3 FA mouse models fail to accurately capture cardiomyopathy, study finds
Work points to difficulty in modeling 'genetically relevant' heart disease
Three mouse models of Friedreich’s ataxia (FA) do not accurately reflect FA-associated cardiomyopathy — a serious heart complication — as seen in patients, underscoring the difficulties in modeling this complication, a study reports.
Across these different models, only one exhibited gene activity changes in the heart consistent with cardiomyopathy and a type of cellular stress that’s been linked to it. But these mice, which were severely deficient in frataxin — the protein that’s lacking in FA — did not show signs of severe heart disease and lived to advanced ages.
“These findings indicate that the mouse heart has low reliance on [frataxin], highlighting the difficulty in modeling genetically relevant FA cardiomyopathy,” the researchers wrote.
The study, “Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency,” was published in Disease Models & Mechanisms.
Cardiomyopathy a serious complication of Friedreich’s ataxia
In FA, a trio of DNA building blocks — GAA — is repeated too many times in the FXN gene, disrupting its function. This so-called trinucleotide expansion in the disease causes a lack of frataxin, which in turn affects mitochondria, the organelles responsible for producing cellular energy.
Muscles are particularly susceptible to energy deficits, and muscle weakness is a hallmark FA symptom. As cardiac muscles become enlarged and weakened, the heart has a harder time pumping blood.
Known as cardiomyopathy, this symptom is a leading cause of death in FA. But patients’ hearts typically maintain normal function until more advanced disease stages, the researchers noted, suggesting that the body makes early adaptions, or compensates, for the loss of frataxin and associated energy deficits.
“This adaptation likely involves metabolic rewiring to allow the utilization of alternative energy sources,” the scientists wrote.
Adaptations to a process called the mitochondrial integrated stress response (ISR-MT) may be involved in this rewiring.
ISR-MT is a complex process by which cells shift their genetic and metabolic activities to enable energy production under conditions of acute cellular stress. But long term or chronic activation can lead to metabolic imbalances that contribute to heart failure.
Evidence of ISR-MT activation has been reported in mouse FA models. However, these models involve the complete loss of frataxin, which does not accurately reflect the human condition, according to the researchers.
Scientists in the U.S. and France examined ISR-MT in three different mouse models with varying degrees of frataxin deficiency: the YG8-800, KIKO-700, and G127V models.
YG8-800 and KIKO-700 are models with a GAA trinucleotide repeat expansion inserted into one copy of the FXNÂ gene. G127V mice have a different type of FXNÂ mutation, one equivalent to the G130V mutation found in FA patients.
Genetic and metabolic profiling of heart tissue was performed in each model and in corresponding groups of healthy control mice at 18 months old, representing advanced age.
While YG8-800 mice exhibited very few metabolic alterations compared to healthy mice and little evidence of ISR-MT, both KIKO-700 and G127V mice showed several metabolic changes, many of which were overlapping between the two mouse lines and might associate with ISR-MT.
G127V mice showed markers of cardiomyopathy but lived to advanced ages
All three mouse lines exhibited genetic changes reflective of cardiac and mitochondrial stress.
However, only mice from the G127V line had prominent markers of cardiomyopathy and changes in specific markers of ISR-MT.
While reasons for the differences between G127V mice and the other two mouse lines “remain to be fully elucidated,” the most evident difference was in the amount of frataxin present, the scientists noted.
Frataxin levels were severely deficient in the G127V mice — about 1% of normal. The two other mouse lines had frataxin levels of more than 20% in the heart, reported to be the level at which certain impairments, including cardiac dysfunction, may be prevented in FA models.
While this likely explains the lack of change in cardiomyopathy and ISR-MT markers in these two models, the severe frataxin deficiency in G127V mice still did not result in severe cardiomyopathy, with the animals living up to 18 months of age.
“Therefore, even very low levels of [frataxin] may be sufficient in the mouse heart,” the scientists wrote, unlike the frataxin “threshold for preservation of cardiac function” needed in the human heart.
Among G127V mice, males exhibited ISR-MT markers at 6 months old, and the hearts of both these male and female mice expressed markers of ISR-MT by age 18 months. Reasons for this sex difference are not known, the researchers wrote, with future studies planned to investigate whether sex hormones play a role in delaying ISR-MT activation.
Study findings, overall, demonstrate that ISR-MT can be observed in the hearts of FA mouse models, the researchers noted. But the preservation of cardiac function in these three models, coupled with long life spans despite frataxin levels as low as 1%, deviates from observations in FA patients.
“In summary, we showed that [ISR-MT] may arise in the heart of mouse models with varying levels of [frataxin]. However, there are limitations to these models, as they only develop a partial cardiac mitochondrial stress response,” the researchers wrote.
“These findings further highlight the difficulty in modeling FA cardiomyopathy in murine models,” the team concluded.
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