Exercise training reverses muscular atrophy caused by cancer and can extend patient lifespan

A study in rats by researchers at institutions in Brazil, the US and Norway investigated the effects of physical exercise on cancer cachexia. The analysis suggested that exercise training can be an ancillary treatment for cancer patients.

By Maria Fernanda Ziegler  |  Agência FAPESP – Regular exercise can be beneficial for cancer patients. In an animal model study by an international research group, aerobic exercise training not only improved physical capacity but also reversed loss of muscle mass, normalized muscle contractile function, and above all extended lifespan by 30% in tumor-bearing rats.

An article reporting the results is published in the journal Molecular Metabolism. Rats with severe cancer cachexia recovered lost functions of skeletal muscle through exercise training. Some of the results obtained via the experiments with animals were confirmed by an analysis of muscle tissue from lung cancer patients.

The study was supported by FAPESP as part of a Thematic Project and via a Regular Research Grant under the auspices of the mobility program São Paulo Researchers in International Collaboration (SPRINT). 

“Cancer patients tend to suffer from muscular atrophy, a loss of muscle tissue known as cancer cachexia. The reason is that for the tumor to develop, it must interact with the organism, and the skeletal muscles can become a reserve energy source. Simply put, the tumor produces several factors to extract all the protein stored in skeletal muscle in order to grow. In this process, the muscles lose mass and strength,” said Christiano Alves, first author of the article.

Alves is a former awardee of a scholarship from FAPESP and is currently doing postdoctoral research at Harvard University in the United States.

The study showed that rats with cancer cachexia lived 30% longer when given exercise training. “Exercise reduced oxidative stress in skeletal muscles and improved their performance, especially contractile capacity,” Alves said.

Proteomics

To investigate the effects of tumors on skeletal muscle, the researchers first analyzed the proteomics of the rats’ muscles, identifying and quantifying all the proteins in the muscle tissue of three groups of animals: those with tumors and cachexia given exercise training or sedentary, and healthy animals.

“We set out to identify the muscle proteins that are altered in cancer cachexia and that could be a therapeutic target for exercise training, in the sense that their expression could be changed back by exercise to a state close to that of healthy animals. The study wasn’t designed to discover or develop a drug because we knew exercise is itself a low-cost therapy and can have several benefits, including a healthier lifestyle,” said Patricia Chakur Brum, last author of the article. Brum is a professor of exercise physiology at the University of São Paulo’s School of Physical Education and Sport (EEFE-USP) in Brazil. 

Twelve of the cancer-altered proteins identified in the proteomic analysis were changed in the opposite direction by exercise, COPS2 (also known as TRIP15/ALIEN) being the most prominent. This protein is widely studied as essential to the maintenance of all types of cell, but had never before been linked specifically to skeletal muscle. In the analysis, expression of COPS2 was clearly reduced in the animals with cancer and was recouped by exercise.

“Skeletal muscle used to be seen only as key to support and locomotion, as well storing proteins important to the metabolism and as an energy substrate for the organism. We now know the musculoskeletal system has other functions. It can be considered an endocrine organ that synthesizes and releases proteins that can act in a range of different tissues,” Brum said.

The proteins produced and released by skeletal muscle cells are called myokines, she added, and act at a distance. “Our research aims to produce knowledge on this topic and show that cancer patients also need physical exercise. Exercise increases production of myokines and serves as a therapeutic instrument. Extrapolating this to cancer patients, physical exercise becomes fundamental,” she said.

Case study

In parallel with the animal model proteomic study, the researchers analyzed muscle tissue samples from six patients undergoing treatment for lung cancer at the São Paulo State Cancer Institute (ICESP) under the supervision of Gilberto de Castro Jr., who collaborated on the project. They compared protein variation in these samples and muscle tissue from four healthy individuals.

“We found that, as in the animal model, expression of COPS2 also fell significantly in lung cancer patients with cachexia. The data is preliminary because a small number of patients were involved, but can be considered proof of concept for the results of the animal model study,” Alves said.

The group of researchers also investigated the mechanisms involved in loss of skeletal muscle mass due to cancer, and how exercise can rebuild it, by analyzing cultured murine and human cells. The analysis showed that increased expression of COPS2 did not alter muscle cell phenotype and metabolism, whereas reduced expression of the protein was beneficial because it regulated F-actin, an important contractile protein associated with oxidative stress.

“We used molecular biology techniques to assess muscle metabolism by inactivating or overexpressing COPS2. Overall, the study showed that COPS2 reduction in cachexia is a compensatory mechanism to protect muscles and that its release is a sign that something is wrong with muscles and that cachexia is occurring,” Alves said.

In this equation, the study demonstrated that exercise stabilizes COPS2 expression. “Exercise brings muscles back to a normal state. Once they have been regularized, COPS2 signaling is no longer required. Analyzed directly, exercise reduces oxidative stress in the muscles, and this is reflected in its prime function, which is contraction-relaxation. Exercise also results in a complete improvement, including in the individual’s metabolism,” Brum said.

The article “Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN” (doi: 10.1016/j.molmet.2020.101012) by Christiano R. R. Alves, Willian das Neves, Ney R. de Almeida, Eric J. Eichelberger, Paulo R. Jannig, Vanessa A. Voltarelli, Gabriel C. Tobias, Luiz R. G. Bechara, Daniele de Paula Faria, Maria J. N. Alves, Lars Hagen, Animesh Sharma, Geir Slupphaug, José B. N. Moreira, Ulrik Wisloff, Michael F. Hirshman, Carlos E. Negrão, Gilberto de Castro Jr, Roger Chammas, Kathryn J. Swoboda, Jorge L. Ruas, Laurie J. Goodyear and Patricia C. Brum is at: www.sciencedirect.com/science/article/pii/S2212877820300867?via%3Dihub#!.