4.7 Article

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

期刊

出版社

MDPI
DOI: 10.3390/ijms231912020

关键词

desmin; desminopathy; cardiomyopathy; mitochondriopathy; desmin knock-out metabolism; glucose; fatty acid; amino acid; creatine kinase; mitochondria

资金

  1. P.U.R.E. (Protein Research Unit Ruhr within Europe)
  2. Center for Protein Diagnostics (ProDi) grants
  3. German Federal Ministry of Education and Research (BMBF) [FKZ 031 A 534A]
  4. Ministry of Innovation, Science and Research of North Rhine-Westphalia, Germany
  5. BONFOR
  6. Ministry of Education, Youth and Sport of the Czech Republic [SVV-260571/2020]
  7. European Regional Development Fund
  8. state budget of the Czech Republic [CZ.1.05/4.1.00/16.0347, CZ.2.16/3.1.00/21515]
  9. German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) [52732026]

向作者/读者索取更多资源

Desmin mutations cause cardiomyopathies and negatively impact mitochondria. The deficiency of desmin results in impaired oxidative phosphorylation and fatty and amino acid metabolism in cardiac mitochondria. Increased glucose utilization and upregulation of fetal creatine kinase are compensatory mechanisms to maintain myocardial energy supply.
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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据