Steroids. A buzzword often featured in news stories, speeches and research. Overlooked in many of these is their place as a treatment for muscle wasting physical conditions like muscular dystrophy. A new discovery published in The Proceedings of the National Academy of Sciences could change that.

Scientists have discovered that glucocorticoids enhance muscular endurance and combat muscular atrophy through activation of the Krüppel-like factor 15 gene, or KLF15.

Glucocorticoids are steroid hormones used which have been used in a clinical setting to treat Duchenne’s muscular dystrophy (DMD) since the 1980s. Their ability to boost athletic performance has also been known for several decades. However, their excessive use can lead to bone fragility, behavioral abnormalities and a host of other negative health conditions. This originally cast doubt on their ability to be used as a long-term treatment option.

Until this recent study, scientists were unable to explain how glucocorticoids produced their benefits.

“This study sheds light on the 25-year mystery of precisely how glucocorticoids exert their beneficial effects in DMD,” the study’s first author, Alexander Morrison-Nozik, PhD, said.

Scientists were aware of the KLF15 gene’s role in muscle cell metabolism, as well as the way it was affected by glucocorticoids. This allowed them to narrow their research.

“It was exciting to discover that KLF15 is both necessary and sufficient to mediate the performance enhancing properties of glucocorticoids,” Morrison-Nozik said.

To come to their conclusion, researchers removed the KLF15 gene from healthy mice and compared their muscular endurance to mice with the gene present. Normal mice were able to run 50 percent longer on a treadmill after being given a dose of glucocorticoid drugs. KLF15-deficient mice did not respond to the drugs. They also experienced muscle atrophy after high steroid exposure.

Scientists then genetically engineered mice with five to six times higher-than-normal levels of KLF15 in skeletal muscle. These mice, equivalent to those who had been given a dose of glucocorticoids, had significantly improved exercise capacity. This demonstrated the KLF15 gene’s role in muscular endurance. These mice also experienced no detrimental side effects.

"We now believe DMD is characterized by KLF15 deficiency, and the full therapeutic effect of glucocorticoids requires KLF15," senior author of the study, Saptarsi Haldar, MD, said.

The next step in the research will attempt to replicate the increased muscular capacity brought on by increased KLF15 levels. These attempts will happen independently of glucocorticoid use.

“Since genetic engineering experiments show that increased KLF15 levels in muscle can improve DMD, the next question is whether we can achieve these same effects by pharmacologically manipulating KLF15 directly," Haldar said.

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