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, ultrastructural mitochondrial defects, and impaired mitochondria-related metabolic pathways including fatty acid transport, activation, and catabolism. Glucose transporter 1 and hexokinase-1 expression and hexokinase activity were increased. While mitochondrial creatine kinase expression was reduced, fetal creatine kinase expression was increased. Proteomic analysis revealed reduced expression of proteins 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. Thus, desmin deficiency elicits a secondary cardiac mitochondriopathy with severely impaired oxidative phosphorylation and fatty and amino acid metabolism. Increased glucose utilization and fetal creatine kinase upregulation likely portray attempts to maintain myocardial energy supply. It may be prudent to avoid medications worsening mitochondrial function and other metabolic stressors. Therapeutic interventions for mitochondriopathies might also improve the metabolic condition in desmin deficient hearts.

Chair of Aerospace Medicine Medical Faculty University of Cologne 50931 Cologne Germany

Department of Cell Biology Faculty of Science Charles University 128 00 Prague Czech Republic

Department of Molecular Cell Biology Institute for Cell Biology University of Bonn 53121 Bonn Germany

Department of Neurology Istanbul Faculty of Medicine Istanbul University 34093 Istanbul Turkey

Department of Ophthalmology University Hospital Erlangen Friedrich Alexander University Erlangen Nürnberg 91054 Erlangen Germany

Department of Physiology Faculty of Science Charles University 128 00 Prague Czech Republic

Division of Neurochemistry Institute of Experimental Epileptology and Cognition Research University of Bonn 53127 Bonn Germany

Institute of Aerospace Medicine German Aerospace Center Linder Höhe 51147 Cologne Germany

Institute of Neuropathology University Hospital Erlangen Friedrich Alexander University Erlangen Nürnberg 91054 Erlangen Germany

Institute of Vegetative Physiology Medical Faculty University of Cologne 50931 Cologne Germany

Medical Proteome Analysis Center for Proteindiagnostics Ruhr University Bochum 44801 Bochum Germany

Medizinisches Proteom Center Medical Faculty Ruhr University Bochum 44801 Bochum Germany

MVZ Dr Eberhard and Partner Dortmund 44137 Dortmund Germany

Optical Imaging Center Erlangen Friedrich Alexander University Erlangen Nürnberg 91058 Erlangen Germany

University Hospital of Pediatrics and Adolescent Medicine St Josef Hospital Ruhr University Bochum 44791 Bochum Germany

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