New research suggests that a liver protein may be to blame for exercise resistance.

In a study of both mice and human subjects, researchers found that higher levels of selenoprotein P - a protein secreted by the liver - was associated with reduced exercise capacity and fewer exercise-related benefits.

Study co-author Hirofumi Misu, of the Kanazawa University Graduate School of Medical Sciences in Japan, and colleagues say that their findings indicate that selenoprotein P may be a driver of exercise resistance.

The researchers recently published their findings in the journal Nature Medicine.

According to current guidelines, adults should engage in around 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity each week in order to maintain good health.

However, responsiveness to exercise - in terms of both endurance and metabolic health - can vary widely from person to person.

"In particular, some people show complete non-responsiveness to exercise training in terms of aerobic improvement. Similarly, 15-20 percent of patients with type 2 diabetes show a poor hypoglycemic effect to regular exercise therapy," the authors note.

"These findings indicate that some people suffer from exercise resistance and derive limited benefits from the health-promoting effects of physical exercise."

The precise mechanisms behind exercise resistance, however, have been unclear. Previous research has indicated that selenoprotein P might play a role, so Misu and colleagues set out to investigate this association further.

Selenoprotein P linked to reduced exercise endurance

Firstly, the team assessed the effects of exercise training on two groups of mice: one that was deficient in selenoprotein P, and one group of wild-type mice (the controls).

Both groups ran on a treadmill for 30 minutes per day for 1 month. The researchers found that the selenoprotein P-deficient mice had double the exercise capacity of the wild-type mice.

Furthermore, at the end of the 1-month exercise training, the selenoprotein P-deficient mice demonstrated a larger reduction in blood glucose levels following an injection with the hormone insulin.

The researchers also administered selenoprotein P to wild-type mice prior to 1 month of exercise training.

These mice showed a reduction in phosphorylation of the enzyme AMPK in their muscles. The researchers explain that AMPK phosphorylation is associated with a number of exercise benefits.

Additionally, the researchers found that mice lacking LRP1 - a selenoprotein P receptor in muscles - were unable to absorb selenoprotein P into their muscles. Furthermore, AMPK phosphorylation was not impacted by exercise training.

Findings may lead to exercise-enhancing drugs

Next, Misu and team sought to determine the effects of selenoprotein P on exercise in humans.

The researchers enrolled 31 women who were healthy but who did not engage in regular exercise.

All women took part in 8 weeks of aerobic training, and their maximal oxygen intake was monitored throughout as a measure of exercise endurance.

The team found that women who had high levels of selenoprotein P in their blood prior to the 8-week exercise program demonstrated a lower maximal oxygen intake than those with lower levels of selenoprotein P.

Taken together, the researchers believe that their results indicate that selenoprotein P contributes to exercise resistance by targeting the LRP1 receptor in muscles.

Further research is needed in order to gain a more detailed understating of how selenoprotein P impacts physical activity, but the team believes that this current study may pave the way for drugs that reduce selenoprotein P production to improve exercise endurance.

Misu and colleagues write:

"The current findings suggest that future screening for inhibitors of the [selenoprotein P]-LRP1 axis could identify exercise-enhancing drugs to treat physical-inactivity-associated diseases such as type 2 diabetes."