Identifying a novel player in skeletal muscle performance and metabolism

This project investigates the previously unrecognized role of fat-specific protein 27 (FSP27) in skeletal muscle, with implications for exercise endurance, insulin sensitivity, metabolic health, and potential therapeutic development. Funded by a four-year $2.6 million R01 grant from the National Institutes of Health, the research builds on earlier research identifying FSP27 in human adipose tissue, where it regulates fat metabolism, and subsequent discovery that FSP27 is present and functional in skeletal muscle. The team’s central aims are captured in two linked hypotheses: that FSP27 fuels skeletal muscle by modulating motor activity of cytoskeletal proteins, and that FSP27 influences exercise endurance and insulin sensitivity through effects on glucagon-like peptide-1 (GLP-1) signaling. The investigators developed an innovative humanized mouse model that expresses the human FSP27 transgene specifically in skeletal muscle. These animals exhibited markedly enhanced physical performance, dramatically upregulated GLP-1 receptors and improved blood glucose regulation, muscle function, and overall metabolic health.

The mice function as preclinical models to probe both physiological roles and the molecular mechanisms by which FSP27 acts in muscle, enabling focused studies of pathway regulation and potential targets for intervention. Results in aged humanized FSP27 mice were particularly notable: 18-month-old mice, corresponding to roughly 60-year-old humans, demonstrated performance characteristic of much younger animals, suggesting that FSP27 may mitigate age-related declines in muscle function. To translate animal findings to humans, the researchers partnered with an expert in human physiology, who has collected human muscle samples showing a strong correlation between FSP27 levels and measures of human performance. The data indicated that FSP27 expression in muscle increases following exercise and training, accompanying improved performance measures.

The grant will also support advanced training for students and fellows, and the project is conducted entirely within Ohio University with institutional support from the Heritage College of Osteopathic Medicine and the Osteopathic Heritage Foundation. With the ultimate goal of drug development, the study seeks to determine whether FSP27 can be targeted to improve muscle function, metabolic health, and resilience to aging, and to clarify its interactions with GLP-1 signaling pathways relevant to widely used therapies. The program combines molecular, physiological, and translational approaches to define FSP27’s roles and therapeutic potential in skeletal muscle.