The toxic effect of R350P mutant desmin in striated muscle of man and mouse

Abstract

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1363-2) contains supplementary material, which is available to authorized users.

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

“…In agreement with our immunoblotting results (Fig. 4c, right panel; and [16]), the quantitative mass spectrometry data showed that the R349P mutant desmin protein levels were markedly reduced to 10 % in homozygous mice.…”

“…Desmin immunoblotting confirmed a markedly decreased level of mutant desmin in homozygous mice. In heterozygous mice the obtained signal is composed of the signals from both R349 wild-type and P349 mutant desmin, as previously demonstrated by high resolution SDS-PAGE and immunoblotting [16]. GAPDH immunoblotting and Coomassie stained SDS-PAGE gels were used as loading controls…”

Intermediate filaments and cellular mechanics

“…These results showed that mutated desmin compromises filament-formation competence (Schr€ oder et al, 2007;Schr€ oder and Schoser, 2009;Clemen et al, 2015). The influence of desmin mutations was described from transfection experiments and in vitro assembly studies, indicating that the majority of desmin rod mutants are either incapable of forming de novo desmin IF networks, or constitute abnormal IF structures, or induce the collapse of a preexisting IF network that leads to desmin-positive protein aggregates.…”

“…Since severe structural changes were most prominent in striated muscles, it was concluded that the lack of desmin results in an increased susceptibility of muscle fibers to physical strain during muscle contraction (Milner et al, 1996;Clemen et al, 2015). Since severe structural changes were most prominent in striated muscles, it was concluded that the lack of desmin results in an increased susceptibility of muscle fibers to physical strain during muscle contraction (Milner et al, 1996;Clemen et al, 2015).…”

Association of Heart Rate Turbulence With Arrhythmia Susceptibility and Heart Disease in Mice

“…In cardiac high‐risk patients, however, these sinus rhythm changes after VPCs are absent, indicating the missing cardioprotective effect of vagal nerve activation . In the present animal study, we investigated inducible VTs as a surrogate for general arrhythmogenesis in mouse models, according to previously established EP protocols . Both HRT parameters, TO and particularly TS, were significantly associated with ventricular electrical vulnerability.…”