iScience (Nov 2024)
MOTS-c modulates skeletal muscle function by directly binding and activating CK2
- Hiroshi Kumagai,
- Su-Jeong Kim,
- Brendan Miller,
- Hirofumi Zempo,
- Kumpei Tanisawa,
- Toshiharu Natsume,
- Shin Hyung Lee,
- Junxiang Wan,
- Naphada Leelaprachakul,
- Michi Emma Kumagai,
- Ricardo Ramirez, II,
- Hemal H. Mehta,
- Kevin Cao,
- Tae Jung Oh,
- James A. Wohlschlegel,
- Jihui Sha,
- Yuichiro Nishida,
- Noriyuki Fuku,
- Shohei Dobashi,
- Eri Miyamoto-Mikami,
- Mizuki Takaragawa,
- Mizuho Fuku,
- Toshinori Yoshihara,
- Hisashi Naito,
- Ryoko Kawakami,
- Suguru Torii,
- Taishi Midorikawa,
- Koichiro Oka,
- Megumi Hara,
- Chiharu Iwasaka,
- Yosuke Yamada,
- Yasuki Higaki,
- Keitaro Tanaka,
- Kelvin Yen,
- Pinchas Cohen
Affiliations
- Hiroshi Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Su-Jeong Kim
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Brendan Miller
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Hirofumi Zempo
- Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan
- Kumpei Tanisawa
- Faculty of Sport Sciences, Waseda University, Saitama, Japan
- Toshiharu Natsume
- Faculty of Medicine, Tokai University, Kanagawa, Japan
- Shin Hyung Lee
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Junxiang Wan
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Naphada Leelaprachakul
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Michi Emma Kumagai
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Ricardo Ramirez, II
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Hemal H. Mehta
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Kevin Cao
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Tae Jung Oh
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea
- James A. Wohlschlegel
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Jihui Sha
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
- Yuichiro Nishida
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
- Noriyuki Fuku
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Shohei Dobashi
- Institute of Health and Sport Sciences, University of Tsukuba, Ibaraki, Japan
- Eri Miyamoto-Mikami
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Mizuki Takaragawa
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Mizuho Fuku
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan; Tsudanuma Central General Hospital, Chiba, Japan
- Toshinori Yoshihara
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Hisashi Naito
- Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan
- Ryoko Kawakami
- Physical Fitness Research Institute, Meiji Yasuda Life Foundation of Health and Welfare, Tokyo, Japan
- Suguru Torii
- Faculty of Sport Sciences, Waseda University, Saitama, Japan
- Taishi Midorikawa
- College of Health and Welfare, J.F. Oberlin University, Tokyo, Japan
- Koichiro Oka
- Faculty of Sport Sciences, Waseda University, Saitama, Japan
- Megumi Hara
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
- Chiharu Iwasaka
- Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Yosuke Yamada
- Sports and Health Sciences, Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan; Medicine and Science in Sports and Exercise, Graduate School of Medicine, Tohoku University, Miyagi, Japan
- Yasuki Higaki
- Laboratory of Exercise Physiology, Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
- Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
- Kelvin Yen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
- Pinchas Cohen
- The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 11
p. 111212
Abstract
Summary: MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.
