Antagonistic Functions of LMNA Isoforms in Energy Expenditure and Lifespan

EMBO Rep. 2014 May;15(5):529-39. doi: 10.1002/embr.201338126. Epub 2014 Mar 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Adipose Tissue / physiology*
  • Aging
  • Alternative Splicing
  • Animals
  • Cells, Cultured
  • Energy Metabolism / genetics*
  • Gene Expression
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lamin Type A / biosynthesis
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism*
  • Longevity / genetics
  • Mice
  • Mice, Transgenic
  • Mitochondria
  • Nuclear Proteins / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Progeria / genetics
  • Protein Isoforms
  • Protein Precursors / genetics
  • Signal Transduction
  • Transcription Factors / metabolism

Substances

  • Intercellular Signaling Peptides and Proteins
  • Lamin Type A
  • Lmna protein, mouse
  • Nuclear Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Protein Isoforms
  • Protein Precursors
  • Sfrp5 protein, mouse
  • Transcription Factors
  • lamin C
  • prelamin A

Associated data

  • GEO/GSE51204