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 2nd; 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

doi:10.1016/j.isci.2024.111212

MOTS-c modulates skeletal muscle function by directly binding and activating CK2

iScience. 2024 Oct 19;27(11):111212. doi: 10.1016/j.isci.2024.111212. eCollection 2024 Nov 15.

Authors

Hiroshi Kumagai¹, Su-Jeong Kim¹, Brendan Miller¹, Hirofumi Zempo², Kumpei Tanisawa³, Toshiharu Natsume⁴, Shin Hyung Lee¹, Junxiang Wan¹, Naphada Leelaprachakul¹, Michi Emma Kumagai^{1

5}, Ricardo Ramirez 2nd¹, Hemal H Mehta¹, Kevin Cao¹, Tae Jung Oh^{1

6}, James A Wohlschlegel⁷, Jihui Sha⁷, Yuichiro Nishida⁸, Noriyuki Fuku⁹, Shohei Dobashi¹⁰, Eri Miyamoto-Mikami⁹, Mizuki Takaragawa⁹, Mizuho Fuku^{9

11}, Toshinori Yoshihara⁹, Hisashi Naito⁹, Ryoko Kawakami¹², Suguru Torii³, Taishi Midorikawa¹³, Koichiro Oka³, Megumi Hara⁸, Chiharu Iwasaka¹⁴, Yosuke Yamada^{15

16}, Yasuki Higaki¹⁷, Keitaro Tanaka⁸, Kelvin Yen¹, Pinchas Cohen¹

Affiliations

¹ The Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
² Department of Administrative Nutrition, Faculty of Health and Nutrition, Tokyo Seiei College, Tokyo, Japan.
³ Faculty of Sport Sciences, Waseda University, Saitama, Japan.
⁴ Faculty of Medicine, Tokai University, Kanagawa, Japan.
⁵ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁶ Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea.
⁷ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
⁸ Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
⁹ Graduate School of Health and Sports Science, Juntendo University, Chiba, Japan.
¹⁰ Institute of Health and Sport Sciences, University of Tsukuba, Ibaraki, Japan.
¹¹ Tsudanuma Central General Hospital, Chiba, Japan.
¹² Physical Fitness Research Institute, Meiji Yasuda Life Foundation of Health and Welfare, Tokyo, Japan.
¹³ College of Health and Welfare, J.F. Oberlin University, Tokyo, Japan.
¹⁴ Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
¹⁵ Sports and Health Sciences, Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
¹⁶ Medicine and Science in Sports and Exercise, Graduate School of Medicine, Tohoku University, Miyagi, Japan.
¹⁷ Laboratory of Exercise Physiology, Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan.

Abstract

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.

Keywords: Physiology; cell biology.