Karolinska helps find a novel protein that makes muscles bigger and stronger

In a study in mice, Swedish and American scientists have identified a previously unknown protein that spurs muscle growth and increased power following resistance exercise - such as bodybuilding or weightlifting. The findings are presented in the journal Cell, and the scientists speculate that artificially raising the novel protein's levels might someday help prevent muscle mass loss caused by, for example, cancer, prolonged inactivity in hospital patients, and aging.

"This is basic science at present, but since the protein can be found also in humans these findings open up exciting possibilities for the future," says Jorge Ruas, a research group leader at Karolinska Institutet, previously at the Dana-Farber Cancer Institute and Harvard Medical School in the US, where the current study was conducted under the supervision of Professor Bruce Spiegelman.

The novel protein is called PGC-1a4 and is a variant of a protein that Professor Spiegelman and his team discovered about a decade ago, which is called PGC-1a. Over the last years, PGC-1a has been shown to be an important regulator of body metabolism that is turned on in muscle by forms of exercise that increase endurance, such as running. The current study revealed that what they first believed to be one single protein, are in fact several variants encoded by the same gene. The same study shows that one of these variants, PGC-1a4, plays an important role in muscle growth following resistance exercise.

Several experiments demonstrated the muscle-enhancing effects of the novel protein. The investigators introduced PGC-1±4 into the leg muscles of mice and found that after some time their muscle fibers were about 60 percent bigger compared to the untreated leg of each mouse. Mice engineered to have extra PGC-1a4 in their skeletal muscles were both stronger and leaner than their normal counterparts, even without any exercise training. These mice showed also a 'dramatic resistance' to cancer-related muscle wasting. In those experiments, tumor-bearing mice with increased muscle PGC-1a4 content lost only 10 percent leg muscle mass compared to about 30 percent loss in mice with cancer that did not have additional PGC-1a4. As a result, the engineered mice were stronger and more active even at later stages of tumor development.

The scientists also investigated the mechanism behind these alterations in muscle. They found that the novel protein controls the activity of two previously known molecular pathways involved in muscle growth. A rise in PGC-1a4 with exercise increases activity of a protein called IGF1 (insulin-like growth factor 1), which facilitates muscle growth. At the same time, PGC-1±4 also represses another protein, myostatin, which normally restricts muscle growth. In effect, PGC-1a4 presses the accelerator and removes the brake to enable exercised muscles to gain mass and strength.

In addition to scientists at Karolinska Institutet and the Dana-Faber Cancer Institute/Harvard Medical School, scientists from the University of Colorado, the University of Virginia, and the Mayo Clinic, all in the US, participated in the study. The work was funded by grants to Jorge Ruas from the Wenner-Gren Foundations and to Bruce Spiegelman from the NIH, and Novartis.