Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy

Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4.

Abstract

Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

MeSH terms

  • Animals
  • Cardiomyopathies* / etiology
  • Cardiomyopathies* / genetics
  • Cardiomyopathies* / metabolism
  • Disease Models, Animal*
  • Female
  • Frataxin*
  • Friedreich Ataxia* / genetics
  • Friedreich Ataxia* / metabolism
  • Iron-Binding Proteins* / genetics
  • Iron-Binding Proteins* / metabolism
  • Male
  • Mice
  • Mice, Knockout*
  • Receptors, GABA
  • Sex Characteristics*
  • Testosterone / blood
  • Testosterone / metabolism

Substances

  • Iron-Binding Proteins
  • Frataxin
  • Testosterone
  • Bzrp protein, mouse
  • Receptors, GABA