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rs6190 helps men build muscle mass and reduce diabetes risk, but increases cholesterol levels and elevates the risk of clogged arteries and heart disease in women.
rs6190 appears to impact men differently then women.
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An obscure gene variant was discovered in skeletal muscle cells, that contains unique symptoms dependent on the patient’s sex.
The gene variant, labeled rs6190 was discovered to effect patients differently based on genetic sexuality. In males, rs6190 improves muscle mass and helps reduce the risk of diabetes according to recent findings in Science Advances. However, according to a paper published in JCI: the Journal of Clinical Investigation, females with the same variant see an increase in cholesterol levels and greater threats of heart disease and clogged arteries.
Mattia Quattrocelli, PhD, a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Children's led both investigations.
"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."1
Researchers also believe that rs6190 has the potential to reduce the unwanted loss of lean muscle mass within users of new GLP-1 agonists for weight loss.
Previous research established that skeletal muscle is the central organ where the body disposes of excess, unused sugar in blood when insulin gets into action. However, if this process falls out-of-balance, insulin resistance can occur in muscle cells, which in turn leads to type 2 diabetes as well as cause additional health risks.
Glucocorticoids hormones are a key aspect to this process and assists the body in regulating glucose, lipids, and proteins during muscle development. For this process to be successful, reliance is placed on muscle cells carrying the Glucocorticoid receptors.
In rs6190’s study, researchers delved into when a gene variant alters the receptors functions. With some studies showing that rs6190 appears to enhance muscle strength and lean body mass in some men.
Studies also appeared to show enhanced metabolic health in some men, yet confirmation on direct effects on metabolic health have not been reached.
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.1
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.1
After both study’s concluded, the research team suspected that the outcomes varied between men and women, due to hormonal differences between the sexes.
"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."1
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