Intermediate Filament and Ecm Mechanics Deduced from Desmin Knockout Muscles

Abstract

Desmin is the skeletal muscle intermediate filament protein that forms a mesh-like network around Z-disks and helps transmit force to the extracellular matrix (ECM). It generally functions as a mechanical integrator of the cell, maintaining lattice connectivity and enabling efficient force transmission. Desmin related myopathies have debilitating effects that range from muscle weakness and atrophy to cardiac and respiratory failure. Studies performed on desmin knockout muscles have begun to elucidate the physiological and biological roles of desmin, but the mechanical properties of the desmin network are still unknown.We performed incremental stress-relaxation tests on fibers and fiber bundles from desmin knockout and wildtype mouse EDL muscles to investigate how the absence of desmin affects the fiber and fiber bundle viscoelastic properties. Using these data, we developed a structural model with explicit elastic and viscous elements representing the desmin, the rest of the fiber and the ECM. Single fibers from desmin knockout muscles were significantly more compliant (linear modulus = 122±61 kPa) compared to wildtype fibers (176±49 kPa, p<0.05). These data demonstrate that the desmin matrix bears 30-40% of the passive load in muscle cells, a much greater fraction than previously believed. In contrast to fibers, bundles of fibers were nonlinear and demonstrated the opposite trend_bundles from desmin knockout muscles were over twice as stiff (440±237 kPa) compared to wildtype bundles (214±97 kPa) at 60% strain (p<0.0001). Time constants for stress-relaxation were larger for fibers than bundles and were significantly larger for knockout bundles compared to wildtype bundles. These data suggest a biological and biomechanical interaction between muscle cells and the ECM and may indicate that the ECM becomes stiffer in desmin knockout muscles in response to the more compliant fibers.