ORCID Profile
0000-0001-5913-1070
Current Organisation
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/JCS.244111
Abstract: RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS is the most frequently mutated oncogene. Here we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidyl serine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by a structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied rocaglamide-mediated effects on RAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and treatment with rocaglamide reduces NSCLC tumours in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2019
DOI: 10.1038/S41598-019-46723-6
Abstract: Mutations in the Des gene coding for the muscle-specific intermediate filament protein desmin lead to myopathies and cardiomyopathies. We previously generated a R349P desmin knock-in mouse strain as a patient-mimicking model for the corresponding most frequent human desmin mutation R350P. Since nothing is known about the age-dependent changes in the biomechanics of affected muscles, we investigated the passive and active biomechanics of small fiber bundles from young (17–23 wks), adult (25–45 wks) and aged ( wks) heterozygous and homozygous R349P desmin knock-in mice in comparison to wild-type littermates. We used a novel automated biomechatronics platform, the MyoRobot , to perform coherent quantitative recordings of passive (resting length-tension curves, visco-elasticity) and active (caffeine-induced force transients, pCa-force, ‘slack-tests’) parameters to determine age-dependent effects of the R349P desmin mutation in slow-twitch soleus and fast-twitch extensor digitorum longus small fiber bundles. We demonstrate that active force properties are not affected by this mutation while passive steady-state elasticity is vastly altered in R349P desmin fiber bundles compatible with a pre-aged phenotype exhibiting stiffer muscle preparations. Visco-elasticity on the other hand, was not altered. Our study represents the first systematic age-related characterization of small muscle fiber bundle preparation biomechanics in conjunction with inherited desminopathy.
Publisher: MDPI AG
Date: 31-07-2020
DOI: 10.3390/IJMS21155501
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 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.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BIOS.2019.04.052
Abstract: We present an enhanced version of our previously engineered MyoRobot system for reliable, versatile and automated investigations of skeletal muscle or linear polymer material (bio)mechanics. That previous version already replaced strenuous manual protocols to characterize muscle biomechanics properties and offered automated data analysis. Here, the system was further improved for precise control over experimental temperature and muscle single fiber sarcomere length. Moreover, it also now features the calculation of fiber cross-sectional area via on-the-fly optical diameter measurements using custom-engineered microscope optics. With this optical systems integration, the MyoRobot 2.0 allows to tailor a wealth of recordings for relevant physiological parameters to be sequentially executed in living single myofibers. Research questions include assessing temperature-dependent performance of active or passive biomechanics, or automated control over length-tension or length-velocity relations. The automatically obtained passive stress-strain relationships and elasticity modules are important parameters in (bio)material science. From the plethora of possible applications, we validated the improved MyoRobot 2.0 by assessing temperature-dependent myofibrillar Ca
Publisher: EMBO
Date: 26-07-2018
Publisher: American Geophysical Union (AGU)
Date: 08-2019
DOI: 10.1029/2019JB017589
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.BIOS.2017.12.003
Abstract: We engineered an automated biomechatronics system, MyoRobot, for robust objective and versatile assessment of muscle or polymer materials (bio-)mechanics. It covers multiple levels of muscle biosensor assessment, e.g. membrane voltage or contractile apparatus Ca
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5SM03114A
Abstract: Granular heaps of particles created by deposition of mono-disperse particles raining from an extended source of finite size are characterized by a non-homogeneous field of density. It was speculated that this inhomogeneity is due to the transient shape of the sediment during the process of construction of the heap, thus reflecting the history of the creation of the heap. By comparison of structural characteristics of the heap with sediments created on top of inclined planes exploiting the method of Minkowski tensors, we provide further evidence to support this hypothesis. Moreover, for the case of sediments generated by homogeneous rain on surfaces, we provide relationships between the inclination of the surface and the Minkowski measures characterizing the isotropy of local particle environments.
No related grants have been discovered for Thorsten Pöschel.