Global and local tension measurements in biomimetic skeletal muscle tissues reveals early mechanical homeostasis

Hofemeier, Arne D.; Limon, Tamara; Muenker, Till M.; Wallmeyer, Bernhard; Jurado, Alejandro; Afshar, Mohammad Ebrahim; Ebrahimi, Majid; Gilbert, Penney M.; Betz, Timo

doi:10.1101/2020.06.24.164988

Cited by 6 publications

(18 citation statements)

References 56 publications

(82 reference statements)

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“…Typical values of muscle tension are 675 ± 123 Pa (mean ± SD, n=8) during single twitch stimulation, and 871 ± 114 Pa during tetanic stimulation. Other studies reported slightly higher twitch tensions between 1-2 kPa for micro-tissues grown from C2C12 skeletal muscle cells (20,21), and 1.7 kPa for micro-tissues grown from satellite cells (35). For comparison, intact soleus (SOL) and extensor digitorum longus (EDL) muscles of young/adult mice generate tetanic tensions of around 150-220 kPa (SOL) and 200-240 kPa (EDL), respectively (37)(38)(39).…”

Section: Discussionmentioning

confidence: 98%

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The desmin mutation R349P increases contractility and fragility of stem cell-generated muscle micro-tissues

Spoerrer

Kah

Gerum

et al. 2021

Preprint

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Desminopathies comprise hereditary myopathies and cardiomyopathies caused by mutations in the intermediate filament protein desmin that lead to severe and often lethal degeneration of striated muscle tissue. Animal and single cell studies hinted that this degeneration process is associated with massive ultrastructural defects correlating with increased susceptibility of the muscle to acute mechanical stress. The underlying mechanism of mechanical susceptibility, and how muscle degeneration develops over time, however, has remained elusive. Here, we investigated the effect of a desmin mutation on the formation, differentiation, and contractile function of in vitro-engineered three-dimensional micro-tissues grown from muscle stem cells (satellite cells) isolated from heterozygous R349P desmin knock-in mice. Micro-tissues grown from desmin-mutated cells exhibited spontaneous unsynchronized contractions, higher contractile forces in response to electrical stimulation, and faster force recovery compared to tissues grown from wild-type cells. Within one week of culture, the majority of R349P desmin-mutated tissues disintegrated, whereas wild-type tissues remained intact over at least three weeks. Moreover, under tetanic stimulation lasting less than five seconds, desmin-mutated tissues partially or completely ruptured, whereas wild-type tissues did not display signs of damage. Our results demonstrate that the progressive degeneration of desmin-mutated micro-tissues is closely linked to extracellular matrix fiber breakage associated with increased contractile forces and unevenly distributed tensile stress. This suggests that the age-related degeneration of skeletal and cardiac muscle in patients suffering from desminopathies may be similarly exacerbated by mechanical damage from high-intensity muscle contractions. We conclude that micro-tissues may provide a valuable tool for studying the organization of myocytes and the pathogenic mechanisms of myopathies.

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Section: Discussionmentioning

confidence: 98%

“…The force generation of this tissue can be measured by the deflection of the flexible pillars. 3-D microtissues grown from skeletal muscle cell sources can thus be used as a platform for studying physiological and mechanical properties of muscles (20,21), for drug testing (22,23), and for disease modeling (23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

The desmin mutation R349P increases contractility and fragility of stem cell-generated muscle micro-tissues

Spoerrer

Kah

Gerum

et al. 2021

Preprint

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“…As recently reported, all of these cell lines are capable of forming functional biomimetic skeletal muscle tissues within 3D protein scaffolds by self-organizing around two vertical posts [42,17] . With these human immortalized myoblast cell lines from healthy and DMD backgrounds, and our previously developed glass bottom chamber for high resolution imaging [22] , we cultured bioengineered skeletal muscles within a 3D fibrin-Geltrex™ scaffold over two weeks (Figure 1 a-d). All of the human immortalized cell lines self-organized nicely to form tissues around the two posts (Figure 1 e).…”

Section: Myotube and Muscle Tissue Morphology Is Dependent On Dystrophinmentioning

confidence: 99%

Dystrophin is a mechanical tension modulator

Hofemeier

Muenker

Herkenrath

et al. 2022

Preprint

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Duchenne muscular dystrophy (DMD) represents the most common inherited muscular disease, where increasing muscle weakness leads to loss of ambulation and premature death. DMD is caused by mutations in the dystrophin gene, and is known to reduce the contractile capacity of muscle tissue both in vivo, and also in reconstituted systems in vitro. However, these observations result from mechanical studies that focused on stimulated contractions of skeletal muscle tissues. Seemingly paradoxical, upon evaluating bioengineered skeletal muscles produced from DMD patient derived myoblasts we observe an increase in unstimulated contractile capacity that strongly correlates with decreased stimulated tissue strength, suggesting the involvement of dystrophin in regulating the baseline homeostatic tension level of tissues. This was further confirmed by comparing a DMD patient iPSC line directly to the gene-corrected isogenic control cell line. From this we speculate that the protecting function of dystrophin also supports cellular fitness via active participation in the mechanosensation to achieve and sustain an ideal level of tissue tension. Hence, this study provides fundamental novel insights into skeletal muscle biomechanics and into a new key mechanical aspect of DMD pathogenesis and potential targets for DMD drug development: increased homeostatic tissue tension.

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“…Elastic beads as pressure sensors. A custom made 37 water-in-oil emulsion was used to prepare the inert PAA beads of Young's modulus E = 3.9 ± 0.9 kPa, by injecting the water-based bead mix in oil dissolved in n-Hexane (Supelco). The PAA beads were fluorescently labelled (Atto 488 NHS-Ester, Atto-Tec) several times until sufficient fluorescent signal was achieved.…”

Section: Mean Squared Displacement (Msd)mentioning

confidence: 99%

Pressure drives rapid burst-like collective migration from 3D cancer aggregates

Raghuraman

Schubert

Bröker

et al. 2021

Preprint

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Collective migration of cells is a key behaviour observed during morphogenesis, wound healing and cancer cell invasion. Hence, understanding the different aspects of collective migration is at the core of further progress in describing and treating cancer and other pathological defects. The standard dogma in cell migration is that cells exert forces on the environment to move and cell-cell adhesion-based forces provide the coordination for collective migration. Here, we report a new collective migration mechanism that is independent of pulling forces on the extra-cellular matrix (ECM), as it is driven by the pressure difference generated inside model tumours. We observe a striking collective migration phenotype, where a rapid burst-like stream of HeLa cervical cancer cells emerges from the 3D aggregate embedded in matrices with low collagen concentration (0.5 mg ml−1). This invasion-like behaviour is recorded within 8 hours post embedding (hpe), and is characterised by high cell velocity and super-diffusive collective motion. We show that cellular swelling, triggered by the soft matrix, leads to a rise in intrinsic pressure, which eventually drives an invasion-like phenotype of HeLa cancer aggregates. These dynamic observations provide new evidence that pressure-driven effects need to be considered for a complete description of the mechanical forces involved in collective migration and invasion.

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Global and local tension measurements in biomimetic skeletal muscle tissues reveals early mechanical homeostasis

Cited by 6 publications

References 56 publications

The desmin mutation R349P increases contractility and fragility of stem cell-generated muscle micro-tissues

The desmin mutation R349P increases contractility and fragility of stem cell-generated muscle micro-tissues

Dystrophin is a mechanical tension modulator

Pressure drives rapid burst-like collective migration from 3D cancer aggregates

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