Neuromuscular endplate pathology in recessive desminopathies

Durmuş, Hacer; Ayhan, Özgecan; Çırak, Sebahattin; Deymeer, Feza; Parman, Yeşim; Franke, André; Eiber, Nane; Chevessier, Frédéric; Schlötzer‐Schrehardt, Ursula; Clemen, Christoph S.; Hashemolhosseini, Said; Schröder, Rolf; Hemmrich-Stanisak, Georg; Tolun, Aslıhan; Serdaroğlu-Oflazer, Piraye

doi:10.1212/wnl.0000000000003004

Cited by 27 publications

(37 citation statements)

References 15 publications

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“…While the vast majority of desminopathies show an autosomal-dominant trait of inheritance and displays morphological signs of protein aggregation pathology in striated muscle, the very rare autosomal-recessive cases can meanwhile be categorized in three distinct subforms: (1) one with the complete absence of desmin protein and no obvious protein aggregation pathology [4][5][6][7], (2) one with markedly reduced protein levels of solely mutant desmin without signs of protein aggregation [8], and (3) one with markedly reduced protein levels of solely mutant desmin but the presence of protein aggregation [9][10][11][12][13]. In contrast to the autosomaldominant cases, these recessive forms display a markedly more severe clinical phenotype and an earlier disease onset already starting in the first or second decade of life.…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies

et al. 2020

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Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wildtype desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 × 10 12 AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wildtype desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.

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Section: Introductionmentioning

confidence: 99%

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies

et al. 2020

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“…Rare cases of recessive myopathies have also been described with loss‐of‐function variants in DES . Two such patients additionally displayed evidence of impaired neuromuscular transmission . Both presented in infancy with delayed motor milestones and progressive generalized weakness, ptosis, and ophthalmoparesis.…”

Section: Hereditary Muscle Diseases With Neuromuscular Transmission Dmentioning

confidence: 98%

“…Salbutamol was effective in one patient, while pyridostigmine was ineffective in the other. A deleterious effect of desmin loss on neuromuscular junction integrity was demonstrated in mice homozygous for a common missense mutation in Des …”

Section: Hereditary Muscle Diseases With Neuromuscular Transmission Dmentioning

confidence: 99%

Trouble at the junction: When myopathy and myasthenia overlap

2019

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Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co‐occurrence of myasthenia gravis or Lambert‐Eaton myasthenic syndrome with an immune‐mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

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“…The deleterious effects of abnormal desmin IF networks, due to either the additional presence of mutant or the complete lack of wild-type desmin protein, are emphasized by the group of human desminopathies that comprise autosomal-dominantly and recessively inherited myopathies and cardiomyopathies Clemen et al (2013) . Human desminopathies are clinically characterized by a broad phenotypic variability ranging from primary distal myopathies, limb girdle muscular dystrophies and scapuloperoneal syndromes to generalized myopathies Walter et al (2007); Baer (2005); Clemen et al (2009); Durmuş et al (2016) . The major problem with elucidating pathophysiological mechanisms of the human phenotypes is that knowledge about early and intermediate stages of the disease is usually elusive, since muscle tissue specimens for research are not available from patients at pre-clinical stages.…”

Section: Introductionmentioning

confidence: 99%

Growing old too early, automated assessment of skeletal muscle single fiber biomechanics in ageing R349P desmin knock-in mice using the MyoRobot technology

Meyer

Haug

Reischl

et al. 2019

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Growing old too early, automated 1 assessment of skeletal muscle single 2 fiber biomechanics in ageing R349P 3 desmin knock-in mice using the 4 MyoRobot technology 5Abstract Muscle biomechanics is determined by active motor-protein assembly and passive 28 strain transmission through cytoskeletal structures. The extrasarcomeric desmin filament network 29 aligns myofibrils at the z-discs, provides nuclear-sarcolemmal anchorage and may also serve as 30 memory for muscle repositioning following large strains. Our previous analyses of R349P desmin 31 knock-in mice, an animal model for the human R350P desminopathy, already depicted pre-clinical 32 changes in myofibrillar arrangement and increased fiber bundle stiffness compatible with a 33 pre-aged phenotype in the disease. Since the specific effect of R349P desmin on axial 34 biomechanics in fully differentiated muscle fibers is unknown, we used our automated MyoRobot 35 biomechatronics platform to compare passive and active biomechanics in single fibers derived 36 from fast-and slow-twitch muscles from adult to senile mice hetero-or homozygous for this 37 desmin mutation with wild-type littermates. Experimental protocols involved caffeine-induced 38 Ca 2+ -mediated force transients, pCa-force curves, resting length-tension curves, visco-elasticity and 39 'slack-tests'. We demonstrate that the presence of R349P desmin predominantly increased single 40 fiber axial stiffness in both muscle types with a pre-aged phenotype over wild-type fibers. Axial 41 viscosity was unaffected. Likewise, no systematic changes in Ca 2+ -mediated force properties were 42 found. Notably, mutant single fibers showed faster unloaded shortening over wild-type fibers. 43 Effects of ageing seen in the wild-type always appeared earlier in the mutant desmin fibers. 44 Impaired R349P desmin muscle biomechanics is clearly an effect of a compromised intermediate 45 filament network rather than secondary to fibrosis. 46 47 48 Skeletal muscle is the largest organ system of the body and under constant mechanical stress, either 49 due to passive strain or through active contraction producing axial and lateral stresses. While lateral 50 forces are distributed between single fibers across anchorage points in the extracellular matrix 51 (ECM) to the intracellular cytoskeleton via the dystrophin-glycoprotein complex (DGC) Ramaswamy 52 et al. (2011) and focal adhesion complexes Ra et al. (1999), axial forces are distributed through 53 contractile (active) and non-contractile (passive) elements. Apart from the giant, roughly 1.5 m 54 long elastomeric protein titin, being responsible for the visco-elastic properties of single muscle 55 fibers through unfolding of globular domains under strain Mártonfalvi and Kellermayer (2014); 56 Powers et al. (2018), connecting proteins of the extra-sarcomeric intermediate filament (IF) family 57 may also be a vital determinant of axial elasticity. An important member of the IFs is the type 58 III filament protein desmin, transversely linking adjacent myofibri...

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Neuromuscular endplate pathology in recessive desminopathies

Cited by 27 publications

References 15 publications

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies

Trouble at the junction: When myopathy and myasthenia overlap

Growing old too early, automated assessment of skeletal muscle single fiber biomechanics in ageing R349P desmin knock-in mice using the MyoRobot technology

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