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Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa, Jaculus jaculus

ABSTRACT: Muscle is a highly adaptable tissue capable of undergoing environmentally-induced changes and remarkable evolutionary adaptations. Muscle atrophy, a common feature in various myopathies as well as other conditions like cancer and diabetes, has been studied at the transcriptomic level, uncovering shared molecular factors. The lesser Egyptian jerboa, adapted for bipedal locomotion in a desert environment, experiences natural muscle loss in its foot. Cellular characterization of this process revealed similarities with human skeletal muscle atrophy, such as the loss of Desmin and upregulation of the ubiquitin proteasome pathway. By using RNA-sequencing, gene candidates associated with muscle loss in jerboa were identified, and genome-wide comparisons with established mouse models of muscle dystrophy/atrophy elucidated shared molecular signatures. These findings provide valuable insights into the genes and pathways involved in natural muscle loss and contribute to understanding the evolutionary relationship between natural and pathological muscle loss.

ORGANISM(S): Mus musculus Jaculus jaculus

PROVIDER: GSE235932 | GEO | 2024/09/01

REPOSITORIES: GEO

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Project description:Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 100 mutations of the human DES gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology is hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and on the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChR subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and a faster rise time of the nerve-independent miniature endplate potentials. The latter is indicating an enhanced opening time of the AChR channels. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian neuromuscular junctions.

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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Gene expression differences associated with intrinsic hindfoot muscle loss in the jerboa, Jaculus jaculus

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