Exercise-induced CLCF1 attenuates age-related muscle and bone decline in mice

Jae Sook Kang, Jung Ha Kim, Min Ju Kim, Byungkuk Min, Seung-Min Lee, Ga-Yeon Go, Ji-Won Kim, Seongwan Kim, Ju Yeon Kwak, Sung-Wook Chun, Wook Song, Hyo Youl Moon, Sun Gun Chung, Dong-Ho Park, Ji Hoon Park, Chuna Kim, Kwang-Pyo Lee, Eun-Soo Kwon, Nacksung Kim (), Ki-Sun Kwon () and Yong Ryoul Yang ()
Additional contact information
Jae Sook Kang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jung Ha Kim: Chonnam National University Medical School
Min Ju Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Byungkuk Min: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seung-Min Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ga-Yeon Go: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ji-Won Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seongwan Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ju Yeon Kwak: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Sung-Wook Chun: Pusan National University
Wook Song: Seoul National University
Hyo Youl Moon: Seoul National University
Sun Gun Chung: Seoul National University
Dong-Ho Park: Inha University
Ji Hoon Park: Osong Medical Innovation Foundation (KBioHealth)
Chuna Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Kwang-Pyo Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Eun-Soo Kwon: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Nacksung Kim: Chonnam National University Medical School
Ki-Sun Kwon: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Yong Ryoul Yang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Skeletal muscle undergoes many alterations with aging. However, the impact of aging on muscle’s ability to secrete myokines and its subsequent effects on the body remain largely unexplored. Here, we identify myokines that have the potential to ameliorate age-related muscle and bone decline. Notably, circulating levels of cardiotrophin-like cytokine factor 1 (CLCF1) decrease with age, while exercise significantly upregulates CLCF1 levels in both humans and rodents. Restoring CLCF1 levels in aged male mice improves their physical performance, glucose tolerance, and mitochondrial activity. Furthermore, CLCF1 protects against age-induced bone loss by inhibiting osteoclastogenesis and promoting osteoblast differentiation in aged male mice. These improvements mirror some of the effects of exercise training. Conversely, blocking CLCF1 activity significantly abolishes these beneficial effects, confirming the crucial role of CLCF1 in mediating the positive effects of exercise on muscle and bone health in male mice. These findings collectively suggest that CLCF1 may contribute to the regulation of age-associated musculoskeletal deterioration, and warrant further investigation into its potential role as a modulator of musculoskeletal health during aging.

Date: 2025
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DOI: 10.1038/s41467-025-59959-w

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