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한국생명공학연구원, UST

Exp. Mol. Med., 08 September 2026 | https://doi.org/10.1038/s12276-026-01830-z N-terminal thrombospondin-1 enhances muscle function and tissue-specific metabolic adaptation in response to exercise and cold exposure

Min Ju Kim ^1,2,13, Hyun-Jun Jang ^3,4,13, Jae Sook Kang^1,2,13, Sung-Wook Chun ⁵, Sun Gun Chung ^6,7, Shinyeong Ju⁸, ByungKuk Min ⁹, Eunhwan Kim ¹, Ju Yeon Kwak ¹, Ji-Won Kim ¹, Seongwan Kim ^1,2, Yeo Jin Shin ¹, Kwang-Pyo Lee ^1,2,10, Cheolju Lee ^8,11, Seung-Min Lee ¹, Jung Jae Won ^1,2, Eun-Soo Kwon ^1,2, Jang Hyun Choi ^4,12*, Ki-Sun Kwon ^1,2,10* and Yong Ryoul Yang ^1,2*

¹Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
²Department of Bio-molecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34113, Republic of Korea.
³Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, Jeollabuk-do 55365, Republic of Korea.
⁴Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
⁵Research Institute of Physical Education & Sports Science, Pusan National University, Pusan, Republic of Korea.
⁶Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁷Institute of Aging, Seoul National University, Seoul, Republic of Korea.
⁸Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
⁹Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
¹⁰Aventi Inc., Daejeon 34141, Republic of Korea.
¹¹Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.
¹²Metadium Therapeutics, Ulsan 44919, Republic of Korea.
¹³These authors contributed equally: Min Ju Kim, HyunJun Jang, Jae Sook Kang.

^*Corresponding authors: Jang Hyun Choi, Ki-Sun Kwon and Yong Ryoul Yang

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.

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