New research conducted by scientists at the University of Michigan and the University of Sydney has unveiled that calorie restriction significantly alters proteins in rat skeletal muscle, leading to molecular changes that enhance insulin sensitivity. This discovery is crucial for improving blood sugar control in older adults. Surprisingly, the study revealed that approximately 70% of these molecular changes were sex-dependent.
The study, published in the Journal of Gerontology: Biological Sciences, identified two key proteins, Lmod1 and Ehbp1l1, which are associated with increased muscle glucose uptake and have strong genetic links to human blood sugar regulation. The research was funded by the National Institutes of Health and the Australian Research Council, highlighting the importance of these findings in developing tailored interventions for age-related diabetes.
Sex-Specific Responses in Muscle Adaptation
Principal investigator Greg Cartee, a professor of movement science at the University of Michigan’s School of Kinesiology, emphasized the significance of studying both sexes in scientific research. “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,” Cartee stated. “Even when the outcome is quite similar, the pathways to getting to that outcome can be different.”
The study focused on identifying specific changes in muscle protein phosphorylation, a process that acts like a chemical switch to regulate protein function, explaining why calorie restriction enhances insulin-stimulated glucose uptake in aged rats of both sexes. The 24-month-old rats were subjected to a diet with 35% less food for eight weeks.
Findings and Implications
Researchers discovered that calorie restriction improved insulin-stimulated glucose uptake in both male and female rats, with females showing greater glucose uptake regardless of diet. Insulin altered phosphorylation on more than twice as many protein sites in females compared to males, with 60 overlapping sites. Conversely, calorie restriction caused altered phosphorylation on about 30% more protein sites in males compared to females.
“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 explained.
Cartee likened the differing pathways to using Google Maps, where multiple routes can lead to the same destination. Males and females may travel the same roads but use different lanes or speeds to achieve increased glucose uptake.
Potential for Therapeutic Targets
The study identified two proteins, Ehbp1l1 and Lmod1, with insulin-responsive phosphorylation sites correlating directly with insulin-stimulated glucose uptake across individuals. These proteins have known genetic associations with glycemic traits in humans, suggesting their potential as therapeutic targets for type 2 diabetes and related conditions.
Cartee noted a parallel experiment analyzing metabolites, chemicals in the body from diet or 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. This indicates that significant numbers of calorie restriction-responsive metabolites were altered in only one sex.
Future Directions and Broader Impact
The findings underscore the need for sex-specific strategies in developing interventions for diabetes and related metabolic disorders. The research team, including co-authors from the University of Michigan and the University of Sydney, aims to further explore these sex-specific differences to inform future therapeutic approaches.
As the scientific community continues to unravel the complexities of metabolic health, this study highlights the importance of considering sex as a critical variable in research. The potential for tailored treatments based on these findings could pave the way for more effective management of diabetes and metabolic diseases in the aging population.
