Protein Linking Exercise to Bigger, Stronger Muscles Discovered; Finding Might Lead to New Therapies for Muscle-Wasting Diseases

Mice given extra doses of the protein gained muscle mass and strength, and rodents with cancer were much less affected by cachexia, the loss of muscle that often occurs in cancer patients, according to the report in the Dec. 7 issue of the journal Cell.

"This is basic science at present," commented Jorge Ruas, PhD, first author of the report. "But if you could find a way to elevate levels of this protein, that would be very exciting. For example, you might be able to reduce muscle wasting in patients in intensive care units whose muscles atrophy because of prolonged bed rest." Other applications, he said, might be in disorders such as muscular dystrophy and the gradual loss of muscle mass from aging.

Bruce Spiegelman, PhD, the senior author, led the Dana-Farber team that identified the protein, PGC-1 alpha-4, in skeletal muscle and said it is present in mice and humans. Resistance exercise, such as weight lifting, causes a rise in PGC-1 alpha-4, which in turn triggers biochemical changes that make muscles larger and more powerful, said the researchers.

The protein is an isoform, or slight variant, of PGC-1 alpha, an important regulatory of body metabolism that is turned on by forms of exercise, such as running, that increase muscular endurance rather than size. "It's pretty amazing that two proteins made by a single gene regulate the effects of both types of exercise," commented Spiegelman.

The researchers found that the new protein controls the activity of two previously known molecular pathways involved in muscle growth. A rise in PGC-1 alpha-4 with exercise increases activity of a protein called IGF1 (insulin-like growth factor 1), which facilitates muscle growth. At the same time, PGC-1 alpha-4 also represses another protein, myostatin, which normally restricts muscle growth. In effect, PGC-1 alpha-4 presses the accelerator and removes the brake to enable exercised muscles to gain mass and strength.

"All of our muscles have both positive and negative influences on growth," Spiegelman explained. "This protein (PGC-1 alpha-4) turns down myostatin and turns up IGF1."

Several experiments demonstrated the muscle-enhancing effects of the novel protein. The investigators used virus carriers to insert PGC-1 alpha-4 into the leg muscle of mice and found that within several days their muscle fibers were 60 percent bigger compared to untreated mice. They also engineered mice to have more PGC-1 alpha-4 in their muscles than normal mice who were not exercising. Tests showed that the treated mice were 20 percent stronger and more resistant to fatigue than the controls; in addition, they were leaner than their normal counterparts.

Mice engineered to have extra PGC-1 alpha-4 showed "dramatic resistance" to cancer-related muscle wasting, the scientists found. The mice lost only 10 percent mass in a leg muscle compared to a 29 percent loss in mice with cancer that did not have additional PGC-1 alpha-4, according to the report. The altered mice were also stronger and more active than the normal mice.

Ruas, the first author, is now in the faculty at the Karolinska Institute in Sweden. Other authors are from Dana-Farber Cancer Institute, Harvard Medical School, the University of Colorado, the University of Virginia, and the Mayo Clinic.

CERN's Large Hadron Collider Reveals New Type of Matter

Collisions between protons and lead ions at the Large Hadron Collider (LHC) have produced unexpected behavior in some of the particles created by the collisions, creating a new type of matter known as color-glass condensate. When beams of particles crash into each other at high speeds, the collisions yield hundreds of new particles, most of which fly away from the collision point at close to the speed of light. However, the Compact Muon Solenoid (CMS) team at the LHC found that in a sample of two million lead-proton collisions, some pairs of particles flew away from each other with their respective directions correlated.

"Somehow they fly at the same direction even though it's not clear how they can communicate their direction with one another. That has surprised many people, including us," says MIT physics professor Gunther Roland, whose group led the analysis of the collision data along with Wei Li, a former MIT postdoc who is now an assistant professor at Rice University. A paper describing the unexpected findings will appear in an upcoming issue of the journal Physical Review B and is now available on arXiv.

The MIT heavy-ion group, which includes Roland and MIT physics professors Bolek Wyslouch and Wit Busza, saw the same distinctive pattern in proton-proton collisions about two years ago. The same flight pattern is also seen when ions of lead or other heavy metals, such as gold and copper, collide with each other.

Those heavy-ion collisions produce a wave of quark gluon plasma, the hot soup of particles that existed for the first few millionths of a second after the Big Bang. In the collider, this wave sweeps some of the resulting particles in the same direction, accounting for the correlation in their flight paths.

It has been theorized that proton-proton collisions may produce a liquid-like wave of gluons, known as color-glass condensate. This dense swarm of gluons may also produce the unusual collision pattern seen in proton-lead collisions, says Raju Venugopalan, a senior scientist at Brookhaven National Laboratory, who was not involved in the current research. Venugopalan and his former student Kevin Dusling theorized the existence of color-glass condensate shortly before the particle direction correlation was seen in proton-proton collisions.

While protons at normal energy levels consist of three quarks, they tend to gain an accompanying cluster of gluons at higher energy levels. These gluons exist as both particles and waves, and theirwave functions can be correlated with each other. This "quantum entanglement" explains how the particles that fly away from the collision can share information such as direction of flight path, Venugopalan says. The correlation is "a very tiny effect, but it's pointing to something very fundamental about how quarks and gluons are arranged spatially within a proton," he says.

The CMS researchers originally set out to use the lead-proton collisions as a "reference system" for comparison with lead-lead collisions. "You don't expect quark gluon plasma effects" with lead-proton collisions, Roland says. "It was supposed to be sort of a reference run—a run in which you can study background effects and then subtract them from the effects that you see in lead-lead collisions."

That run lasted only four hours, but in January, the CMS collaboration plans to do several weeks of lead-proton collisions, which should allow them to establish whether the collisions really are producing a liquid, Roland says. This should help narrow down the possible explanations and determine if the effects seen in proton-proton, lead-proton and lead-lead collisions are related.