Study provides molecular look at how healthy muscle adapts to exercise

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  • Succinate, a metabolite generated within cells, is released by muscle during exercise to trigger a cascade of protective changes
  • Finding may lead to drugs that provide some of the benefits of exercise to people who are unable to exercise

Of all the benefits of exercise, scientists have known surprisingly little about the basic interactions that cause muscles to grow stronger and better able to absorb excess blood glucose. In a new study, scientists at Dana-Farber Cancer Institute, Harvard Medical School, and the University of Copenhagen map this process in precise detail, showing how a molecule long thought to be confined within cells becomes an intrepid signal-carrier in response to exercise and serves as a linchpin for the muscle-remodeling mechanism.

The research, described in a paper published today by Cell, describes how this unassuming molecule, a metabolic product called succinate, acts as an intermediary between different types of cells within muscle to orchestrate changes that occur with exercise. The findings may not only lead to tests capable of identifying people who stand the most to gain from exercise to lower their glucose levels, but also to new drugs able to deliver some of the benefits of exercise to those who, because of physical limitations, cannot exercise adequately.

“Exercise is among the most powerful lifestyle interventions for maintaining cardiovascular health and preventing diabetes, obesity, and, as we’re beginning to appreciate, for fighting cancer,” said study senior author Edward Chouchani, PhD, of Dana-Farber. “Despite this, there are some major gaps in our understanding of the mechanisms by which exercise elicits these benefits. In this study, we focused on one of the key adaptations that occurs during exercise: the remodeling of the very muscles that engage in exercise.”

Part of remodeling is familiar to anyone who regularly lifts weights or rides a bicycle: exercising causes muscle strength to increase. In scientific terms, remodeling refers to the process by which muscles become stronger, bigger, and better at siphoning glucose from the blood, helping stave off diabetes, which results from a surplus of blood sugar.

Remodeling is known to be a group activity, involving not just the cells that cause muscle to stretch and contract, but other cells in muscle tissue as well. “We wanted to understand how muscle fibers ‘talk to’ other cell types during exercise – what are the signals that cause them to coordinate their response?” Chouchani remarked.

The researchers sought these signals among muscle cell metabolites, small molecules that serve as energy reservoirs and building blocks for certain cell structures. Evidence gathered over the past decade has shown that in addition to storing energy and providing construction materials, some metabolites also act as signals between cells, enabling cells to adapt to changed conditions.

In a series of experiments, Chouchani and his colleagues sampled the blood and extracellular fluids in muscle of animal and human subjects to see if muscle cells selectively released certain metabolites during exercise. They found one in particular – succinate, a metabolite that had been thought to operate solely the cell, where it helps generate energy in mitochondria. (Previous sightings of succinate in blood had been thought to be the result of cell damage, which caused succinate to leak out.)

The experiments in human subjects were conducted by researchers at the University of Copenhagen. They inserted a catheter into participants’ femoral artery, which supplies blood to the thigh and leg muscles, and another artery into the femoral vein, which carries blood away from those muscles. As participants exercised on a stationary cycle, the researchers looked for metabolites released by exercising muscle by tracking their elevation in the femoral vein.

“We found a selective and transient elevation of succinate during exercise, and as soon as participants got off the exercise bicycle, their succinate levels went down,” Chouchani related.

The researchers discovered that succinate has a unique property that renders it especially prone to be released during exercise. “It’s well known that exercise can produce acidosis, a buildup of protons in muscle cells. We found that when succinate encounters this acidic environment, its chemical properties changes so it acquires an additional proton,” Chouchani explained. “This transformation causes it to be secreted by cells.”

Succinate, in other words, acts as an energy sensor. Alerted to muscle activity by the rise in acidity, it grabs onto more protons, becoming more positively charged and ready for entry into the bloodstream.

Once freed from the cell interior, succinate triggers a spree of signaling activity in muscle tissue. It does so, researchers found, by interacting with a receptor that responds to succinate and is present on different kinds of cells within muscle, including connective cells called stromal cells, immune cells, and muscle cell precursors known as satellite cells.

“This signaling appears to be critical to the way muscle adapts to exercise,” Chouchani commented. “It increases muscle innervation – the content of nerves within muscles – which is essential for improving muscle strength.”

The importance of the connection between succinate and cell receptors in muscle was borne out in a series of animal experiments. Researchers generated mice whose muscle cells lacked the receptor for succinate and put them as well as normal mice on an exercise regimen. Whereas the normal mice became stronger over a period of weeks, as would be expected, the others ran and ran but gained no muscle strength. “It was a futile effort: their muscles were doing at least the same amount of work as the control mice but they didn’t adapt in the way they normally would,” Chouchani commented.

Other investigators have already developed small molecules that mimic succinate in their ability to latch onto receptors on muscle cells. These molecules could be repurposed as the basis of future drugs that stimulate muscle remodeling in much the same way as succinate does, potentially enabling people prevented from exercising by disability or age to reap some of the benefits of exercise, Chouchani said. The research could also lead to the identification of biomarkers that can be used to identify individuals for whom exercise is most likely to be helpful in lowering glucose levels.

The first authors of the study are Anita Reddy of Dana-Farber and Luiz HM Bozi, PhD, of Dana-Farber and the Institute of Biomedical Sciences at the University of Sao Paulo, Brazil. Co-authors are Omar K. Yaghi, Joao A. Paulo, PhD, Diane Mathis, PhD, and Steven P. Gygi, PhD, of Harvard Medical School; Evanna L. Mills, PhD, Haopeng Xiao, PhD, Ryan Garrity, Dina Laznik-Bogoslavski, and Hilary E. Nicholson, PhD, of Dana-Farber; Margherita Paschini, PhD, of Boston Children’s Hospital; Julio CB Ferreira, of the University of Sao Paulo; Christian S. Carl, Kim A. Sjøberg, PhD, Jørgen Wojtaszewski, Bente Kiens, PhD, ScD, and Erik A. Richter, MD, DMSci, of the University of Copenhagen, and Jacob F. Jeppesen, of Novo Nordisk A/S, Denmark.

The research was supported by the American Heart Association and National Institutes of Health (grants DK123095; AR070334, and NIGMS T32GM007753); the JPB Foundation; the Sao Paulo Research Foundation (grant 2019/07221-9), and the National Cancer Center. The human studies were supported by Novo Nordisk A/S.

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