Preaged remodeling of myofibrillar cytoarchitecture in skeletal muscle expressing R349P mutant desmin

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

“…Our previous work in small fiber bundles from SOL muscles demonstrated an increased axial stiffness in R349P desmin knock-in mice Diermeier et al (2017a); Haug et al (2019) . However, since we also documented increased fibrosis in these muscles Diermeier et al (2017a) , it cannot be ruled out to which extent the observed fibrosis would impact on the increased axial stiffness. To eliminate the influence of ECM components on biomechanics recordings, a preparation of single fibers represented the best possible experimental solution.…”

“…Again, our findings in young animals of increased tissue stiffness were confirmed in both muscle entities with a pre-aged phenotype in the desminopathy model. However, since also ECM re-modeling has been shown with increased levels of tissue fibrosis with age in the R349P background Diermeier et al (2017a) , an unambiguous explanation towards the link of increased axial stiffness to the disrupted desmin network could not be drawn. This is because in small fiber bundles, both the ECM and the intracellular cytoskeleton still contribute to the overall axial compliance.…”

“…Therefore, a patient-mimicking knock-in mouse strain carrying the R349P desmin mutation, the murine orthologous of the human R350P mutation, was generated Clemen et al (2015) . This model already allowed detailed systematic studies of clinical and myopathological phenotypes as well as age-dependent effects on the disease progression in heterozygous (het) and homozygous (hom) desminopathy mice over their wild-type (wt) littermates Diermeier et al (2017a) . In particular, our previous work demonstrated that the expression of R349P mutated desmin compromised the three-dimensional arrangement and the order of the myofibrillar lattice already starting in young mice before presenting muscle.…”

“…The latter findings were interpreted as a pre-aged phenotype of muscle structural ageing in the R349P environment Diermeier et al (2017b) . Moreover, biomechanical analyses of small fiber bundles, initially in slow-twitch, load-bearing M. soleus (SOL) from young het and hom R349P desmin mice, showed a marked increase in passive bundle stiffness compared to wt bundles Clemen et al (2015); Diermeier et al (2017a) . Since robust biomechanical experiments in small muscle fiber bundle preparations are difficult to carry out and require precise actuation to record steady-state resting length tension curves at slow strain speeds, we engineered a novel automated biomechatronics system that also contains a sensitive force transducer technology for recordings of active and passive axial muscle forces Haug et al (2018) .…”

Imbalances in protein homeostasis caused by mutant desmin

“…The term ‘desminopathies’ refers to a clinically heterogeneous group of familial and sporadic myopathies and cardiomyopathies that are caused by mutations of the human desmin ( DES ) gene on chromosome 2q35. Desmin, the muscle‐specific intermediate filament protein, is a major component of the three‐dimensional extrasarcomeric cytoskeleton, which exerts multiple roles in the alignment and anchorage of myofibrils, the positioning of mitochondria and myonuclei, mechanosensation, stress endurance and cell signalling . The vast majority of desminopathies follows an autosomal‐dominant trait of inheritance; the few autosomal‐recessive cases may be subdivided in cases with maintained expression of mutant desmin and others with a complete lack of desmin .…”