Dataset Information

Fiber type-specific proteomic alterations in R349P desminopathy mice

ABSTRACT: Desminopathies refer to a group of rare human myopathies and cardiomyopathies, caused by mutations in the desmin gene. So far, there is no causative treatment and little is known about early pathological effects, since alterations in muscle biopsies usually reflect late stages of the disease. Thus, effort has been made to create animal models closely mirroring the human disease pathology. In the present work, we studied the effects of wild type desmin, as well as one of the most common mutations causing desminpathy in humans either heterozygously or homozygously expressed in a mouse model system. With our innovative approach coupling laser microdissection and mass spectrometry, we were able to define disease-associated alterations on the level of muscle fiber types. This allowed us to determine fiber-type specific changes in response to the desmin mutation, revealing profound differences in the proteomic profile of type I and type IIa fibers of homozygous mice. Desmin levels were severly decreased, leading to alterations in the expression of extracellular matrix and myofibrillary proteins. Further a clear mitochondrial pathology could be verified, whereby lower levels of mitochondrial complexes I and V could be observed, as well as a decreased expression of essential mitochondrial transporters, adding to the complexity of molecular symptoms caused by the mutation in the desmin gene.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle Fiber, Muscle Cell

DISEASE(S): Myofibrillar Myopathy 1

SUBMITTER: Britta Eggers

LAB HEAD: Katrin Marcus

PROVIDER: PXD049207 | Pride | 2025-05-26

REPOSITORIES: Pride

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Fiber Type-Specific Proteomic Alterations in R349P Desminopathy Mice.

Eggers Britta B Schork Karin K Turewicz Michael M Barkovits Katalin K Eisenacher Martin M Schröder Rolf R Clemen Christoph Stephan CS Marcus Katrin K

Muscle & nerve 20250303 6

<h4>Introduction/aims</h4>Desminopathies are a group of rare human myopathies and cardiomyopathies caused by pathogenic variants of the desmin gene. Here, we analyzed the effects of the R349P mutant desmin on the proteomic profiles of individual fiber types of murine skeletal muscle.<h4>Methods</h4>Soleus and tibialis anterior muscles from hetero- and homozygous R349P desmin knock-in mice and wild-type siblings were used to collect fiber type-specific material by laser microdissection to determi ...[more]

PMID: 40033788

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Project description:Background: Mutations of the desmin gene cause familial and sporadic cardiomyopathies and myopathies. Previous studies showed that both the lack of desmin and expression of mutated desmin negatively impact on number, structure and function mitochondria implying a metabolic dysfunction as disease promoting factor. Here, we exploited desmin knock-out mice to analyse the general metabolic performance of cardiac tissue. Methods: We analysed left ventricular cardiac muscle tissue derived from six-month-old homozygous desmin knock-out mice as well as wild-type siblings. Employing a multi-method approach comprising morphological, clinical chemistry, biochemical, genetic, and proteomic techniques, we specifically addressed energy, fatty acid, glucose, and amino acid metabolism. Results: We demonstrated that the lack of desmin in left ventricular cardiac tissue led to a significant decrease in the number of mitochondria in conjunction with ultrastructural defects of mitochondria. Analysis of mitochondria-related metabolic pathways revealed significantly impaired processes of fatty acid transport, activation, and catabolism associated with increased blood levels of short, medium, and long chain acyl-carnitines. In addition to increased amounts of glucose transporter 1 and hexokinase 1, we detected a significantly increased hexokinase enzyme activity. While the amount of mitochondrial creatine kinase was markedly reduced, fetal creatine kinase was increased. The picture of a highly dysbalanced metabolic state was complemented by our quantitative proteomic analysis that revealed significantly reduced levels of multiple proteins centrally involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Conclusions: Our data denoted a picture of widespread metabolic dysfunction far reaching beyond the level of mitochondria in left ventricular cardiac tissue of desmin knock-out mice. The increase of glucose utilisation along with increased level of fetal creatine kinase likely is a compensatory measure counteracting the severely hampered fatty acid metabolism and oxidative phosphorylation. The degree of metabolic disbalance, already observed in desmin knock-out mice kept under standard ‘sedentary’ housing conditions, renders it likely that acute strenuous physical exercise with its steeply increased energy demand will push the cardiac tissue into severe metabolic crisis.

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