Understanding how LINC complex mediated signaling regulates satellite stem and progenitor cell cycle

McKee-Muir, Olivia (1), Moyle, Louise (2), Cancelliere, Sabrina (2), Montgomery-Song, Aaryn (2), Gilbert, Penney (2)

(1) Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

(2) Institute of Biomaterials and Biomedical Engineering, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

Emery-Dreifuss Muscular Dystrophy (EDMD) is a disease characterized by progressive skeletal muscle wasting and cardiomyopathy. This disease is linked to several mutations in genes that encode proteins forming the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. The LINC complex creates a bridge across the nuclear membranes to link the cytoskeleton to the nuclear lamina. In this complex, KASH (Klarsicht/ANC-1/Syne homology) domain proteins, positioned at the outer nuclear membrane, interact with SUN (Sad1/UNC84) domain proteins found at the inner nuclear membrane. KASH domain proteins also interact with cytoplasmic actin filaments, while SUN domain proteins bind the nuclear lamina, which is intimately associated with chromatin. Recent work demonstrated that the LINC complex can transduce physical cues from the extracellular matrix into changes in gene expression. Indeed, the complex, under tension, can open inaccessible regions of the genome permitting the transcription of genes that are otherwise silenced. Our prior work showed that the satellite cell (SC) niche undergoes dynamic changes in physical properties, and we speculate that this may serve to modulate the SC transcriptome in a LINC complex dependent manner. Using dominant negative and siRNA approaches, we find that disrupting the LINC complex in muscle fiber associated SCs and myoblasts alters proliferation in culture and regenerative potential in vivo. These striking observations suggest that EDMD may be a SC myopathy. Current studies are aimed at uncovering the cellular and molecular mechanisms through which the LINC complex modulates the satellite cell and myoblast cell cycle to identify new therapeutic entry-points to treat EDMD.