Using nuclear envelope mutations to explore age-related skeletal muscle weakness

Abstract

Skeletal muscle weakness is an important determinant of age-related declines in independence and quality of life but its causes remain unclear. Accelerated ageing syndromes such as Hutchinson-Gilford Progerin Syndrome, caused by mutations in genes encoding nuclear envelope proteins, have been extensively studied to aid our understanding of the normal biological ageing process. Like several other pathologies associated with genetic defects to nuclear envelope proteins including Emery-Dreifuss muscular dystrophy, Limb-Girdle muscular dystrophy and congenital muscular dystrophy, these disorders can lead to severe muscle dysfunction. Here, we first describe the structure and function of nuclear envelope proteins, and then review the mechanisms by which mutations in genes encoding nuclear envelope proteins induce premature ageing diseases and muscle pathologies. In doing so, we highlight the potential importance of such genes in processes leading to skeletal muscle weakness in old age.

Keywords: aging; nuclear envelopes; skeletal muscle.

Figure 1. A muscle nucleus connected to sarcomeres through nuclear membrane and cytoskeletal proteins

Chromatin (grey) is organised into exposed, transcriptionally active sections (euchromatin) and tightly packed, transcriptionally repressed sections located at nucleoli and the nuclear periphery (heterochromatin). Heterochromatin associates with DNA interaction proteins BAF and HDAC3, which associate with inner nuclear membrane (INM) proteins such as Emerin, and the nuclear lamina, which interacts with SUN 1/2. SUN 1/2 bind to Nesprins to form the LINC complex, which links the nucleus to actin, as well as microtubules and Desmin via Kinesin and Plectin, respectively. Desmin binds to the Z-disk of sarcomeres, completing the connection between nuclei and myofibrils. Through this network of proteins, transcriptional activity is responsive to cytoskeletal changes; INM, inner nuclear membrane, ONM, outer nuclear membrane.

Figure 2. Production of Lamin A, Progerin and Prelamin A from the LMNA gene

In normal cells, a series of post-translational modifications occurs to form Prelamin A, before cleavage by ZMPSTE24 to produce mature Lamin A. In ZMPSTE24-deficient cells, Prelamin A cannot be cleaved, leading to accumulation of this premature form of Lamin A. In Hutchinson–Gilford progerin syndrome (HGPS) cells, a 50 amino acid deletion removes the site where cleavage by ZMPSTE24 occurs, leading to accumulation of mutant farnesylated Prelamin A, named Progerin. Modified, with permission, from [52]. Enzymes required for the modification steps are in light blue.

Figure 3. Hypothetical age-related defects in mechanotransduction in skeletal muscle fibres

(Left panel) In young, healthy skeletal muscle fibres, the LINC complex and its associated nuclear envelope proteins effectively transduce cytoskeletal forces to the nucleus to regulate signalling pathways, normal chromatin organisation and gene expression. (Right panel) In aged skeletal muscle, the content or distribution of the LINC complex and its associated proteins may be altered, leading to defective mechanotransduction and a gene transcription that may affect expression of contractile proteins.