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Antagonistic functions of LMNA isoforms in energy expenditure and lifespan
Author(s) -
LopezMejia Isabel C,
Toledo Marion,
Chavey Carine,
Lapasset Laure,
Cavelier Patricia,
LopezHerrera Celia,
Chebli Karim,
Fort Philippe,
Beranger Guillaume,
Fajas Lluis,
Amri Ez Z,
Casas François,
Tazi Jamal
Publication year - 2014
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1002/embr.201338126
Subject(s) - lmna , lamin , progeria , biology , gene isoform , microbiology and biotechnology , mitochondrial biogenesis , mitochondrion , genetics , gene , nucleus
Alternative RNA processing of LMNA pre‐ mRNA produces three main protein isoforms, that is, lamin A, progerin, and lamin C. De novo mutations that favor the expression of progerin over lamin A lead to Hutchinson‐Gilford progeria syndrome (HGPS), providing support for the involvement of LMNA processing in pathological aging. Lamin C expression is mutually exclusive with the splicing of lamin A and progerin isoforms and occurs by alternative polyadenylation. Here, we investigate the function of lamin C in aging and metabolism using mice that express only this isoform. Intriguingly, these mice live longer, have decreased energy metabolism, increased weight gain, and reduced respiration. In contrast, progerin‐expressing mice show increased energy metabolism and are lipodystrophic. Increased mitochondrial biogenesis is found in adipose tissue from HGPS‐like mice, whereas lamin C‐only mice have fewer mitochondria. Consistently, transcriptome analyses of adipose tissues from HGPS and lamin C‐only mice reveal inversely correlated expression of key regulators of energy expenditure, including Pgc1a and Sfrp5. Our results demonstrate that LMNA encodes functionally distinct isoforms that have opposing effects on energy metabolism and lifespan in mammals.