Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles

J Physiol. 2003 Sep 1;551(Pt 2):491-501. doi: 10.1113/jphysiol.2003.045104. Epub 2003 Jun 24.

Abstract

Congestive heart failure (CHF) induces alterations in energy metabolism and mitochondrial function that span cardiac as well as skeletal muscles. Whether these defects originate from altered mitochondrial DNA copy number and/or mitochondrial gene transcription is not known at present, nor are the factors that control mitochondrial capacity in different muscle types completely understood. We used an experimental model of CHF induced by aortic banding in the rat and investigated mitochondrial respiration and enzyme activity of biochemical mitochondrial markers in cardiac, slow and fast skeletal muscles. We quantified mitochondrial DNA (mtDNA), expression of nuclear (COX IV) and mitochondrial (COX I) encoded cytochrome c oxidase subunits as well as nuclear factors involved in mitochondrial biogenesis and in the necessary coordinated interplay between nuclear and mitochondrial genomes in health and CHF. CHF induced a decrease in oxidative capacity and mitochondrial enzyme activities with a parallel decrease in the mRNA level of COX I and IV, but no change in mtDNA content. The expression of the peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1 alpha) gene was downregulated in CHF, as well as nuclear respiratory factor 2 and mitochondrial transcription factor A, which act downstream from PGC-1 alpha. Most interestingly, only the level of PGC-1 alpha expression was strongly correlated with muscle oxidative capacity in cardiac and skeletal muscles, both in healthy and CHF rats. Mitochondrial gene transcription is reduced in CHF, and PGC-1 alpha appears as a potential modulator of muscle oxidative capacity under these experimental conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Southern
  • Body Weight / physiology
  • Citrate (si)-Synthase / biosynthesis
  • Citrate (si)-Synthase / genetics
  • DNA Primers
  • DNA, Mitochondrial / biosynthesis
  • Gene Expression Regulation, Enzymologic / genetics
  • Gene Expression Regulation, Enzymologic / physiology
  • Heart / physiology*
  • Heart Failure / enzymology
  • Heart Failure / metabolism*
  • Kinetics
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / metabolism*
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Organ Size / physiology
  • Oxidation-Reduction
  • Oxidative Phosphorylation
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics
  • RNA, Messenger / biosynthesis
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / biosynthesis*
  • Transcription, Genetic / physiology*

Substances

  • DNA Primers
  • DNA, Mitochondrial
  • RNA, Messenger
  • Transcription Factors
  • Prostaglandin-Endoperoxide Synthases
  • Citrate (si)-Synthase