Why the study?
The effect of R349P desmin on axial biomechanics in fully differentiated single muscle fibers was unknown.
Does the R349P desmin mutation alter passive visco-elasticity and active contractile biomechanics in single muscle fibers of mice?
Does the R349P desmin mutation alter passive visco-elasticity and active contractile biomechanics in single muscle fibers of mice?
The R349P desmin mutation increases axial stiffness in single muscle fibers, suggesting that compromised muscle biomechanics in desminopathy originates from an impaired intermediate filament network rather than exclusively from fibrosis.
Preclinical myofibrillar changes in desmin knock-in mice warrant caution in human extrapolation; leaves open clinical translation.
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 Ca2+-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.
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Pollmann et al. (2020) studied this question.
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