MOTS-c modulates skeletal muscle function by directly binding and activating CK2
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.
Authors
- Tae Jung Oh (ORCID: https://orcid.org/0000-0002-5078-6123)
- Megumi Hara (ORCID: https://orcid.org/0000-0002-8708-3237)
- James Akira Wohlschlegel (ORCID: https://orcid.org/0000-0003-3399-901X)
- Kevin Cao (ORCID: https://orcid.org/0000-0002-0226-7687)
- Yuichiro Nishida (ORCID: https://orcid.org/0000-0003-2320-7234)
- Hiroshi Kumagai (ORCID: https://orcid.org/0000-0002-0520-6214)
- Pinchas Cohen (ORCID: https://orcid.org/0000-0002-0035-8366)
- Koichiro Oka (ORCID: https://orcid.org/0000-0001-5571-042X)
- Michi Emma Kumagai
- Hisashi Naito
- Toshinori Yoshihara (ORCID: https://orcid.org/0000-0002-8465-5439)
- Brendan Miller (ORCID: https://orcid.org/0000-0002-7461-7973)
- Kelvin Yen (ORCID: https://orcid.org/0000-0003-4595-971X)
- Taishi Midorikawa (ORCID: https://orcid.org/0000-0001-7985-1905)
- Suguru Torii (ORCID: https://orcid.org/0000-0002-8729-531X)
- Shin Hyung Lee
- Kumpei Tanisawa (ORCID: https://orcid.org/0000-0002-9334-7104)
- Shohei Dobashi (ORCID: https://orcid.org/0000-0003-4397-3219)
- Naphada Leelaprachakul
- Noriyuki Fuku (ORCID: https://orcid.org/0000-0001-7792-5835)
- Eri Miyamoto‐Mikami (ORCID: https://orcid.org/0000-0002-4864-8581)
- Keitaro Tanaka (ORCID: https://orcid.org/0000-0002-5725-4736)
- Jihui Sha (ORCID: https://orcid.org/0000-0002-7358-1606)
- Mizuki Takaragawa (ORCID: https://orcid.org/0000-0002-4422-2065)
- Toshiharu Natsume
- Yosuke Yamada (ORCID: https://orcid.org/0000-0002-4284-6317)
- Ryoko Kawakami (ORCID: https://orcid.org/0000-0001-8211-1553)
- Mizuho Fuku
- Hirofumi Zempo (ORCID: https://orcid.org/0000-0003-2248-8580)
- Chiharu Iwasaka (ORCID: https://orcid.org/0000-0003-2384-5121)
- Yasuki Higaki (ORCID: https://orcid.org/0000-0001-5127-4552)
- Su‐Jeong Kim (ORCID: https://orcid.org/0000-0002-4435-5757)
- Ricardo Ramírez
- Hemal H. Mehta (ORCID: https://orcid.org/0000-0002-8439-278X)
- Junxiang Wan
Institutions
- University of Southern California (US)
- Tokai University (JP)
- J. F. Oberlin University (JP)
- University of Tsukuba (JP)
- Waseda University (JP)
- University of California, Los Angeles (US)
- Saga University (JP)
- Tohoku University (JP)
- Tokyo Seiei College (JP)
- Seoul National University Bundang Hospital (KR)
- Fukuoka University (JP)
- Juntendo University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Meiji Yasuda Life Foundation of Health and Welfare (JP)
- Hakodate Central General Hospital (JP)
Publication Details
- Journal
- iScience
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1016/j.isci.2024.111212
- Citations
- 10
- Primary Topic
- GDF15 and Related Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.70
Funders
- Ministry of Education, Culture, Sports, Science and Technology
- National Institutes of Health
- Japan Society for the Promotion of Science