More severe heart problems, shorter survival seen in FA male mice
Lifespans significantly different when scaled to human terms
Male mouse models of Friedreich’s ataxia (FA) in a study showed worse heart function than females, with weaker heart pumping and a larger left ventricle, the heart’s main pumping chamber.
The differences are relevant as these mice are widely used for preclinical testing of new treatments for the disease.
Researchers also observed that while these mice die prematurely due to severe cardiomyopathy (disease of the cardiac muscle), males started to die about two weeks earlier and survived a median of 10 days less than females, which translates to a meaningful difference when scaled to human lifespan.
“In a model where lifespan is already short, this is a proportionally larger difference if the calculations are made in terms of human life,” the researchers wrote in the study, “Sexual dimorphism in a mouse model of Friedreich’s ataxia with severe cardiomyopathy,” published in Communications Biology.
Although men and women have equal chances of inheriting Friedreich’s ataxia, a genetic disease, research suggests that women may experience milder heart problems, perhaps due to differences in heart function.
Larger hearts
The most common heart problem caused by Friedreich’s ataxia is hypertrophic cardiomyopathy, in which the cardiac muscle lining the heart thickens, limiting its capacity to pump blood out to the body.
To better understand how cardiomyopathy manifests by sex, the researchers turned to a mouse model lacking the Fxn gene — the one mutated in Friedreich’s ataxia — in cardiac muscle. These mice have a lifespan of 76 days (2.5 months), much shorter than the usual two years or longer of healthy mice.
In both male and female mice, about 15% of frataxin, the protein coded by the Fxn gene, remained in cardiac muscle. However, male mice began to die 15 days earlier than females, with the first death at day 61 versus day 76. There also was a 10-day difference in median survival (71.5 days vs. 81.5 days).
To explore the reason for these differences, the researchers studied the hearts of both male and female mice at day 56, before severe weight loss was seen. Compared with healthy (control) mice, model mice had a significantly larger heart. Its size was increased by 45% in males and 30% in females.
The volume of the heart’s left ventricle at systole, when the heart muscle contracts to pump blood, was larger in males than in females, indicating volume overload, which occurs when the heart is required to pump a larger-than-normal amount of blood.
Ejection fraction, a measure of how much blood the left ventricle pumps out with each contraction, was significantly lower in model mice than in control mice. On average, ejection fraction decreased by about 70% in males and 39% in females.
“Cardiac dysfunction and structural changes were more pronounced in … male mice,” the researchers wrote, “which could explain their premature death in survival studies.” Male mice also had smaller kidneys and more severe kidney problems.
Those male mice also had reduced activity of the Fxn gene in their testes, whereas no differences were found in the ovaries of female mice. Consistent with smaller testes, model mice also had lower levels of circulating testosterone, the primary male sex hormone, than control mice.
Less testosterone was linked to lower levels of proteins that help move cholesterol into mitochondria, the energy-producing structures in cells, a step that is needed for hormones to be produced. Less testosterone increases the risk of heart problems, and male mice indeed had lower levels of RyR2 and SERCA2, two proteins that are important for the heart to beat regularly.
“Further studies need to be conducted with testosterone and estrogen [the primary female sex hormone] supplementation to determine the specific role of these hormones in the development of cardiomyopathy in this mouse model,” the researchers wrote. “This discovery is critical as this mouse model often serves as a model for therapeutic drug development and testing in FA. Importantly, the study supports clinical findings that FA may be more severe in male individuals,” they added.
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