| [PMID]: | 22837538 |
| [Au] Autor: | Ramos FJ; Chen SC; Garelick MG; Dai DF; Liao CY; Schreiber KH; MacKay VL; An EH; Strong R; Ladiges WC; Rabinovitch PS; Kaeberlein M; Kennedy BK |
| [Ad] Endereço: | Department of Pathology, University of Washington, Seattle, WA 98195, USA. |
| [Ti] Título: | Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. |
| [So] Source: | Sci Transl Med;4(144):144ra103, 2012 Jul 25. |
| [Is] ISSN: | 1946-6242 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. |
| [Mh] Termos MeSH primário: |
Coração/efeitos de drogas
Lamina Tipo A/deficiência
Músculo Esquelético/efeitos de drogas
Proteínas/metabolismo
Sirolimo/farmacologia
|
| [Mh] Termos MeSH secundário: |
Animais
Desmina/metabolismo
Feminino
Lamina Tipo A/genética
Masculino
Camundongos
Músculo Esquelético/metabolismo
Miocárdio/metabolismo
Proteínas/genética
Transdução de Sinal/efeitos de drogas
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Desmin); 0 (Lamin Type A); 0 (Proteins); 0 (mTORC1 complex, mouse); 53123-88-9 (Sirolimus) |
| [Em] Mês de entrada: | 1212 |
| [Cu] Atualização por classe: | 130502 |
[Lr] Data última revisão:
| 130502 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 120727 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1126/scitranslmed.3003802 |
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