LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

Abstract

Skeletal muscle demonstrates a high degree of adaptability in response to changes in mechanical input. The phenotypic transformation in response to mechanical cues includes changes in muscle mass and force generating capabilities, yet the molecular pathways that govern skeletal muscle adaptation are still incompletely understood. While there is strong evidence that mechanotransduction pathways that stimulate protein synthesis play a key role in regulation of muscle mass, there are likely additional mechano-sensitive mechanisms important for controlling functional muscle adaptation. There is emerging evidence that the cell nucleus can directly respond to mechanical signals (i.e., nuclear mechanotransduction), providing a potential additional level of cellular regulation for controlling skeletal muscle mass. The importance of nuclear mechanotransduction in cellular function is evident by the various genetic diseases that arise from mutations in proteins crucial to the transmission of force between the cytoskeleton and the nucleus. Intriguingly, these diseases preferentially affect cardiac and skeletal muscle, suggesting that nuclear mechanotransduction is critically important for striated muscle homeostasis. Here we discuss our current understanding for how the nucleus acts as a mechanosensor, describe the main cytoskeletal and nuclear proteins involved in the process, and propose how similar mechanoresponsive mechanisms could occur in the unique cellular environment of a myofiber. In addition, we examine how nuclear mechanotransduction fits into our current framework for how mechanical stimuli regulates skeletal muscle mass.

Nuclear SUN1 stabilizes endothelial cell junctions via microtubules to regulate blood vessel formation

“…The LINC complex is important for mechanotransduction in muscle fibers with high mechanical loads ( van Ingen and Kirby, 2021 ), and sprouting angiogenesis is regulated by mechanical forces arising from blood pressure and blood flow ( Huang et al, 2003 ). To determine whether SUN1 also regulates sprouting dynamics under laminar flow in vivo, we analyzed embryonic zebrafish using a Tg(fli:LifeAct-GFP ) reporter that labels the endothelial actin cytoskeleton.…”

“…Global Sun2 loss affects epidermal nuclear positioning and cell adhesion, leading to alopecia ( Stewart et al, 2015 ), while global loss of both Sun genes impairs epidermal differentiation due to altered integrin signaling ( Carley et al, 2021 ). A role for the LINC complex in mechanotransduction in vivo is suggested by findings that perturbations in mechanically active skeletal and cardiac muscle affect function ( Zhang et al, 2005 ; Zhang et al, 2010 ; Lei et al, 2009 ; Banerjee et al, 2014 ; Stroud et al, 2017 ; Zhou et al, 2017 ; van Ingen and Kirby, 2021 ). However, while global deletion of multiple LINC components that disrupt the entire complex highlight its importance ( Lei et al, 2009 ; Zhang et al, 2009 ; Carley et al, 2021 ), these studies do not reveal functions of individual LINC components in specific tissues.…”

Nuclear SUN1 Stabilizes Endothelial Cell Junctions via Microtubules to Regulate Blood Vessel Formation

“…The LINC complex is important for mechanotransduction in muscle fibers with high mechanical loads (van Ingen & Kirby, 2021), and sprouting angiogenesis is regulated by mechanical forces arising from blood pressure and blood flow (Huang et al, 2003). To determine whether SUN1 also regulates sprouting dynamics under laminar flow in vivo , we analyzed embryonic zebrafish using a Tg(fli:LifeAct-GFP) reporter that labels the endothelial actin cytoskeleton.…”

“…Global Sun2 loss affects epidermal nuclear positioning and cell adhesion, leading to alopecia (Stewart et al, 2015), while global loss of both Sun genes impairs epidermal differentiation due to altered integrin signaling (Carley et al, 2021). A role for the LINC complex in mechanotransduction in vivo is suggested by findings that perturbations in mechanically active skeletal and cardiac muscle affect function (Zhang et al, 2005, 2010; Lei et al, 2009; Banerjee et al, 2014; Stroud et al, 2017; Zhou et al, 2017; van Ingen & Kirby, 2021). However, while global deletion of multiple LINC components to disrupt the entire complex highlight its importance (Lei et al, 2009; Zhang et al, 2009; Carley et al, 2021), these studies do not reveal functions of individual LINC components in specific tissues.…”

A Multisensory Network Drives Nuclear Mechanoadaptation

“…These pathologies frequently involve malfunctioning of mechanically challenged tissues. Typical pathologies where these pathways are altered include, cardiovascular disease [168], muscular dystrophies [169,170], lipodystrophies [171] and progeria [172]. Thus, it is important to understand the molecular mechanisms by which these proteins function in response to mechanical signals.…”