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R405W Desmin Knock-In Mice Highlight Alterations of Mitochondria, Protein Quality Control and Myofibrils in
Sabrina Batonnet-Pichon1,2, Florence Delort1, Alain Lilienbaum1
1Basic and Translational Myology, Unit of Functional and Adaptive Biology, Université Paris Cité/CNRS UMR 8251, Paris, France.
Background:
Mutations in the desmin gene cause skeletal myopathies and cardiomyopathies. The objective of this study was to elucidate the molecular pathology induced by the expression of R405W mutant desmin in murine skeletal muscle.
Methods:
A comprehensive characterization of the skeletal muscle pathology in hetero- and homozygous R405W desmin knock-in mice was performed. This included grip strength, blood acylcarnitine and amino acid, histological, ultrastructural, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing and proteomic analyses.
Results:
Both hetero- and homozygous R405W desmin knock-in mice showed classical myopathological features of a myofibrillar myopathy with desmin-positive protein aggregation, degenerative changes of the myofibrillar apparatus and mitochondrial alterations. Muscle weakness and increased blood concentrations of acylcarnitines and amino acids were only present in homozygous animals. During its translation, mutant desmin did not induce terminal ribosomal stalling. Analyses of RNA sequencing and proteomic data from soleus muscle of 3-month-old mice depicted 59 up- and 3 down-regulated mRNAs and 101 up- and 18 down-regulated proteins that were shared between the heterozygous and homozygous genotypes in the respective omics datasets compared to the wild-type genotype. Combined analysis of the omics data demonstrated 187 significantly dysregulated candidates distributed across four groups of regulation. A down-regulation on the mRNA and protein levels was observed for a multitude of mitochondrial proteins including essential proton gradient-dependent carriers. Up-regulation on both omics levels was present for the transcription factor Mlf1, which is a binding partner of protein quality control related Dnajb6. Down-regulated on mRNA but up-regulated on the protein level was the sarcomeric lesion marker Xirp2 (xin actin-binding repeat-containing protein 2), whereas Ces2c (acylcarnitine hydrolase) was regulated in the opposite way.
Conclusions:
The present study demonstrates that the expression of mutant desmin results in a myofibrillar myopathy in hetero- and homozygous R405W desmin knock-in mice. Combined morphological, transcriptomic and proteomic analyses helped decipher the complex pattern of early pathological changes induced by the expression of mutant desmin. Our findings highlight the importance of major mitochondrial alterations, including essential proton gradient-dependent carriers as well as Dnajb6-related protein quality control and Xin-related myofibrillar damage, in the molecular pathogenesis of desminopathies.
Insights
Mutant desmin causes myofibrillar myopathy in mice, impacting mitochondrial function and protein quality control. This study reveals key molecular changes in desminopathies, highlighting therapeutic targets.
Area of Science:
- Muscle biology
- Molecular pathology
- Genetics
Background:
- Desmin gene mutations are linked to skeletal myopathies and cardiomyopathies.
- Understanding the R405W mutant desmin's molecular pathology is crucial.
Purpose of the Study:
- To elucidate the molecular pathology of R405W mutant desmin in murine skeletal muscle.
- To characterize skeletal muscle pathology in R405W desmin knock-in mice.
Main Methods:
- Comprehensive analysis of R405W desmin knock-in mice (heterozygous and homozygous).
- Included grip strength, blood analysis, histology, ultrastructure, immunofluorescence, immunoblot, ribosomal stalling, RNA sequencing, and proteomics.
Main Results:
- R405W desmin expression induced myofibrillar myopathy with protein aggregation and mitochondrial alterations.
- Homozygous mice exhibited muscle weakness and altered blood acylcarnitines/amino acids.
- Multi-omics analysis revealed dysregulated mitochondrial proteins, Mlf1, Xirp2, and Ces2c.
Conclusions:
- Mutant desmin expression causes myofibrillar myopathy in mice.
- Combined omics and morphological analyses deciphered early pathological changes.
- Mitochondrial dysfunction, protein quality control, and myofibrillar damage are key in desminopathies.
