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A new study suggests that a hormone known to prevent weight gain and normalize metabolism may also help maintain healthy muscles in mice. The results offer new ways to treat muscle wasting conditions associated with age, obesity, or cancer, according to scientists at the University of Southern California’s Leonard Davis School of Gerontology.

The study, published this month in the American Journal of Physiology-Endocrinology and Metabolism, looks at the associated problems of age- and obesity-related muscle loss, which can lead to increased risk of falls, diabetes, and other negative health effects. It also contributes to a growing body of evidence describing the beneficial effects of MOTS-c, a mitochondrial-derived peptide known to mimic the effects of exercise.

In this study, treating mice on a high-fat diet with MOTS-c helped prevent obesity-related muscle atrophy by lowering levels of myostatin, a protein that inhibits muscle growth. The myostatin level in MOTS-c treated mice was 40% lower than in control mice. The researchers also found that higher MOTS-c levels in humans correlated with lower myostatin levels.

The results of the mice show that MOTS-c not only improves metabolic function, but also muscle mass.

Through molecular analysis, the researchers also identified the specific signaling pathway regulated by MOTS-c, showing, for the first time, “that MOTS-c modulates the CK2-PTEN-AKT-FOXO1 pathway to control myostatin expression and muscle wasting The exercise mimetic effect of MOTS-c can be derived from its previously unknown role as a myostatin inhibitor, according to the paper.

“Understanding the pathway affected by MOTS-c is really important in discovering potential treatments,” said author Su Jeong Kim, a professor at USC Leonard Davis School. “This finding provides a target for potential drug development efforts and can be quickly translated into clinical trials with MOTS-c and related analogues.”

Although several other myostatin inhibitors have been identified, they have yet to successfully reduce the conditions for muscle wasting in clinical trials. This could be because improving muscle mass alone isn’t enough, say the USC researchers. They believe increasing mitochondrial function is also vital, and say MOTS-c-derived treatments could be particularly promising in this regard.

Corresponding author Pinchas Cohen, professor of gerontology, medicine, and life sciences and dean of USC Leonard Davis School, and Changhan David Lee, assistant professor at USC Leonard Davis School, first described MOTS-c and its metabolic effects in 2015. Their mouse studies have shown that administration of MOTS-c improves insulin resistance caused by high fat diets and aging, as well as increased exercise capacity and mean lifespan.

“Taken together, our work suggests that MOTS-c can treat mitochondrial dysfunction,” says Cohen. “This study can help improve healthy aging by opening up new avenues for research into conditions such as insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting conditions including sarcopenia.”

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More information:
Hiroshi Kumagai et al., MOTS-c Reduces Myostatin Signaling and Muscular Atrophy, American Journal of Physiology-Endocrinology and Metabolism (2021). DOI: 10.1152 / ajpendo.00275.2020 Provided by the University of Southern California

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