USP19 inhibition protects against muscle wasting

Researchers have discovered a new gene involved in the muscle wasting syndrome cachexia that could be a good target for drug development.

It is estimated that half of all cancer patients suffer from a muscle wasting syndrome called cachexia. Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients. Currently, there is no approved treatment for muscle wasting.

The findings could have huge clinical implications, as muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis and chronic obstructive pulmonary disease and is also a prominent feature of aging.

“We discovered that the gene USP19 appears to be involved in human muscle wasting and that in mice, once inhibited, it could protect against muscle wasting, ”says Dr Simon Wing, McGill University Health Centre (MUHC) endocrinologist and professor of Medicine at McGill University. “Muscle wasting is a huge unmet clinical need. Recent studies show that muscle wasting is much more common in cancer than we think.”

In this study, researchers created mice models that were lacking USP19 (USP19 KO mice) and decided to look at two common causes of muscle wasting. They observed whether such mice were resistant to muscle wasting induced by a high level of cortisol – a stress hormone released in your body any time you have a stressful situation such as an illness or a surgery. They also looked at the loss of nerve supply because muscle atrophy can occur following a stroke when people are weak and bedbound. In addition, they looked at USP19 levels in human muscle samples from the most common cancers that cause muscle wasting: lung and gastrointestinal.

Inhibiting USP19 protected against muscle wasting

“We found that USP19 KO mice were wasting muscle mass more slowly; in other words, inhibiting USP19 was protecting against both causes of muscle wasting,” explains Dr Wing who is also the director of the Experimental Therapeutics and Metabolism Programme at MUHC. “Our results show there was a very good correlation between the expression of this gene in the human muscle samples and other biomarkers that reflect muscle wasting.”

According to recent studies, the prevalence of cachexia is high, ranging from 5 to 15% in chronic heart failure and COPD, and from 60 to 80% in advanced cancer. In all of these chronic conditions, muscle wasting predicts earlier death.

Dr Antonio Vigano, director of the cancer rehabilitation programme and cachexia clinic at the MUHC said, “At the McGill Nutrition and Performance Laboratory we specialize in cachexia and sarcopenia. By treating these two pathologic conditions through inhibiting the USP19 gene, at an early, rather than late, stage of the cancer trajectory, not only can we potentially improve the quality of life of patients, but also allow them to better tolerate their oncological treatments, to stay at home for a longer period of time, and to prolong their lives.”