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August 2, 2018

Exercise Pathway That Regulates Muscle Remodeling May Have Implications for Metabolic Diseases

  • Scientists at the Joslin Diabetes Center have identified a molecular switch that appears to help direct whether we build muscle mass, or develop better aerobic capacity in response to exercise. The protein, c-Jun N-terminal kinase (JNK) is known to be a key regulator of cellular stress and has been associated with inflammatory responses, as well as metabolic diseases such as diabetes. The new findings, reported by a team headed by Sarah Lessard, Ph.D., an assistant investigator at Joslin's section of clinical, behavioral and outcomes research, suggest that targeting JNK could represent a novel therapeutic approach both to help boost muscle mass in muscle wasting diseases, but also potentially to reduce the risk of diabetes.

    "We've begun to figure out how muscle decides whether it will grow or adapt for endurance, which really hasn't been known," Dr. Lessard states. "We've identified an exercise-activated biological pathway that hasn't been studied at all … And we're finding that this process is directly linked to the risk of type 2 diabetes.” So, it's possible that if overactivation of JNK during endurance exercise is shown to boost the risk of diabetes, and if it proves possible to block that process, “we might be able to reverse the risk in some people.”

    The Joslin team and colleagues in the U.S. and in Australia reported their findings in Nature Communications, in a paper titled, “JNK regulates muscle remodeling via myostatin/SMAD inhibition.”

    Exercise that boosts aerobic capacity has been shown to reduce the risk of metabolic disorders such as type 2 diabetes and cardiovascular disease, whereas exercise that is designed to bolster muscle mass and strength can help to reduce age- or cancer-related muscle wasting. However, we all respond differently to different types of exercise.  “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," Dr. Lessard notes. And while some of this variability will be due to factors such as age and predisposing illness, our genes are also believed to play a role in how our skeletal muscles adapt.

    The Joslin team had previously carried out studies in rodent models that had bred over generations to demonstrate low, or high adaptive responses to endurance exercise. These experiments had implicated the JNK pathway in how the animals’ skeletal muscles adapted and remodeled in response to endurance exercise training – which in rodents equates to running on treadmills. In effect, activation of the JNK pathway was linked with reduced adaptive aerobic response and poor adaptation to endurance exercise was also linked with increased risk for chronic metabolic disease.

    Based on these previous findings, the researchers reasoned that blocking JNK might boost how the animals’ skeletal muscle would remodel and demonstrate aerobic adaptations in response to endurance exercise. Initial wheel running tests showed that after 10 weeks of training, endurance capacity in JNK knockout mice was 45% higher than it was in wild-type controls. The knockout animals developed more blood vessels and also more muscle fibers that are characteristic of high endurance capacity. Effectively, the JNK knockouts exhibited muscle features that mimicked those of human endurance-trained athletes. “These experiments demonstrate that JNK is a negative regulator of endurance remodeling in muscle, and identify inhibition of JNK as a strategy to improve endurance adaptations,” the authors write.

    In contrast, they found that JNK activity was necessary for the rodents to boost muscle mass in response to surgical muscle manipulation that mimicked resistance training in humans. “These data demonstrate that JNK is necessary for increased muscle mass and myofiber hypertrophy in response to increased load, supporting the hypothesis that JNK is a positive regulator of hypertrophic adaptation in muscle.”

    "It's like a switch," Dr. Lessard remarks. "If the switch is on, you'll have muscle growth. If it's turned off, you have endurance adaptation in the muscle."

    Further studies in rodents suggested that the JNK activation pathway in muscle suppresses myostatin, a protein that acts to hold back muscle growth.  “In addition to playing a negative role in regulating muscle mass, studies in animal models suggest that myostatin may act as a positive regulator of endurance capacity,” the authors point out.  “In support of a positive role for myostatin in endurance adaptations, we demonstrate that knockout of JNK in skeletal muscle, which would act to enhance myostatin activity, can increase endurance capacity and promote an endurance phenotype (i.e., oxidative fiber type and increased capillary density) in skeletal muscle.”

    The team next collaborated with Vernon Coffey, associate professor of exercise and sports science at Bond University in Australia, to carry out tests in healthy human volunteers.  The results showed that JNK was highly activated in the skeletal muscles of humans carrying out weight lifting, a resistance exercise. In contrast, muscle JNK was generally less activated in response to cycling, an endurance exercise. Interestingly, however, the level of JNK signaling did vary among test subjects, suggesting that this variability may impact how well each person’s muscles might adapt to endurance exercise.

    The researchers are now investigating potential approaches to inhibit JNK activation, and to find out whether the exercise-related variation in JNK activation between people might be related to how much mechanical stress the muscle undergoes. Studies are also ongoing in animal models to see how JNK or related molecular targets might be inhibited.

    “To date, JNK has been known as an important regulator of cellular stress and inflammatory responses,” the authors write. “This work identifies JNK as a molecular switch that, when active, stimulates muscle fibers to grow, leading to increased muscle mass. Conversely, when JNK is inhibited, an alternative adaptive program is induced, leading to endurance adaptations and enhanced aerobic capacity … These data enhance our understanding of the fundamental mechanisms that mediate muscle reprogramming and remodeling in vivo.”

     


     

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