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 Ramírez, 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
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.