Florida News Times (EUA)

Molecules have been discovered that regulate muscle adaptation to exercise

Publicado em 01 dezembro 2020

Por Karina Toledo | Agência FAPESP

Initiating an athletic program can cause muscle soreness and prevent movement as easy as getting up from the couch. With time and a little tenacity, the muscles get used to the effort and develop stronger and endurance. Researchers at Harvard University in the United States and the University of Sao Paulo (USP) in Brazil describe in a journal the cell mediators that enable them to adapt to this movement. cell..

The mediator is succinic acid, a metabolite previously known only for its involvement in mitochondrial respiration. The author of this article is a professor at the USP Institute for Biomedical Sciences (ICB) and a member of the Redoxome Center for Biomedical Sciences (Redoxome), one of the Centers for Research, Innovation and Dissemination (RIDC). Includes Julio Cesar Batista Ferreira. It was funded by FAPESP (Sao Paulo Research Foundation) and postdoctoral fellow Luis Enrique Boji, who conducted a study while working as a research intern at Harvard with the support of FAPESP.

“Our results show that succinic acid leaves muscle cells during exercise and signals its neighbors to trigger the process of muscle tissue remodeling,” Ferreira explained to Agencia FAPESP. “Motor neurons create new effects, muscle fibers become more uniform, gain muscle strength during contraction, and increase blood glucose uptake in all cells to produce ATP. [adenosine triphosphate, the cellular fuel].. Improves efficiency. “

The findings reported in this article are based on numerous experiments with animal and human volunteers. Initially, it involved a comparison of over 500 metabolites present in the muscles of the mouse legs before and after the mouse ran out on the treadmill.

“In addition to muscle fibers, muscle tissue also contains immune cells, nerve cells, and endothelial cells. If each is a home, the streets between the homes can be interstitial or interstitial spaces. Analyzed each house and street separately. We examined changes in the neighborhood after exercise and observed a significant increase in succinic acid only in muscle fibers and the interstitial space, “Fereira said.

A similar phenomenon was observed in healthy volunteers aged 25-35 years during 60 minutes of intense exercise on an exercise bike. In this case, researchers analyzed blood samples obtained via femoral artery and femoral vein catheters and found that succinic acid levels increased significantly in venous blood leaving the muscle and decreased rapidly during recovery. discovered.

At this point, researchers were convinced that muscle cells released succinic acid in response to exercise-induced stress, but they want to know how, and above all, why. I was thinking. Volunteer blood analysis provided clues: Another compound that increased with exercise in both venous and arterial blood was lactate (an ionized form of lactate), indicating that the cells activated the emergency energy production system. I have.

“Succinic acid is a metabolite that normally cannot cross the cell membrane and leave the cell. Within the cell, it is involved in the Krebs cycle, a series of chemical reactions that occur in the mitochondria and lead to ATP formation.” Bozi explained. “But when energy demand rises sharply and mitochondria can’t keep up, the anaerobic system is activated, causing excess lactic acid formation and cell acidification. This change in pH causes the chemical structure of succinic acid. Changes and escapes through the membrane to the extracellular medium. “

Transport proteins that help succinic acid exit cells have been identified by proteomics, an analysis of all proteins in the membranes of mouse and human muscle cells. The results showed an increase in MCT1 in muscle tissue after exercise. MCT1 is a protein specialized in transporting monocarboxylic acids extracellularly.

“The type of molecule that MCT1 transports is similar to succinic acid when chemically modified in an acidic medium. It becomes a monocarboxylic acid instead of a dicarboxylic acid. Confirms that this is an exercise-induced mechanism. We did some in vitro experiments to do this, “says Bozi. ..

One of the experiments consisted of exposing cultured muscle cells to hypoxia (oxygen deficiency) in order to activate the anaerobic energy production mechanism and produce lactic acid. This appeared to be sufficient to induce the release of succinic acid into the interstitial space.

Another experiment involved germ cells (oocytes) of frogs that were genetically modified to express human MCT1. Researchers have found that oocytes release succinic acid only when placed in acidic media.

“By this stage, we knew that acidity would protonate succinic acid, a chemical process that binds to MCT1 and passes through the membrane into the extracellular medium, but in the interstitial space. The importance of succinic acid accumulation is not yet known. During exercise. “


The importance of cell-cell communication in the adaptation of organisms to all types of stress is well established in the scientific literature. The signal is exchanged by molecules released into the interstitial space and binds to proteins in the membrane of nearby cells. Activation of these membrane receptors triggers processes that lead to structural and functional tissue modification.

“Our hypothesis was that succinic acid played a role in this regulation in muscle by binding to a protein called SUCNR1. [succinate receptor 1] For example, it is highly expressed in the membranes of motor neurons. “

To test the theory, they conducted experiments in mice genetically modified to not express SUCNR1. Mice were allowed to run freely for 3 weeks on a resistance wheel, which was considered long enough for morphological and functional changes to occur in muscle tissue.

“Muscle fibers were expected to be more uniform and stronger, but they weren’t,” Ferreira said. “In addition, exercise did not promote branching of motor neurons, which is important for increased systolic efficiency, and cell glucose uptake was not increased, and insulin sensitivity was lower than in wild mice acting as controls. Was also observed, that is, exercise-induced remodeling would not have occurred without succinate receptors. “

According to Ferreira, this study warns nearby cells that the paracrine action of succinic acid in muscle tissue, ie, internal processes need to be modified to adapt to “new normality,” its intercellular signaling. This is the first to show the role.

“The next step is whether this mechanism is disrupted by other diseases characterized by altered energy metabolism and cell acidification, such as neurodegenerative diseases in which astrocyte-neuron communication is important for disease progression. Is to look up, “he said.

Molecules have been discovered that regulate muscle adaptation to exercise