1. MOTS-c modulates skeletal muscle function by directly binding and activating CK2.
- Author
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Kumagai, Hiroshi, Kim, Su-Jeong, Miller, Brendan, Zempo, Hirofumi, Tanisawa, Kumpei, Natsume, Toshiharu, Lee, Shin, Wan, Junxiang, Leelaprachakul, Naphada, Kumagai, Michi, Ramirez, Ricardo, Mehta, Hemal, Cao, Kevin, Oh, Tae, Wohlschlegel, James, 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, and Cohen, Pinchas
- Subjects
Physiology ,cell biology - 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.
- Published
- 2024