title: Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival.
abstract: 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.
authors: Department of Pathology, University of Washington,                     Seattle, WA 98195, USA.
authors: Fresnida J
authors: FJ
authors: Ramos
authors: Steven C
authors: SC
authors: Chen
authors: Michael G
authors: MG
authors: Garelick
authors: Dao-Fu
authors: DF
authors: Dai
authors: Chen-Yu
authors: CY
authors: Liao
authors: Katherine H
authors: KH
authors: Schreiber
authors: Vivian L
authors: VL
authors: MacKay
authors: Elroy H
authors: EH
authors: An
authors: Randy
authors: R
authors: Strong
authors: Warren C
authors: WC
authors: Ladiges
authors: Peter S
authors: PS
authors: Rabinovitch
authors: Matt
authors: M
authors: Kaeberlein
authors: Brian K
authors: BK
authors: Kennedy
mesh_terms: D000818:Animals; D003893:Desmin / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects*; D034904:Lamin Type A / Q000172:deficiency* / Q000235:genetics; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D003893:Desmin; D034904:Lamin Type A; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus