A team from the Joslin Diabetes Center has found that a molecular switch that occurs in the muscles may explain why some people respond better to aerobic exercise and strength training, while others do not.

After researching both lab animals and humans, the scientists discovered that c-Jun N-terminal kinase (JNK) aids in driving the response to exercise. If the protein is activated, exercise will stimulate skeletal muscle growth and if it is not activated, muscles will improve their adaption for endurance and aerobic capacity.

“We've identified an exercise-activated biological pathway that hasn't been studied at all,” Sarah Lessard, PhD, an assistant investigator in Joslin's section of Clinical, Behavioral and Outcomes Research and first author on the paper, said in a statement. “It's like a switch. If the switch is on, you'll have muscle growth. If it's turned off, you have endurance adaptation in the muscle.

“If a hundred people do the exact same aerobic training program, some will have huge improvements in aerobic capacity, and some will have little to no response,” she added.

The researchers previously examined which genes were activated in two groups of lab rats that had been bred for several generations to respond either very well or poorly to endurance exercise training, such as running on treadmills. They discovered that activation of the JNK biological pathway predicted how an animal would respond to endurance exercise training.

The researchers then opted to study mice that had been genetically modified to knock out the production of JNK in their muscles. The genetically modified mice remained perfectly healthy and ran vigorously on wheels in cages similar to normal mice.

However, when both groups of mice were trained to run, the JNK knockout mice had a significantly higher increase than normal mice in aerobic exercise capacity, as well as higher levels of blood vessels and a type of muscle fiber specialized to give endurance.

The researchers then ran an experiment that promotes muscle growth in animals, where normal mice doubled the mass of their affect muscle, but the JNK knockout mice did not increase their muscle mass as much. The team found that JNK works through a well-known pathway involving myostatin—a protein that restrains muscle growth.

After collaborating with researchers in Australia, the team found that JNK was highly activated in the muscles of humans lifting leg weights but was not activated when the volunteers performed an endurance exercise like cycling.

However, a significant minority of the test subjects did show some JNK activation in their leg muscles during the endurance exercise, which could prevent endurance adaptations and explain why some people do not respond as well to endurance exercise.

The team now is looking at various ways to inhibit JNK activation, including developing approaches to reduce mechanical stress on the muscles. They are also trying to treat the condition with drugs that inhibit JNK or related molecular targets.

Exercise that promotes aerobic capacity is a powerful factor in preventing diabetes, cardiovascular disease and other chronic metabolic diseases. However, that capacity is not evenly distributed among us.

The Joslin study has direct implications for the prevention of these diseases and could prove useful for developing therapeutic approaches to build muscle to fight muscle-wasting diseases.

“We've begun to figure out how muscle decides whether it will grow or adapt for endurance, which really hasn't been known,” Lessard said. “And we're finding that this process is directly linked to the risk of type 2 diabetes.”

The study was published in Nature Communications.