Better muscles thanks to a genetic knock-out

A team of researchers has improved the muscle structure and stamina of mice and nematodes by reducing the function of a natural inhibitor, suggesting treatments for age-related or genetically caused muscle degeneration are within reach.

If they weren’t held back by the effect of a natural inhibitor, our muscles would be stronger, more powerful and better formed than they are in reality. This is the surprising conclusion reached by scientists in EPFL’s Laboratory of Integrative Systems Physiology (LISP), in collaboration with a group in the Center for Integrative Genomics at the University of Lausanne and the Salk Institute in California. By acting on a receptor (NCoR1), they were able to modulate the transcription of certain genes, creating a strain of “mighty mice” whose muscles were twice a strong as those of normal mice.

Two protein-building “regulators”
The process of transcription, in which proteins are manufactured by an organism in response to instructions contained in its DNA, is modulated by so-called “co-factors.” These either favor (coactivators) or inhibit (corepressors) transcription, for example during the buildup of fat or muscle tissues. They respond in principle to the concentration of certain hormones in the body, which are in turn associated with the organism’s environment.

In an article appearing today in the journal Cell, a team led by EPFL professor Johan Auwerx reports on the results of experiments done in parallel on mice and nematodes. The researchers were able to suppress the NCoR1 corepressor, which normally acts to inhibit the buildup of muscle tissues.

Better muscles
The effect was impressive. Without this natural inhibitor, the muscle tissue developed much more effectively. The mice with the mutation became true “marathoners”, capable of running faster and longer before showing any signs of fatigue. In fact, they were able to cover almost twice the distance run by mice that hadn’t received the treatment. They also exhibited better cold tolerance.

Unlike other, older “super-mice” experiments, this study does not only address the way the energy is burnt in the muscle but modifies the way the muscle itself is built while the mouse grows. It has been confirmed under the microscope that the muscle fibers of the modified mice are denser, the muscle is more massive, and the cells also contain higher numbers of mitochondria – organelles in the cell that deliver energy to the muscles.
All these results were also observed in nematodes, allowing the scientists to conclude that their results could be applicable to a large range of living creatures.

Obese but not diabetic
According to a second article published in the same journal, also involving EPFL’s LISP Laboratory, suppressing this NCoR1 receptor in adipose tissues also led to interesting results. By acting on this corepressor, it was possible to fundamentally change the corpulence of the mice being studied. Remarkably, “the specimens that became obese via this treatment did not suffer from diabetes, unlike mice who become obese for other reasons,” notes Auwerx.

Even better, the scientists have not yet detected any deleterious side effects associated with eliminating the NCoR1 receptor from muscle and fat tissues.

Although the experiments involved genetic modifications, the researchers are already investigating potential drug molecules that could be used to reduce the receptor’s effectiveness.

Treating degeneration
These results are a milestone in our understanding of certain fundamental mechanisms of living organisms and the little-studied role of corepressors. In addition, they already give a glimpse of possible long term therapeutic applications. “This could be used to combat muscle weakness (called frailty) in the elderly, which leads to falls and is an important contributor to hospitalizations,” emphasizes Auwerx. “In addition, we think that this could be used as a basis for developing a treatment for genetic muscular dystrophy.”

If these results are confirmed in humans, there’s no question that the research will attract a huge amount of interest from athletes. “It will be important for anti-doping authorities to monitor that these treatments are not used in an unauthorized manner,” concludes Auwerx.