Dataset Information

Desmin knock-out cardiomyopathy: a heart on the verge of metabolic crisis

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cardiocyte

DISEASE(S): Cardiomyopathy,Myopathy

SUBMITTER: Britta Eggers

LAB HEAD: Prof. Dr. Katrin Marcus

PROVIDER: PXD030938 | Pride | 2022-10-21

REPOSITORIES: Pride

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Publications

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis.

Elsnicova Barbara B Hornikova Daniela D Tibenska Veronika V Kolar David D Tlapakova Tereza T Schmid Benjamin B Mallek Markus M Eggers Britta B Schlötzer-Schrehardt Ursula U Peeva Viktoriya V Berwanger Carolin C Eberhard Bettina B Durmuş Hacer H Schultheis Dorothea D Holtzhausen Christian C Schork Karin K Marcus Katrin K Jordan Jens J Lücke Thomas T van der Ven Peter F M PFM Schröder Rolf R Clemen Christoph S CS Zurmanova Jitka M JM

International journal of molecular sciences 20221010 19

Desmin mutations cause familial and sporadic cardiomyopathies. In addition to perturbing the contractile apparatus, both desmin deficiency and mutated desmin negatively impact mitochondria. Impaired myocardial metabolism secondary to mitochondrial defects could conceivably exacerbate cardiac contractile dysfunction. We performed metabolic myocardial phenotyping in left ventricular cardiac muscle tissue in desmin knock-out mice. Our analyses revealed decreased mitochondrial number, ultrastructura ...[more]

PMID: 36233322

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Project description:Background: High-altitude hypoxia significantly impacts cardiovascular function, but the effects of adipose/metabolic factors on cardiovascular regulation remain unclear. Thus, a deeper understanding of adipose/metabolic factors’ role in cardiovascular function changes is needed. Methods: We assessed lung ventilation function, cardiovascular function, electrocardiogram, plasma CK-MB, sPecam-1, and 11 plasma adipose/metabolic factors in expeditioners at Antarctic Kunlun Station (4087m). To investigate adipose/metabolic factors’ effects and mechanisms on cardiac function, we constructed a rat model exposed to simulated hypobaric hypoxia (5000 m) with the same oxygen concentration as Kunlun Station. Echocardiography, ELISA, histology, and gene and protein expression studies were employed to examine cardiac function changes, pathological alterations, and leptin’s role in cardiac pathology under acute and chronic hypoxic exposure. Results: The Antarctic ice plateau environment significantly altered lung ventilation function, weakened cardiac pumping and contractile function, increased systematic vascular resistance (SVR), induced adaptive changes in cardiac conduction, significantly increased plasma CK-MB and Pecam-1, and significantly reduced plasma leptin, resistin, insulin, and lipocalin-2 levels. Decreased leptin was significantly correlated to cardiopulmonary function. Rats chronically exposed to simulated hypobaric hypoxia at 5000m exhibited pulmonary arterial hypertension (PAH), right ventricular hypertrophy (RVH), impaired left ventricular systolic and diastolic function, and significant deteriorated left ventricular global longitudinal strain (GLS), lateral and radial strains of the myocardium, with increased plasma CK-MB and sPecam-1 in hypoxic rats. Protein levels of leptin/ob-Rb, JAK2/STAT3, PI3K/AKT/GSK3β, and ERK/JNK were decreased in biventricular myocardial tissues of chronic hypoxia-exposed rats, accompanied by increased myocytes hypertrophy, fibrosis, lipid deposition, cell apoptosis, and mitochondrial dysfunction, and decreased metabolic gene levels. Left ventricular transcriptome analysis revealed that decreased myocardial leptin in hypoxic rats regulated cardiac pathology via down-regulated genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton. Conclusion: Our findings suggest that leptin is a crucial metabolic factor in regulating cardiac pathological changes and cardiac contractile and diastolic function under high altitudes. These regulatory pathways may involve leptin's classical signaling pathways and genes related to circadian rhythm, sodium/potassium ion transport, and cell skeleton in the heart.

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.

Dataset Information

Desmin knock-out cardiomyopathy: a heart on the verge of metabolic crisis

Publications

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis.

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