N-terminal thrombospondin-1 enhances muscle function and tissue-specific metabolic adaptation in response to exercise and cold exposure.

Exercise and cold exposure elicit partly overlapping metabolic adaptations through distinct mechanisms. Here, we sought to identify circulating factors shared by these stimuli. We found that exercise and cold exposure upregulated thrombospondin-1 (TSP1) expression in skeletal muscle and brown adipose tissue (BAT) and induced the release of its N-terminal fragment (N-TSP1). In high-fat-diet-induced obese mice, N-TSP1 administration enhanced muscle strength, increased energy expenditure and attenuated insulin resistance and hepatic steatosis. N-TSP1 also increased mitochondrial respiration and oxidative metabolism in skeletal muscle and stimulated thermogenic marker gene expression in brown adipocytes. In aged mice, N-TSP1 administration significantly improved physical performance and was associated with tissue-specific metabolic remodelling. In humans, plasma N-TSP1 levels correlated positively with muscle mass and physical performance. Together, these findings support a role for N-TSP1 as an exercise- and cold-responsive circulating factor that modulates skeletal muscle function and tissue-specific metabolic adaptation, with potential relevance to obesity- and age-related functional decline.