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.

Do lamin A and lamin C have unique roles?

“…4b). Noteworthy, recently, it has been shown that LMNA isoforms lamin C and progerin have distinct and opposite functions regarding energy expenditure and lifespan (Lopez-Mejia et al 2014). There are other examples of other protein isoforms that differ in several biological aspects despite being generated from the same gene (reviewed in Stamm et al 2005).…”

Modulation of LMNA splicing as a strategy to treat prelamin A diseases

“…A deficiency of both lamin A and lamin C causes death in mice from muscular dystrophy/cardiomyopathy (12), but the elimination of lamin C synthesis alone or lamin A synthesis alone has no obvious adverse effects (13)(14)(15). For example, "lamin C-only" knockin mice, in which all of the output of the Lmna gene is channeled into the production of lamin C, are free of disease phenotypes and have a normal life span (13).…”

Comparison of expression levels of fourteen genes involved in the lipid and energy metabolism in two pig breeds

“…The majority of the genes selected, such as PLIN2, SORT1, PLIN1, MTTP, ACACA, ACLY, ENO3, FASN, ACVR1C, PLTP and CES3 are well known for their role in energy and lipid metabolism (Supplementary Table S1), while LMNA, INSIG2 and NAMPT are not directly involved in lipid metabolism but have already been considered in other species for a putative role in adipogenesis or lipid metabolism. LMNA, whose main role is related to nuclear stability and chromatin structure, also has a putative role in fat deposition (Verstraeten et al, 2011;Lopez-Mejia et al, 2014) and for this reason was included among the genes selected. Furthermore, INSIG2 was reported by Malzahn et al (2014) as a gene associated with the body mass index in humans, even if this association is still under debate.…”