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MOTS-c modulates skeletal muscle function by directly binding and activating CK2
- Kumagai, Hiroshi;
- Kim, Su-Jeong;
- Miller, Brendan;
- Zempo, Hirofumi;
- Tanisawa, Kumpei;
- Natsume, Toshiharu;
- Lee, Shin Hyung;
- Wan, Junxiang;
- Leelaprachakul, Naphada;
- Kumagai, Michi Emma;
- Ramirez, Ricardo;
- Mehta, Hemal H;
- Cao, Kevin;
- Oh, Tae Jung;
- Wohlschlegel, James A;
- Sha, Jihui;
- Nishida, Yuichiro;
- Fuku, Noriyuki;
- Dobashi, Shohei;
- Miyamoto-Mikami, Eri;
- Takaragawa, Mizuki;
- Fuku, Mizuho;
- Yoshihara, Toshinori;
- Naito, Hisashi;
- Kawakami, Ryoko;
- Torii, Suguru;
- Midorikawa, Taishi;
- Oka, Koichiro;
- Hara, Megumi;
- Iwasaka, Chiharu;
- Yamada, Yosuke;
- Higaki, Yasuki;
- Tanaka, Keitaro;
- Yen, Kelvin;
- Cohen, Pinchas
Published Web Location
https://doi.org/10.1016/j.isci.2024.111212Abstract
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.
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