The Nucleoskeleton: Crossroad of Mechanotransduction in Skeletal Muscle

Abstract

Intermediate filaments (IFs) are a primary structural component of the cytoskeleton extending throughout the muscle cell (myofiber). Mechanotransduction, the process by which mechanical force is translated into a biochemical signal to activate downstream cellular responses, is crucial to myofiber function. Mechanical forces also act on the nuclear cytoskeleton, which is integrated with the myofiber cytoskeleton by the linker of the nucleoskeleton and cytoskeleton (LINC) complexes. Thus, the nucleus serves as the endpoint for the transmission of force through the cell. The nuclear lamina, a dense meshwork of lamin IFs between the nuclear envelope and underlying chromatin, plays a crucial role in responding to mechanical input; myofibers constantly respond to mechanical perturbation via signaling pathways by activation of specific genes. The nucleus is the largest organelle in cells and a master regulator of cell homeostasis, thus an understanding of how it responds to its mechanical environment is of great interest. The importance of the cell nucleus is magnified in skeletal muscle cells due to their syncytial nature and the extreme mechanical environment that muscle contraction creates. In this review, we summarize the bidirectional link between the organization of the nucleoskeleton and the contractile features of skeletal muscle as they relate to muscle function.

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

“…We hypothesized that STIM1 has an essential role in nuclear-cytosolic connectivity and interacts with proteins of the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex is composed of several proteins that span the nuclear envelope and include lamin A/C in the nuclear lamina, Sad1 and UNC84 domain–containing proteins (SUN1/2) of the inner nuclear membrane (INM), and Kash/Nesprin proteins of the outer nuclear membrane (ONM) ( 13 ). Compromise of the nuclear-cytosolic connectivity can influence nuclear morphology, induce apoptosis, and influence gene expression, as occurs in Emery Dreifuss muscular dystrophy (EDMD) and other laminopathies ( 14 ).…”

Heat Shock alters the distribution andin vivointeraction of major nuclear structural proteins – Lamin B with DNA Topoisomerase II, and with nucleic acids

“…Lamins are type V intermediate filament proteins which play a critical role in all nuclear functions in Metazoan starting from mechanical and organizational functions supporting nuclear envelope, nuclear lamina, nuclear pore complexes, chromatin structure and subnuclear compartmentalization as well as involvement (directly and/or indirectly) in replication, regulation of transcription, splicing, transport as well as a hub or platform for integrating nucleo-cytoplasmic signalling (Dechat et al, 2010). Lamins and interacting proteins are also directly involved in the positioning and transport of cell nuclei within cells as well as in mechanical properties of cell nuclei, mechanosensing (Osmanagic-Myers, Dechat and Foisner, 2015) and mechanotransduction of signals from other parts of the cell and extracellular matrix (Iyer, Folker and Lovering, 2021); (Donnaloja et al, 2020). All of these functions lamins play directly or indirectly by forming different protein complexes within different nuclear subcompartments.…”

Life at the crossroads: the nuclear LINC complex and vascular mechanotransduction

“…Here we provide a brief overview of the LINC complex, followed by a specific focus on its function in vascular endothelial cells. Other recent excellent reviews discuss the role of the LINC complex in non-vascular cells and in non-endothelial vascular cells ( Iyer et al, 2021 ; Salvador and Iruela-Arispe, 2022 ). The LINC complex consists of inner nuclear membrane-localized SUN (Sad1, UNC84) proteins that interact with lamin intermediate filaments in the nucleus and KASH (Klarsicht/ANC-1/Syne Homology) proteins in the outer nuclear membrane that in turn interact with the actin, microtubule, and intermediate filament cytoskeletons outside the nucleus ( Starr, 2019 ; McGillivary et al, 2023 ).…”