Excessive mTOR and AKT Signaling May Underlie Cardiomyopathy in FA
Overactivation of signaling pathways linked to heart disease in mouse model
Higher than normal activation of the mTOR and AKT signaling pathways — both key to proper cardiovascular function — may underlie the heart disease called cardiomyopathy that is common in people with Friedreich’s ataxia (FA), according to a new study using a mouse model of FA.
When the mice were treated with a compound to block mTOR signaling, lifespan was significantly increased, researchers found. However, other signs of cardiac abnormalities and AKT activation persisted.
The data suggest that “parallel mTOR and AKT inhibition might be necessary to further improve the lifespan and healthspan,” of FA patients, the team wrote, also noting that more work is needed to identify an appropriate combination of treatments.
The study, “Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia,” was published in the journal Heliyon.
Iron-sulfur clusters (ISCs) are groups of molecules essential for cell functions like DNA repair, metabolism, and energy production in cell compartments called mitochondria.
Frataxin, the protein that’s deficient in FA, is a necessary factor for producing ISCs — thus causing ISCs to be deficient in FA. Cardiomyopathy, a disease of the heart muscle known to affect FA patients, also is common in other diseases marked by ISC deficiencies.
Signaling pathways key to heart function
The mTOR and AKT molecules are part of a complex signaling network critical for cardiovascular function. But excessive activation of these pathways has been previously associated with cardiomyopathy, heart enlargement called cardiac hypertrophy, and early death in mice.
Now, researchers at the National Institutes of Health aimed to investigate whether activation of mTOR and AKT might underlie cardiac problems in FA and other ISC deficiencies.
Signs of mTOR and AKT overactivation were found in cell models lacking ISCs, as well as in a mouse model of FA with cardiomyopathy. In the mouse model, this excessive activation was seen in the heart, but not the skeletal muscles.
In cell models, the team next investigated the mechanisms by which ISC loss might lead to the overactivation of these signaling pathways.
Levels of proteins that require ISCs to function were experimentally reduced in cell cultures. These proteins were broadly involved in metabolic processes that produce cellular energy in the mitochondria. Their reduction resulted again in excess activation of mTOR and AKT.
“These data suggest that mTORC1 and AKT are activated in response to metabolic stress induced by defects in ISC biogenesis,” the researchers wrote.
Additional data suggested that increased oxidative stress resulting from ISC deficiencies might also contribute to aberrant mTOR and AKT signaling. Oxidative stress is a type of cellular stress that occurs when there are not enough antioxidants to battle the so-called free radical molecules that cause cellular damage.
The team next examined whether inhibiting or blocking mTOR signaling might ease cardiac problems in the FA mice. The mice were treated with a compound called rapamycin, a immune suppressant that blocks mTOR, either via injection or orally.
Rapamycin treatment significantly increased the lifespan of the mice. Specifically, mice injected with the treatment lived for an average of 114 days, whereas those who received it orally lived for 119 days. Those survival rates compared with 82 days among untreated mice.
Still, treated mice died significantly earlier relative to healthy mice, due to persistent deficits associated with a lack of ISCs. The treatment also did not impact heart enlargement or other heart abnormalities observed with an echocardiogram.
Notably, no signs of reduced AKT activation were observed with rapamycin, “suggesting that hyperactivation of [AKT] also contributes to cardiomyopathy” in Friedreich’s ataxia, the researchers noted. Additionally, the data suggest that AKT’s actions are independent from mTOR.
The data overall have “important implications on several [FA] therapeutics under evaluation,” the researchers wrote.
“Taken together, our results suggest that the use of combination therapies consisting of mTORC1 and AKT inhibitors, antioxidants, and agents that boost the expression levels of [frataxin] and other ISC biogenesis genes may be needed to further improve the healthspan and lifespan of patients with ISC biogenesis defects,” they wrote.
While these pathways could be therapeutic targets for FA and other diseases with cardiomyopathy, their excessive inhibition could cause problems with iron metabolism that have negative effects.
“Future studies should focus on evaluating the appropriate targets, intervention timing, dose-response profiles, and the use of combination therapies,” the researchers wrote.
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