Creatine is a compound that plays a key role in supplying energy to the brain, muscles and heart. It works in tandem with the creatine kinase system to maintain stable energy levels in cells. Creatine deficiency is a metabolic disorder in which the body either has too little creatine or cannot properly use it within cells.

Previous studies have shown that patients with dilated cardiomyopathy — a condition where the heart is enlarged and weakened — exhibit lower creatine levels, which have been linked to higher mortality rates. This has raised the question of whether low creatine kinase activity might be a direct cause of heart failure. However, animal studies involving creatine-deficient mice have so far produced conflicting results.

An uninterrupted energy system

A recent study conducted in collaboration between Tallinn University of Technology (TalTech) and the University of Oslo focused on how heart muscle cells behave in mice with creatine deficiency.

The heart, whether in humans or mice, requires a large amount of energy to pump blood. Its primary energy source is ATP, or adenosine triphosphate, which is produced in the cell's so-called powerhouses: the mitochondria.

According to Professor Marko Vendelin, head of the Systems Biology Lab at TalTech's Institute of Cybernetics and a participant in the study, the creatine kinase system also plays a key role in heart function. Its main role is not so much to store energy, but to rapidly and continuously transfer it from the mitochondria to the areas where it is most needed — primarily near the contractile proteins. "For the heart, it's that uninterrupted flow of energy that is critical — not just isolated moments of exertion," Vendelin explained.

Put simply, contractile proteins are the engines of muscle tissue. If we think of the heart as a pump, something must physically do the pumping. Inside cells, that job is carried out by specialized proteins — chiefly actin and myosin — that can slide past one another, shortening the cell and causing it to contract.

The function of the creatine kinase system, in turn, depends on the availability of creatine, which the body either synthesizes on its own or gets from food. Researchers have developed various animal models in which creatine synthesis is impaired. One such model is the AGAT knockout (KO) mouse.

Calcium not behaving as expected

In collaboration with Norwegian scientists, the researchers studied calcium signaling in the heart muscle cells of both creatine-deficient and normal mice. Calcium is the primary regulator of heart muscle contraction, and in cases of heart failure, these signals are typically weakened.

But the results came as a surprise. In the heart muscle cells of AGAT KO mice, calcium signals were actually stronger than in healthy mice. The reason turned out to be an increased amount of stored calcium within the cells.

"This doesn't fit the pattern of heart failure. Our findings show that a lifelong absence of creatine does not lead to heart failure," Vendelin said.

The study also revealed unexpected aspects of how heart muscle cells function. Until now, it was generally assumed that disruptions in the energy system would primarily affect processes that directly consume energy. However, the study showed the opposite: the most affected processes were those that do not themselves consume energy, such as calcium release during each heartbeat.

Vendelin emphasized that this points to a much greater adaptability in heart muscle cells than previously believed. "Energy issues can trigger broad cellular restructuring that impacts the overall function of the cell," he said.

Important knowledge also for rare diseases

The study's findings are also significant for individuals with creatine deficiency syndrome (CDS), a rare but severe condition that causes developmental delays, seizures and learning difficulties. While the disorder is thought to be underdiagnosed, early detection and dietary intervention can greatly improve patients' quality of life.

Although the heart is not the primary organ affected in people with CDS, the new findings suggest that creatine deficiency triggers more complex cellular adaptations than previously expected — adaptations that may impact multiple organ systems.

The research paper was published in the American Journal of Physiology – Heart and Circulatory Physiology.

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