Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are Lmna−/− mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in Lmna−/− mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in Lmna−/− mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for S6K1 ubiquitously extended lifespan of Lmna−/− mice (Lmna−/− S6K1+/− mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of S6K1 specifically in muscle tissue also extended survival of Lmna−/− mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of Lmna−/− mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in Lmna−/− mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.
Date Issued
2017-10-31
Date Acceptance
2017-09-04
Citation
Cell Discovery, 2017, 3
ISSN
2056-5968
Publisher
Nature Publishing Group
Journal / Book Title
Cell Discovery
Volume
3
Copyright Statement
© The Author(s) 2017. This work is licensed under a Creative Commons
Attribution 4.0 International License. The images or
other third party material in this article are included in the article
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Creative Commons license, unless indicated otherwise in the
credit line; if the material is not included under the Creative
Commons license, users will need to obtain permission from the
license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International License. The images or
other third party material in this article are included in the article
’
s
Creative Commons license, unless indicated otherwise in the
credit line; if the material is not included under the Creative
Commons license, users will need to obtain permission from the
license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Grant Number
BB/H020527/2
098565/Z/12/Z
Publication Status
Published
Article Number
17039