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

Abstract

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. Exercise and cold exposure enhance metabolic health, yet the underlying mechanisms remain incompletely understood. Using transcriptome and proteome analyses, this study identifies thrombospondin-1 (TSP1) as a factor commonly induced by both stimuli in humans and rodents. Exercise and cold exposure increased TSP1 levels in skeletal muscle and brown adipose tissue, with the N-terminal fragment (N-TSP1) emerging as a key mediator. N-TSP1 enhanced thermogenesis in adipocytes and improved mitochondrial function in muscle cells. In mice fed a high-fat diet, N-TSP1 improved glucose tolerance and insulin sensitivity. In aged mice, N-TSP1 enhanced muscle strength and endurance, accompanied by molecular changes consistent with tissue-specific metabolic adaptation. Together, these findings establish N-TSP1 as a mediator of the metabolic benefits induced by exercise and cold exposure and highlight its potential in metabolic disease management. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.