Northwestern University researchers develop RNA therapy to preserve muscle

We have identified, for the first time, an RNA therapy that promotes thermogenesis and, when combined with the GLP-1 drug semaglutide, helps preserve lean muscle mass, Joseph Bass stated. Researchers have developed an experimental RNA therapy that, when paired with the weight-loss drug semaglutide, cuts lean muscle mass loss roughly in half while burning more fat in obese mice.

Semaglutide and Muscle Loss During Treatment

Semaglutide and similar GLP-1 receptor agonists function by mimicking a gut hormone that signals the brain that a meal has arrived, leading to reduced food intake and subsequent weight loss. However, appetite reduction is not selective to fat tissue. In both animal studies and human patients, these treatments reduce muscle mass alongside fat, while the remaining muscle tissue can lose strength at a faster rate than it loses size, reported. Energy expenditure also declines during the process, meaning the body burns fewer calories than it did prior to treatment, which contributes to weight regain once injections stop.

Silencing the ZFP423 Gene to Promote Thermogenesis

To counteract the metabolic slowdown, researchers targeted a specific mechanism governing fat cells. White fat normally stores energy, whereas beige fat burns energy to produce heat through a process known as thermogenesis. A gene named ZFP423 acts as a brake to block white fat from converting into calorie-burning beige fat. Joseph Bass, who directs the center for diabetes and metabolism at Northwestern University Feinberg School of Medicine, worked alongside first author Anneke Thorne to build a short strand of RNA designed to find the gene’s instructions inside fat cells and shut them down before any protein is produced. Ionis Pharmaceuticals supplied the RNA chemistry for the project, which was tagged with a fatty acid to ensure optimal delivery to fat tissue.

Combined Drug Trial Results in Obese Mice

In the main experimental trial, mice spent 10 weeks on a high-fat diet until they became obese. The animals were then divided to receive daily semaglutide, weekly injections of the RNA therapy, both treatments combined, or no treatment for a three-week period, reported. While each drug on its own reduced weight by about 0.23 ounces (6.6 grams) by the end of the study, the combination treatment successfully removed 0.32 ounces (9.2 grams). Body fat finished at 0.28 ounces (7.9 grams) on semaglutide alone, 0.23 ounces (6.4 grams) on the RNA therapy alone, and 0.15 ounces (4.2 grams) when using both. Mice treated with semaglutide alone lost about 10 percent of their initial lean mass, whereas mice receiving both treatments lost only 5.5 percent.

The experimental therapy remains untested in humans, as the RNA strand was specifically engineered against the mouse version of the gene rather than the human version. Northwestern University has filed a provisional patent application listing Bass and Thorne as inventors, alongside two co-authors employed by Ionis Pharmaceuticals. Anneke Thorne noted that translating the findings to patients will require an extended development timeline. Novel therapies typically require many years of research, development, and financial support before they can reach patients, Thorne said. The full study was published in the journal Proceedings of the National Academy of Sciences.

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