Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy

David T. Lucas, Prafulla Aryal, Luke I. Szweda, Walter J. Koch, Leslie A. Leinwand

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by varying degrees of ventricular hypertrophy and myofibrillar disarray. Mutations in cardiac contractile proteins cause HCM. However, there is an unexplained wide variability in the clinical phenotype, and it is likely that there are multiple contributing factors. Because mitochondrial dysfunction has been described in heart disease, we tested the hypothesis that mitochondrial dysfunction contributes to the varying HCM phenotypes. Mitochondrial function was assessed in two transgenic models of HCM: mice with a mutant myosin heavy chain gene (MyHC) or with a mutant cardiac troponin T (R92Q) gene. Despite mitochondrial ultrastructural abnormalities in both models, the rate of state 3 respiration was significantly decreased only in the mutant MyHC mice by ∼23%. Notably, this decrease in state 3 respiration preceded hemodynamic dysfunction. The maximum activity of α-ketogutarate dehydrogenase as assayed in isolated disrupted mitochondria was decreased by 28% compared with isolated control mitochondria. In addition, complexes I and IV were decreased in mutant MyHC transgenic mice. Inhibition of β-adrenergic receptor kinase, which is elevated in mutant MyHC mouse hearts, can prevent mitochondrial respiratory impairment in mutant MyHC mice. Thus our results suggest that mitochondria may contribute to the hemodynamic dysfunction seen in some forms of HCM and offer a plausible mechanism responsible for some of the heterogeneity of the disease phenotypes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume284
Issue number2 53-2
StatePublished - Feb 1 2003

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Hypertrophic Cardiomyopathy
Myosin Heavy Chains
Genes
Mitochondria
Phenotype
Respiration
Familial Hypertrophic Cardiomyopathy
Hemodynamics
Contractile Proteins
Troponin T
Adrenergic Receptors
Hypertrophy
Transgenic Mice
Heart Diseases
Oxidoreductases
Phosphotransferases
Mutation

Keywords

  • Mitochondria
  • Transgenic

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy. / Lucas, David T.; Aryal, Prafulla; Szweda, Luke I.; Koch, Walter J.; Leinwand, Leslie A.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 284, No. 2 53-2, 01.02.2003.

Research output: Contribution to journalArticle

Lucas, David T. ; Aryal, Prafulla ; Szweda, Luke I. ; Koch, Walter J. ; Leinwand, Leslie A. / Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy. In: American Journal of Physiology - Heart and Circulatory Physiology. 2003 ; Vol. 284, No. 2 53-2.
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