Researchers identify precise cause of muscle weakness and loss due to aging.

As humans grow older, they lose strength and muscle mass. Skeletal muscle weakness and atrophy are among the most pervasive and disruptive effects of aging. In nearly all people, even elite athletes, a subtle loss of muscle strength begins between the ages of 30 and 40. Over the next 2-3 decades, strength continues to erode while muscle mass typically declines to a lesser degree. As a result, reduced muscle quality is a hallmark of the aging process. By the age of 65, overt muscle loss (age-related muscle atrophy, or sarcopenia) is apparent in many individuals, and nearly all elderly persons report a gradual loss of strength and muscle over the course of their lives.

The clinical consequences of age-related weakness and muscle loss are significant. Weakness limits activity, impairs quality of life, contributes to falls and fractures, and can create a vicious cycle of muscle disuse and further muscle loss and weakness. In its later stages, age-related muscle atrophy can lead to frailty, debilitation and loss of independent living. This is exacerbated by the fact that the cause of age-related muscle weakness and atrophy is still unclear.

Now, researchers at the University of Iowa have discovered the first example of a protein that causes muscle weakness and loss during aging. The lab explain that the protein, ATF4, is a transcription factor that alters gene expression in skeletal muscle, causing reduction of muscle protein synthesis, strength, and mass. The new study also identifies two natural compounds, one found in apples and one found in green tomatoes, which reduce ATF4 activity in aged skeletal muscle. The team states that their findings could lead to new therapies for age-related muscle weakness and atrophy. The opensource study is published in the Journal of Biological Chemistry.

Previous studies show that despite their broad impact, age-related muscle weakness and atrophy cannot be reliably prevented by physical therapy or current nutritional approaches, and a pharmacologic therapy does not exist. The development of effective interventions has been somewhat hindered by the fact that the molecular basis of age-related muscle weakness and atrophy is largely unknown. The slow progression of age-related muscle atrophy represents a significant barrier to its study, and suggests that the condition may reflect subtle molecular and cellular changes that accumulate in muscle over many years. Earlier nutritional studies from the group identified ursolic acid, which is found in apple peel, and tomatidine, which comes from green tomatoes, as small molecules that can prevent acute muscle wasting caused by starvation and inactivity. Those studies set the stage for testing whether ursolic acid and tomatidine might be effective in blocking the largest cause of muscle weakness and atrophy, aging.

In the current study elderly mice with age-related muscle weakness and atrophy were fed diets lacking or containing either 0.27 percent ursolic acid, or 0.05 percent tomatidine for two months. The results show that both compounds increased muscle mass by 10 percent, and more importantly, increased muscle quality, or strength, by 30 percent. Data findings show that the sizes of these effects suggest that the compounds largely restored muscle mass and strength to young adult levels. The lab state that based on these results, ursolic acid and tomatidine appear to have a lot of potential as tools for dealing with muscle weakness and atrophy during aging. They also hypothesize that ursolic acid and tomatidine could be used as tools to find a root cause of muscle weakness and atrophy during aging.

The researchers also investigated the molecular effects of ursolic acid and tomatidine in aged muscle. Results show that both compounds turn off a group of genes that are turned on by the transcription factor ATF4. This led the lab to engineer and study a new strain of mice that lack ATF4 in skeletal muscle. They go on to conclude that like old muscles that were treated with ursolic acid and tomatidine, old muscles lacking ATF4 were resistant to the effects of aging.

The team surmise that by reducing ATF4 activity, ursolic acid and tomatidine allow skeletal muscle to recover from effects of aging. For the future the researchers are now working to translate ursolic acid and tomatidine into foods, supplements, and pharmaceuticals that can help preserve or recover strength and muscle mass as people grow older.

Source: University of Iowa