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

• DOI: 10.1016/j.isci.2024.111212
• Publication Date: 2024-10-19T20:36:36Z
• Authors: Hiroshi Kumagai; Su-Jeong Kim; Brendan Miller; Hirofumi Zempo; Kumpei Tanisawa; Toshiharu Natsume; Shin Hyung Lee; Junxiang Wan; Naphada Leelaprac...; Michi Emma Kumagai; Ricardo Ramirez; Hemal H. Mehta; Kevin Cao; Tae Jung Oh; James A. Wohlschl...; 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
• Keywords: Physiology; 1.1 Normal biological development and functioning; Musculoskeletal; Science; Health Sciences; Diabetes; cell biology; Q; 2.1 Biological and endogenous factors; Biochemistry and Cell Biology; Biological Sciences; Metabolic and endocrine; Article

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.