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

Salinas, Lili; Montgomery, Claire B.; Figueroa, Francisco; Thai, Phung N.; Chiamvimonvat, Nipavan; Cortopassi, Gino; Dedkova, Elena N.

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. Sexual dimorphism is identified in a mouse model of Friedreich's ataxia, with males exhibiting a worse cardiac phenotype, low survival rate, as well as kidney and reproductive organ deficiencies.

FRIEDREICH'S ataxia; GENITALIA; SEXUAL dimorphism; CALCIUM channels; FRATAXIN; MITOCHONDRIAL membranes; TRANSLOCATOR proteins

Communications Biology, 2024, Vol 7, Issue 1, p1

2399-3642

Academic Journal

10.1038/s42003-024-06962-4