
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.
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