To Evolution

The muscle 'switch' can control the benefits of exercise

    Abdulaziz Sobh
    By Abdulaziz Sobh

    Categories: Beauty & Fitness, Health


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    Some people respond well to both aerobic exercise and strength training, while others do not. And some of us respond well only to one of those things, but not to both. The scientists at the Joslin Diabetes Center have now discovered a surprising molecular "switch" that can help explain why this happens.

    "We have identified a biological pathway activated by exercise that has not been studied at all," says Sarah Lessard, Ph.D., an assistant researcher in Joslin's clinical, behavioral and results in research section and first author in a paper that presents the research in the journal Nature Communications.

    When studying laboratory animals and humans, Lessard, and his colleagues discovered that a protein called c-Jun N-terminal kinase (JNK) helps boost the response to exercise. If JNK is activated during exercise, the researchers say, that stimulates the growth of skeletal muscle. If it is not activated, the muscles improve their adaptation for endurance and aerobic capacity.

    "It's like a switch," says Lessard. "If the switch is on, it will have muscle growth, if it's off, it will have an adaptation of resistance in the muscle."

    Exercise is the basis of our overall health, and 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.

    "If one hundred people perform exactly the same aerobic training program, some will have great improvements in aerobic capacity, and some will have little or no response," says Lessard. Your laboratory studies the biological signals that tell a muscle that adapts to aerobic capacity or muscle growth.

    In a previous work, the Joslin team observed which genes were activated in two groups of laboratory rats that had been bred for many generations to respond very well or very badly to endurance training (running on treadmills). The scientists found that activation of the JNK biological pathway predicted that an animal would respond poorly to resistance training.

    That finding was a bit unexpected as the researchers knew that JNK was associated with inflammation in metabolic diseases such as type 2 diabetes and obesity. So, why will the protein be activated with exercise?

    Lessard and his colleagues began their current study with mice that had been genetically engineered to knock out JNK production in their muscles. These "JNK knockout" mice remain perfectly healthy and will run vigorously on wheels in their cages much like normal mice. ("Mice really enjoy running several kilometers a night," says Lessard).

    But when both groups of mice were trained to run, the researchers found that JNK knockout mice had a much higher increase than normal mice in aerobic exercise capacity, along with higher levels of blood vessels and a type of specialized muscle fiber to provide resistance.

    Then, Joslin researchers conducted an experiment that promotes muscle growth in animals. The normal mice doubled the mass of their affected muscles, but the JNK knockout mice did not increase their muscle mass nearly as much.

    Deepening the biological mechanisms underlying these results, the scientists discovered that JNK works through a well-studied pathway that involves myostatin, a protein that slows muscle growth. Myostatin is the target in some clinical trials that seek to increase muscle mass in aging and in diseases such as advanced cancer, where the loss of muscle mass is often a serious problem.

    The Joslin researchers then collaborated with Vernon Coffey, an associate professor of exercise and sports science at Bond University in Gold Coast, Queensland, Australia, on tests on healthy human volunteers. The results of the Coffey group indicated that similar biological mechanisms were in operation.

    The tests showed that JNK was activated a lot in the muscles of humans by lifting leg weights, a resistance exercise. In contrast, JNK was generally not activated in the muscle when the volunteers performed cycling, a resistance exercise.

    But a significant minority of test subjects showed some activation of JNK in the muscles of their legs during resistance exercise. Such activation could avoid resistance adaptations and could explain why some people do not respond as well to endurance exercise.

    The Joslin team is looking for several ways to inhibit JNK activation. Among them, scientists think that the activation of JNK during exercise depends on the amount of mechanical stress in the muscle and that some people experience a higher level of mechanical stress during aerobic exercise. If so, developing approaches to reduce this stress could improve the response.

    In addition, researchers are experimenting with animal models to treat this disease with drugs that inhibit JNK or related molecular targets.

    The Joslin study has direct implications for the prevention of type 2 diabetes, the reduction of complications of diabetes and the prevention of cardiovascular diseases. It could also be useful to develop therapeutic approaches to build muscle and fight diseases that cause muscle loss. (It can also help explain the "interference phenomenon" experienced by athletes during concurrent training).

    "We have begun to discover how the muscles decide whether it will grow or adapt for resistance, which is not really known," says Lessard. "And we discovered that this process is directly related to the risk of type 2 diabetes."

    Lessard and his colleagues are now testing this hypothesis in a study that looks at the JNK pathway during resistance exercise, comparing people at increased risk of type 2 diabetes compared to people at normal risk.

    If over-activation of the JNK pathway during resistance exercise actually increases the risk of diabetes, and if scientists can find a way to stop that process, "we may be able to reverse the risk in some people," Lessard speculates.