Exercise plays an important role in preventing cancer and slowing down aging, among other things. However, we already know that exercise affects different people in significantly different ways. The health-promoting effects of regular exercise have become a big problem for some people with little benefit. Researchers have reported that people with type 2 diabetes have higher concentrations of selenoprotein P in their blood, a protein produced and secreted by the liver that enhances insulin resistance, which causes elevated blood sugar levels. They proposed to call this hormone “hepatokine,” which is secreted by the liver and transported through the bloodstream to organs and tissues throughout the body, where it exerts different effects. However, the role of selenoprotein P, a hepatokine, in health promotion through physical exercise has not been clear in the past. Results The research team members from Kanazawa University, two other universities, a company and a Chinese hospital explored the effects of selenoprotein P on physical exercise outcomes through mouse experiments, cultured myoblasts and clinical studies, and obtained the following results. Mice were exercised on a treadmill for 30 minutes per day for one month. The team found that after one month of exercise, selenoprotein P-deficient mice showed twice as much exercise capacity than indicated than wild-type (WT) mice. After exercise, selenoprotein P-deficient mice also showed a greater reduction in blood glucose levels caused by insulin injections than WT mice. The study showed that muscle AMPK phosphorylation levels were reduced after one month of exercise in WT mice given selenoprotein P; AMPK phosphorylation is thought to be associated with a variety of good training effects. In addition, it was shown that mice lacking the muscle selenoprotein P receptor LRP1, given selenoprotein P does not enter the muscle and AMPK phosphorylation levels are not affected after exercise. A total of 31 healthy sedentary women without obesity and without type 2 diabetes underwent 8 weeks of aerobic training, and maximal oxygen consumption was measured to assess exercise capacity. In general, maximal oxygen consumption increased after training, but some women did not show a large increase. These women had higher blood levels of selenoprotein P prior to training. These results suggest that selenoprotein P affects muscle through the receptor LRP1, resulting in “exercise resistance” and therefore counteracting the effects of exercise. Significance Higher blood levels of selenoprotein P have been reported in patients with type 2 diabetes or fatty liver, as well as in the elderly. There is also a possibility that due to high selenoprotein P levels, these individuals are “exercise-resistant” and do not fully reap the health-promoting benefits of exercise. The results of this study are expected to lead to the development of “exercise enhancing drugs” by finding drugs that reduce the production of selenoprotein P in the liver and that compete with the muscle selenoprotein P receptor LRP1. In the future, by measuring selenoprotein P levels in the blood, different people may be diagnosed as “exercising effectively” or “exercising ineffectively”.