Journal article
Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival
Science translational medicine, Vol.4(144), pp.144ra103-144ra103
07/25/2012
DOI: 10.1126/scitranslmed.3003802
PMCID: PMC3613228
PMID: 22837538
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.
Details
- Title: Subtitle
- Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival
- Creators
- Fresnida J Ramos - Department of Pathology, University of Washington, Seattle, WA 98195, USASteven C Chen - Department of Biochemistry, University of Washington, Seattle, WA 98195, USAMichael G Garelick - Department of Biochemistry, University of Washington, Seattle, WA 98195, USADao-Fu Dai - Department of Pathology, University of Washington, Seattle, WA 98195, USAChen-Yu Liao - Buck Institute for Research on Aging, Novato, CA 94945, USAKatherine H Schreiber - Buck Institute for Research on Aging, Novato, CA 94945, USAVivian L MacKay - Department of Biochemistry, University of Washington, Seattle, WA 98195, USAElroy H An - Department of Pathology, University of Washington, Seattle, WA 98195, USARandy Strong - The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USAWarren C Ladiges - Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USAPeter S Rabinovitch - Department of Pathology, University of Washington, Seattle, WA 98195, USAMatt Kaeberlein - Department of Pathology, University of Washington, Seattle, WA 98195, USABrian K Kennedy - Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.4(144), pp.144ra103-144ra103
- DOI
- 10.1126/scitranslmed.3003802
- PMID
- 22837538
- PMCID
- PMC3613228
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Grant note
- R01 AG033373 || AG / National Institute on Aging : NIA R01 AG024287 || AG / National Institute on Aging : NIA
- Language
- English
- Date published
- 07/25/2012
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984046906002771
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