Two-faced gene variant appears good for men, bad for women

In men, this gene variant, known as rs6190, appears to help build muscle mass and reduce diabetes risk, according to findings published online July 9, 2025, in the journal Science Advances. But in women, the same variant increases cholesterol levels and elevates the risk of clogged arteries and heart disease, according to a paper currently "in press" in JCI: the Journal of Clinical Investigation. Both studies were led by corresponding author Mattia Quattrocelli, PhD, a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Children's.

"Our study indicates that muscle cells play a deeper than expected role in regulating the body's overall metabolism," Quattrocelli says. "Through studying this nuclear receptor coding variant, this research unveils novel regulators of muscle metabolism that could have wide ranging effects upon obesity, diabetes and heart disease." 

One potential application may be to help reduce the unwanted loss of lean muscle mass that many people experience when taking new GLP-1 agonists for weight control. 

A closer look at glucocorticoids

Decades of previous research have established that skeletal muscle is the primary organ to dispose of excess, unused sugar in blood when insulin gets into action. When this process falls out-of-balance, insulin resistance occurs in muscle cells, which in turn can lead to type 2 diabetes and a cascade of other problems.

Hormones called glucocorticoids play a central role in this process by helping regulate levels of glucose, lipids and protein during muscle development. For glucocorticoids to do their job, they rely upon muscle cells carrying glucocorticoid receptors. This study delved into what happens when a gene variant changes how those receptors function.

Some studies have already shown that the gene variant rs6190 appears to enhance muscle strength, lean body mass and metabolic health in some men, but how the variant directly affects metabolic health has not been understood.

To find out, a team led by postdoctoral fellow Ashok Prabakaran, PhD, in the Quattrocelli lab at Cincinnati Children's developed a mouse model genetically edited to mimic the effects of rs6190. Their three-year long series of experiments in murine muscles and analysis of data from the Uk Biobank and All of Us human datasets revealed that two previously uncharacterized genes in muscle -- Foxc1 and Arid5A – function differently when influenced by rs6190. Combined, they changed insulin sensitivity in the mice and the rate of lipid (fat) accumulation around muscle cells.

When normal "wild type" male mice were fed high-fat, high-calorie diets, they became obese, as expected. But when the same diet was fed to the rs6190 mice, the males grew to similar lengths but were leaner and had less body fat. 

Further testing revealed that their muscles could absorb and use more glucose during exercise, allowing them to run longer and exert more force. Higher levels of insulin sensitivity also allowed these mice to eliminate more of the glucose they could not burn off during exercise.

The team's analysis traced these changes to increased activation of the genes Foxc1 and Arid5A. While Foxc1 appears to help canonical insulin action in muscle cells, Arid5A appears to reduce lipids; combining for a positive effect in muscle health.

Potential targets for improving exercise tolerance

Importantly, the study used human medical data from the large UK Biobank and All of Us datasets to confirm that the same genes and variants detected in the mouse experiments also occur in people.

Overall, less than 3% of the people sampled in the two biobanks had the rs6190 variant. However, the men who had it tended to show lower BMI, more lean mass and higher hand grip strength. Similar trends were found in women but with smaller magnitude.

However, the team determined that the rs6190 variant did not have to be present to induce more activity from either Arid5A or Foxc1. In mice, gene editing or intermittent prednisone treatment were sufficient to overexpress these genes and produce similar outcomes even without the rs6190 variant.

"This suggests that if we can develop safe ways to regulate these genes in human muscle, we could be able to more effectively re-balance disrupted, unhealthy metabolisms, whether or not the people share the rs6190 variant," Quattrocelli says.

A different story for women

In addition to the study in Science Advances, a parallel three-year long study, led by research assistant Bindu Durumutla, MS, in the Quattrocelli lab, found that the rs6190 variant triggers a very different outcome in women. Details of these findings appear in the journal JCI: Journal of Clinical Investigation.

Differently from muscle, in the liver the variant appears to cause two other genes -- Pcsk9 and Bhlhe40 -- to become less active. In mice, this change resulted in elevated cholesterol, including both low-density lipoprotein (LDL) and high-density lipoprotein (HDL). In mice, this effect was specific to females but not males.

When looking at data from women in the UK Biobank and All Of Us datasets, those with the unusual rs6190 variant also were more likely to have high cholesterol and plaque build-up in their arteries. Similarly to mice, this effect was absent in men.

Again, the team determined that the rs6190 variant was not required for the changed gene activity to cause the cholesterol increases. The outcome could be mimicked in mice by directly editing the expression of the genes.

"In both studies, studying the variant helped point us to the key genes involved. Importantly, this means the findings are more likely to apply to larger populations than only those who have the rs6190 variant," Quattrocelli says.

Why did outcomes different between sexes?

The research team suspects that hormonal differences between men and women explain why a shared gene variant can have such different effects on cholesterol and plaque build-up.

For example, in male mice, corticosterone and testosterone prevented the rs6190 variant from increasing atherosclerosis in male mice. But the same variant added to the risk of high cholesterol as females lost estrogen with age.

"These results indicate that biological sex is likely an important factor to consider when treating muscle mass loss and maintaining cholesterol levels in check," Quattrocelli says. "The combination of the sex effect with the rs6190 variant effect suggests more aggressive monitoring or treatment for women with that variant when addressing other hormonal and clinical changes."

About the studies

Cincinnati Children's co-authors on both studies included: Hima Bindu Durumutla, MS, Ashok Daniel Prabakaran, PhD, Kevin McFarland, MS, Hannah Latimer, BS, and Olukunle Akinborewa, BS.

Fabian Montecino-Morales, PhD, Thirupugal Govindarajan, PhD, Chiara Villa, PhD, and Douglas Millay PhD, also contributed to the Science Advances publication.

April Haller, BS, Greta Noble, BS, Akanksha Rajput, PhD, Bahram Namjou-Khales, MD, and David Hui, PhD, contributed to the JCI publication.

Funding sources included the National Institutes of Health (R01HL166356-01, R03DK130908-01A1, R01AG078174-01); the Cincinnati Children's Research Foundation, an AFM-Telethon-Trampoline Grant, and support from the GFB-ONLUS-Project.

SOURCE Cincinnati Children's Hospital Medical Center