Ursolic acid -- a waxy substance found in apple peel -- reduces muscle wasting and promotes muscle growth in mice; it also reduces fat, blood sugar levels, cholesterol and triglycerides in the animals.
For Popeye, spinach was the key to extra muscle. For the mice in a new University of Iowa study, it was apples, or more precisely a waxy substance called ursolic acid that's found in apple peel.
The UI study, published in the June 8 issue of the journal Cell Metabolism, showed that ursolic acid reduced muscle atrophy (also known as muscle wasting) and promoted muscle growth in mice. It also reduced fat, blood sugar levels, cholesterol and triglycerides in the animals. The findings suggest that the compound may be useful for treating muscle wasting and possibly metabolic disorders such as diabetes.
"Muscle atrophy causes big problems. It's also very common -- it affects most people at some point in their lives, during illness or aging. But, there's no medicine for it," said Christopher Adams, M.D., Ph.D., UI endocrinologist and senior author of the study. "We studied muscle gene activity in people with atrophy and used that information to find chemicals that might block atrophy. One of those chemicals was especially interesting. It's called ursolic acid and it's particularly concentrated in apple peels.
"The old saying goes that 'an apple a day keeps the doctor away.' So, we tested ursolic acid in mice, and found that it increased the size and strength of their muscles," Adams added. "It did this by helping two hormones that build muscle: insulin-like growth factor-1 (IGF1) and insulin. Because ursolic acid increased muscle, it reduced muscle atrophy. Surprisingly, it had some other beneficial effects in mice: for example, it reduced body fat, and lowered blood glucose and cholesterol."
Adams and colleagues homed in on ursolic acid by using connectivity maps, a relatively new technique that compares gene expression patterns in cells under different conditions. The team determined which genes are turned on or off in human muscle during atrophy and compared that pattern with gene expression patterns in cultured cell lines treated with a library of different compounds. They discovered that one of those compounds -- ursolic acid -- causes a pattern of gene expression that is the opposite of the pattern caused by atrophy. This suggested that ursolic acid might reverse atrophy.
In follow-up experiments, the researchers proved that mice fed ursolic acid were indeed protected from muscle atrophy caused by both fasting and nerve damage. Furthermore, healthy mice fed ursolic acid developed larger, stronger muscles than mice that did not receive the compound.
The study suggests that ursolic acid's ability to both inhibit muscle wasting and promote muscle growth stems from its ability to influence IGF1. This hormone, and its close cousin insulin, both bind to receptors on muscle cells setting off a cascade of cellular pathways that either enhance muscle growth or block atrophy. Ursolic acid appears to increase the activity of the receptors for IGF1 and insulin, amplifying the beneficial effects of these hormones in muscle.
Interestingly, although ursolic acid increased muscle weight in mice, it did not increase total body weight, and further investigation showed that mice fed ursolic acid had less body fat than mice that were not fed the compound.
Adams and his colleagues now hope to move the research toward human trials.
In search of a way to prevent the muscle wasting that comes with illness and aging, researchers have landed a natural compound that might just do the trick. The findings reported in the June issue of Cell Metabolism, a Cell Press publication, identify a component of apple peels as a promising new drug candidate for the widespread and debilitating condition that affects nearly everyone at one time or another.
"Muscle wasting is a frequent companion of illness and aging," said Christopher Adams of The University of Iowa, Iowa City. "It prolongs hospitalization, delays recoveries and in some cases prevents people from going back home. It isn't well understood and there is no medicine for it."
Motivated by the desire to change that, Adams' team first looked at what happens to gene activity in muscles under conditions that promote weakening. Those studies turned up 63 genes that change in response to fasting in both people and mice and another 29 that shift their expression in the muscles of both people who are fasting and those with spinal cord injury. Comparison of those gene expression signatures to the signatures of cells treated with more than 1300 bioactive small molecules led them to ursolic acid as a compound with effects that might counteract those of atrophy.
"Ursolic acid is an interesting natural compound," Adams said. "It's part of a normal diet as a component of apple peels. They always say that an apple a day keeps the doctor away…"
The researchers next gave ursolic acid to fasted mice. Those experiments showed that ursolic acid could protect against muscle weakening as predicted. When ursolic acid was added to the food of normal mice for a period of weeks, their muscles grew. Those effects were traced back to enhanced insulin signaling in muscle and to corrections in the gene signatures linked to atrophy.
Animals given ursolic acid also became leaner and had lower blood levels of glucose, cholesterol and triglycerides. The findings therefore suggest that ursolic acid may be responsible for some of the overall benefits of healthy eating.
"We know if you eat a balanced diet like mom told us to eat you get this material," Adams said. "People who eat junk food don't get this."
It is not yet clear whether the findings in mice will translate to human patients, Adams says, but his goal now is to "figure out if this can help people." If so, they don't yet know whether ursolic acid at levels that might be consumed as part of a normal diet might or might not be enough.
Contacts and sources:
University of Iowa Health Care Media Relations, 200 Hawkins Drive, Room W319 GH, Iowa City, Iowa 52242-1009
In addition to Adams, the UI research team included Steven Kunkel, M.D., Manish Suneja, M.D., Scott Ebert, Kale Bongers, Daniel Fox, Sharon Malmberg, Fariborz Alipour, Ph.D., Richard Shields, Ph.D., and Michael Welsh, M.D.
The study was funded by the Doris Duke Charitable Foundation, the National Institutes of Health, the Department of Veterans Affairs, the American Diabetes Association, the UI Institute for Clinical and Translational Science, the UI Research Foundation and the University of Iowa Fraternal Order of Eagles Diabetes Research Center.