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. Synopsis The LMNA gene encodes functionally distinct isoforms that have opposite effects on energy metabolism and lifespan. Mice expressing lamin C only are obese and have an extended lifespan, whereas mice expressing progerin are lean and die early. Mice exclusively expressing the lamin C isoform exhibit decreased energy metabolism and mitochondrial activity. Exclusive lamin C expression in mice results in an increased lifespan and weight gain. Progerin-expressing mice present a higher energy metabolism and are lipodystrophic. Key modulators of energy expenditure are inversely regulated in lamin C- and progerin-expressing mice. The LMNA gene encodes functionally distinct isoforms that have opposite effects on energy metabolism and lifespan. Mice expressing lamin C only are obese and have an extended lifespan, whereas mice expressing progerin are lean and die early. © 2014 The Authors.