Eating less may rewire aging muscles in surprisingly different ways for males and females.
A new study shows that cutting calorie intake triggers sweeping changes in the proteins of rat skeletal muscle, reshaping molecular pathways that improve insulin sensitivity. According to researchers at the University of Michigan and the University of Sydney, these changes are especially important for maintaining healthy blood sugar levels as people age.
The scientists were surprised to find that about 70 percent of the molecular adjustments muscles used to adapt differed between males and females. The research also highlighted two proteins, Lmod1 and Ehbp1l1, that were linked to increased muscle glucose uptake and are already known to have strong genetic connections to blood sugar regulation in humans.
Supported by funding from the National Institutes of Health and the Australian Research Council, the study points to the importance of sex specific approaches when designing treatments for age related diabetes and diabetes more broadly. The researchers note that the proteins they identified could eventually become targets for therapies aimed at conditions such as type 2 diabetes.
Why sex differences matter
“I think now we agree that we need to study men and women; you can’t study one and assume it means the truth for the other,” said principal investigator Greg Cartee, professor of movement science at the U-M School of Kinesiology. “And even when the outcome is quite similar, the pathways to getting to that outcome can be different.”
Cartee explained that the “discovery study,” published in the Journal of Gerontology: Biological Sciences, set out to pinpoint the precise changes in muscle protein phosphorylation that explain why calorie restriction improves insulin-stimulated glucose uptake in the skeletal muscle of older rats of both sexes. Phosphorylation functions like a chemical switch, adjusting a protein’s activity by turning it up, down, on, or off.
Testing calorie restriction in aging muscle
In the experiment, 24-month-old rats consumed 35 percent fewer calories for eight weeks. The researchers found that insulin-stimulated glucose uptake increased in both males and females under calorie restriction, although females showed higher glucose uptake overall, regardless of diet.
Insulin caused altered phosphorylation on more than twice as many protein sites in females compared to males, with 60 overlapping sites. However, calorie restriction caused altered phosphorylation on about 30% more protein sites of males compared to females, Cartee said. In other words, males and females don’t use identical internal strategies to adapt to the low-calorie diet, but both strategies lead to the same positive result: better muscle sugar metabolism.
“The key functional outcome that we studied––insulin-stimulated glucose uptake––was similarly increased by calorie restriction in each sex even though the two sexes differed considerably in their protein phosphorylation patterns,” Cartee said. “An imperfect analogy is that when you use Google Maps, you typically are given multiple routes to reach the destination. Males and females don’t use completely separate ‘roads’ to achieve increased glucose uptake; they may travel the same roads but use different lanes or drive at different speeds along the way.”
Proteins linked to blood sugar control
Two proteins, Ehbp1l1 and Lmod1, were identified as having insulin-responsive phosphorylation sites that correlated directly with insulin-stimulated glucose uptake across individuals. Both proteins have known genetic associations with glycemic traits in humans.
Cartee said researchers recently performed a parallel experiment using a similar design, but instead analyzed the levels of a large number of metabolites—chemicals in the body that originate from the diet or from the body’s metabolism.
“Of the approximately 1,000 different metabolites that we measured, the levels of about 40% were altered by calorie restriction within each sex,” he said. “A number of the metabolites were altered in both sexes, but significant numbers of these CR-responsive metabolites were altered in only one sex.”
Reference: “Sex-specific phosphoproteome responses to calorie restriction and insulin in skeletal muscle from older rats” by Haiyan Wang, Søren Madsen, Elise J. Needham, Sean J. Humphrey, Amy Zheng, Edward B. Arias, Jacqueline Stöckli, Harry B. Cutler, David E. James and Gregory D. Cartee, November 2025, Journal of Gerontology: Biological Sciences.
DOI: 10.1093/gerona/glaf231
The research was funded by the National Institutes of Health and the Australian Research Council.
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