Abstract
Muscle biomechanics relies on active motor protein assembly and passive strain transmission through cytoskeletal structures. The desmin filament network aligns myofibrils at the z-discs, provides nuclear–sarcolemmal anchorage and may also serve as memory for muscle repositioning following large strains. Our previous analyses of R349P desmin knock-in mice, an animal model for the human R350P desminopathy, already depicted pre-clinical changes in myofibrillar arrangement and increased fiber bundle stiffness. As the effect of R349P desmin on axial biomechanics in fully differentiated single muscle fibers is unknown, we used our MyoRobot to compare passive visco-elasticity and active contractile biomechanics in single fibers from fast- and slow-twitch muscles from adult to senile mice, hetero- or homozygous for the R349P desmin mutation with wild type littermates. We demonstrate that R349P desmin presence predominantly increased axial stiffness in both muscle types with a pre-aged phenotype over wild type fibers. Axial viscosity and Ca-mediated force were largely unaffected. Mutant single fibers showed tendencies towards faster unloaded shortening over wild type fibers. Effects of aging seen in the wild type appeared earlier in the mutant desmin fibers. Our single-fiber experiments, free of extracellular matrix, suggest that compromised muscle biomechanics is not exclusively attributed to fibrosis but also originates from an impaired intermediate filament network.
Highlights
Skeletal muscle is the largest organ system of the body and under constant mechanical axial and lateral stress, either due to passive strain or through active contraction
Unlike caffeine-induced force, maximum Ca2+-saturated force was unchanged in extensor digitorum longus (EDL) single fibers, regardless of age or genotype (Figure 1C)
Within SOL fibers, no difference among genotypes was seen, while age had a strong negative effect on force amplitudes, which were significantly reduced in wt preparations through age, and in het/hom fibers between the adult and the senile age group
Summary
Skeletal muscle is the largest organ system of the body and under constant mechanical axial and lateral stress, either due to passive strain or through active contraction. Due to its intrinsic self-assembling properties, it builds three-dimensional networks, starting with supercoil formation via dimerization of two desmin molecules. Two such dimers associate into tetramers that represent the repetitive add-on units for spontaneous assembly to 60 nm long filaments, the so-called unit-length filaments (ULFs [8]). Long filaments reduce their diameter by spontaneous radial compaction to form the mature IF network. This network connects to multiple intracellular adhesion sites by cross-bridging proteins from the spectrin superfamily, i.e., plectin and nesprins [9]
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