Heart’s shift to sugar as fuel linked to damage in Friedreich’s ataxia
Study: Subset of patients develops severe thickening of muscle in organ
In Friedreich’s ataxia (FA), a subset of patients develops severe thickening of the heart muscle as the heart shifts to using glucose (sugar) as a fast but less effective energy source. This switch is linked to poorer heart function and early signs of damage, a study suggests.
These patients “may be at increased risk of complications,” researchers wrote in the study, “Positron emission tomography reveals increased myocardial glucose uptake in a subset of Friedreich ataxia patients,” which was published in Scientific Reports.
FA caused by defects in essential protein
FA is caused by defects in frataxin, a mitochondrial protein essential for the cell’s main energy-producing processes. The condition leads to a wide range of symptoms, such as muscle weakness, spinal curvature, diabetes marked by elevated blood glucose, and various heart abnormalities.
Why some individuals develop severe cardiac complications while others do not remains unclear. One hypothesis is that mitochondrial dysfunction alters the heart’s ability to generate energy. To investigate this, the researchers examined cardiac metabolism in 11 patients with FA and five healthy control participants.
All patients had a genetic diagnosis of FA, and none had diabetes. They were divided into two groups based on left ventricular mass index, a measure of the thickening of the wall of the heart’s main pumping chamber. The first group was in the normal range, while the second group had severe thickening.
To track how the heart uses glucose and fatty acids, the researchers performed positron emission tomography (PET) scans with three tracers: one for glucose, one for fatty acids, and another for blood flow. After 12 hours of fasting, PET scans showed that most patients (73%) had a very high glucose uptake in the heart.
All patients in the second group relied much more on glucose than fatty acids for energy in their hearts. They also showed signs of damage to the heart muscle, as measured by the protein cardiac troponin I, and had faster heart rates, even with beta-blockers, which normally slow the heart.
Using more glucose relative to fatty acids linked to weaker contractions
Electrocardiograms, which record the heart’s electrical activity, showed that normal electrical signals were disrupted for many patients with severe thickening of the heart muscle. These patients also had larger hearts and reduced movement of a valve that prevents blood from flowing back, which is a measure of how well the heart contracts.
In these patients, using more glucose relative to fatty acids was associated with both weaker contractions and poorer relaxation of the heart. The use of fatty acids was similar in patients with and without thickening of the heart muscle, suggesting the main change was an increase in glucose uptake.
Experiments using a mouse model of FA supported this finding. Compared with wild-type (healthy) mice, the hearts from mice with the disease exhibited increased activity of genes that promote glucose uptake and glycolysis, the process of breaking down glucose for fast production of energy in the absence of oxygen.
Meanwhile, the activity of genes involved in producing energy in the mitochondria from fatty acids — a process that requires oxygen but yields more energy than glycolysis — was reduced, indicating the use of a less effective energy source. Signs of incomplete glucose breakdown confirmed problems with the mitochondria.
“Fatty acids are the preferred fuel in the heart, but in [disease], such as [heart failure] or ischemia, the heart can shift fuel utilization to glucose, which is more efficient and requires less oxygen but generates less energy,” the researchers wrote. “These findings may have implications for the clinical management of patients.”
Patients with severe thickening of the heart’s left ventricle relied more on glucose, which was linked to poorer heart function and signs of damage. This shift may provide a way to identify high-risk patients and target treatments.
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