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.
Highlights
Intermediate filaments (IFs) contribute to force transmission, cellular integrity, and signaling in skeletal muscle
IFs are classified into major families, with types I–IV localized in the cytoplasm, type V comprised of the lamins inside the nucleus, and type VI comprised of neural and lens proteins
Because gene expression is dependent on chromatin organization (Nava et al, 2020), which can be affected by interaction with the lamina or directly by the application of force, it is likely that muscle development and homeostasis are closely tied to the mechanical state of the cell (Bronshtein et al, 2015)
Summary
Intermediate filaments (IFs) contribute to force transmission, cellular integrity, and signaling in skeletal muscle. To support the large cytoplasm in the skeletal myofiber, the nuclei are evenly positioned along the cell periphery to maximize the distance between nuclei (Bruusgaard et al, 2006) This even spatial distribution of nuclei minimizes transport distances, such that each nucleus regulates the gene products in a fixed volume of a muscle fiber, a concept known as the myonuclear domain (Hall and Ralston, 1989). Each nucleus contributes to the organization of the myofiber cytoskeleton, but importantly the nuclei throughout a single fiber act as cellular mechano-sensors (Cho et al, 2017). Nuclear spatial distribution distributes the “centers” that organize the cytoskeleton and mechanical hubs that are critical mechanical sensors and responders These hubs are integrated with the force-producing myofibrils through the cytoplasmic IF network (Roman and Gomes, 2018). Understanding the individual contributions of distinct IF networks and how these distinct pathways interact is critical to understanding muscle weakness with aging and disease
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