Overtraining: the cause of symptoms caused by excessive physical exercise has been discovered

In tests with rodents, researchers from the State University of Campinas and their collaborators found that hyperactivation of the PARP1 protein after exhaustive training was associated with decreased performance, fatigue, and behavioral symptoms of overtraining. Animals treated with a drug that inhibits the molecule’s activity did not exhibit the condition.

By André Julião  |  Agência FAPESP – Excessive physical exercise, especially without adequate rest, can damage the human body in various ways. In severe cases, it can progress to overtraining syndrome, which is characterized by decreased performance and appetite, chronic fatigue, muscle pain, increased injuries, and changes in the immune system and metabolism.

A study published in the journal Molecular Metabolism points to excessive protein expression as the cause of the syndrome.

A research team from the State University of Campinas’s School of Applied Sciences (FCA-UNICAMP) in Limeira in the state of São Paulo, Brazil, demonstrated that mice subjected to excessive training exhibited performance loss, fatigue, and behavioral symptoms, such as inactivity under stress and increased self-cleaning behaviors, due to overexpressing the PARP1 protein in their skeletal muscles.

“The protein is activated when there’s some stress in the body, preventing cell death, and has been well described as increased in skeletal muscle in conditions of obesity and muscular dystrophies. We confirmed that its hyperactivation is related to muscle damage caused by excessive exercise,” explains Barbara Crisol, who conducted the work as part of her doctoral studies at FCA-UNICAMP with a scholarship from FAPESP.

The study is part of a project coordinated by Eduardo Ropelle, a professor at FCA-UNICAMP.

There is no specific treatment for overtraining syndrome besides suspending training partially or completely for weeks or even months. While it can be especially harmful to professional athletes’ careers, non-athletes can also experience the symptoms.

The researchers observed in the study that mice treated with a drug that inhibits PARP1 activity did not experience a decline in performance or other symptoms of overtraining when subjected to an excessive exercise protocol.

In breast and ovarian tumors, the drug olaparib inhibits PARP1 activity, facilitating the death of cancer cells. In the animals, the drug prevented the hyperactivation of the protein in muscle tissue, thereby preventing overtraining.

“For the first time, a pharmacological agent capable of preventing overtraining has been introduced. This was one of the major advances of the study. However, it must be made clear that this isn’t a drug that can be used for this purpose, as it has several side effects, including suppressing the immune system,” warns Ropelle.

The researchers are searching for a natural compound that can reduce PARP1 production in muscle tissue, thereby preventing or treating overtraining.

Humans

In addition to the mouse studies, which used an overtraining model in Limeira, another part of the study was conducted with humans at the Swedish School of Sport and Health Sciences in Stockholm. There, researchers subjected a group of healthy volunteers to a three-week routine of high-intensity interval training (HIIT).

Over the weeks, the researchers increased the number of training sessions while reducing the recovery time between them. This was done to mimic excessive training. Then, muscle biopsies were taken from the volunteers and analyzed.

“It isn’t easy to obtain data on overtraining in humans, not least because it’d be unethical to induce the condition in people. Therefore, this protocol approximates what may be happening in the muscles of people who have undergone excessive training,” says Crisol, who is currently pursuing postdoctoral research at the Centre de Recherche en Myologie in France, which is dedicated to the study of muscle conditions.

The analyses revealed that the exercise protocol decreased glucose tolerance, mitochondrial function (which is related to energy production in cells), and physical performance by the end of the third week of training.

The European group first published these results in the journal Cell Metabolism.

During an internship at the Swedish institution, Crisol conducted her own analysis of the data with support from FAPESP. She observed that excessive exercise in healthy individuals increased muscle paralysis, a phenomenon resulting from PARP1 activity in cells.

This finding is consistent with a series of discoveries about the relationship between the protein and muscle conditions. For example, high levels of PARP1 have been found in the muscles of people with Duchenne muscular dystrophy, a genetic disease that primarily affects children.

The protein is also associated with obesity and cachexia, the latter of which is a syndrome that causes muscle loss in cancer patients. High levels of PARP1 have been found in cases of sepsis. Therefore, searching for compounds that can inhibit the protein without causing side effects may be beneficial for treating different conditions.

“Overtraining itself greatly weakens a person, including psychologically. In mice, we saw that the expression or non-expression of the protein makes a difference even in this regard. Preventing or mitigating the effects with some compound would be very beneficial,” concludes Ropelle.

The work was also supported by FAPESP through three other projects (13/07607-8, 21/08354-2 and 22/08930-6).

The article “Excessive exercise elicits poly (ADP-ribose) Polymerase-1 activation and global protein PARylation driving muscle dysfunction and performance impairment” can be read at: www.sciencedirect.com/science/article/pii/S2212877825000420.