title: Antagonistic functions of LMNA isoforms in energy expenditure and lifespan.
abstract: 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.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier CNRS UMR 5535 Universities of Montpellier 1 and Montpellier 2, Montpellier, France.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Lopez-Mejia
authors.forename: Marion
authors.initials: M
authors.lastname: de Toledo
authors.forename: Carine
authors.initials: C
authors.lastname: Chavey
authors.forename: Laure
authors.initials: L
authors.lastname: Lapasset
authors.forename: Patricia
authors.initials: P
authors.lastname: Cavelier
authors.forename: Celia
authors.initials: C
authors.lastname: Lopez-Herrera
authors.forename: Karim
authors.initials: K
authors.lastname: Chebli
authors.forename: Philippe
authors.initials: P
authors.lastname: Fort
authors.forename: Guillaume
authors.initials: G
authors.lastname: Beranger
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.forename: Ez Z
authors.initials: EZ
authors.lastname: Amri
authors.forename: Francois
authors.initials: F
authors.lastname: Casas
authors.forename: Jamal
authors.initials: J
authors.lastname: Tazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000375:Aging; D017398:Alternative Splicing; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000235:genetics*; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D034904:Lamin Type A / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria; D009687:Nuclear Proteins / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011371:Progeria / Q000235:genetics; D020033:Protein Isoforms; D011498:Protein Precursors / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D034904:Lamin Type A; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D011498:Protein Precursors; D014157:Transcription Factors; C576142:Lmna protein, mouse; C485290:Ppargc1a protein, mouse; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C440308:lamin C; C090764:prelamin A