In Vivo Multiscale and Spatially-Dependent Biomechanics Reveals Differential Strain Transfer Hierarchy in Skeletal Muscle

Abstract

Biological tissues have a complex hierarchical architecture that spans organ to subcellular scales and comprises interconnected biophysical and biochemical machinery. Mechanotransduction, gene regulation, gene protection, and structure-function relationships in tissues depend on how force and strain are modulated from macro to micro scales, and vice versa. Traditionally, computational and experimental techniques have been used in common model systems (e.g., embryos) and simple strain measures were applied. But the hierarchical transfer of mechanical parameters like strain in mammalian systems is largely unexplored in vivo. Here, we experimentally probed complex strain transfer processes in mammalian skeletal muscle tissue over multiple biological scales using complementary in vivo ultrasound and optical imaging approaches. An iterative hyperelastic warping technique quantified the spatially-dependent strain distributions in tissue, matrix, and subcellular (nuclear) structures, and revealed a surprising increase in strain magnitude and heterogeneity in active muscle as the spatial scale also increased. The multiscale strain heterogeneity indicates tight regulation of mechanical signals to the nuclei of individual cells in active muscle, and an emergent behavior appearing at larger (e.g. tissue) scales characterized by dramatically increased strain complexity.

Deformation microscopy for dynamic intracellular and intranuclear mapping of mechanics with high spatiotemporal resolution

“…Skeletal muscle of the Lmna -/- mice show compromised nuclear phenotype. We applied a neuromuscular stimulation in vivo to quantify the nuclear strain in skeletal muscle as described previously ( 36 ). Briefly, anesthetized animals were kept in supine position and their gastrocnemius was exposed.…”

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

“…Recently, an emerging technique—deformation microscopy—has revealed high‐resolution strain maps of cells under deformation in vitro and in vivo, thus providing mechanistic insight into nuclear mechanics with compromised intracellular components, such as lamin A/C and the linker of nucleoskeleton and cytoskeleton complexes. [ 12,13 ] However, because the distribution of deforming loads within a cell is unknown, discriminating the intrinsic role of the nuclear modulus remains difficult.…”

Nuclear envelope mechanobiology: linking the nuclear structure and function

“…Spatial mapping of deformation within the nucleus is accomplished using fluorescence anisotropy [160] and texture correlation [153,161]. Recently, deformation microscopy, based on hyperelastic warping and deformable image registration [155], demonstrated the ability to map biophysical and biochemical interactions due to substrate stiffness or hyperosmotic changes, or LINC disruption treatments, and have been used broadly to describe the mechanics of nuclei in cardiomyocytes, chondrocytes, and skeletal muscle in vivo [155,161,162]. Additionally, detailed strain patterns have been associated with distinct epigenetic modifications that impact development [163].…”