MOTS-c modulates skeletal muscle function by directly binding and activating CK2
Open accessAbstract
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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MOTS-c administration enhances muscle glucose uptake, boosts exercise endurance, and prevents muscle atrophy by directly binding and activating casein kinase 2.
“MOTS-c administration enhances muscle glucose uptake, boosts exercise endurance, and prevents muscle atrophy by directly binding and activating casein kinase 2 (CK2) [25].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [25]
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References 65 · Cited by 15
- Authors
- Kumagai, H., Kim, S.-J., Miller, B., Zempo, H., Tanisawa, K., Natsume, T., Lee, S. H., Wan, J., Leelaprachakul, N., Kumagai, M. E., Ramirez, R., Mehta, H. H., Cao, K., Oh, T. J., Wohlschlegel, J. A., Sha, J., Nishida, Y., Fuku, N., Dobashi, S., Miyamoto-Mikami, E., Takaragawa, M., Fuku, M., Yoshihara, T., Naito, H., Kawakami, R., Torii, S., Midorikawa, T., Oka, K., Hara, M., Iwasaka, C., Yamada, Y., Higaki, Y., Tanaka, K., Yen, K., & Cohen, P.
- Affiliations
- University of Southern California (US)
- Tokyo Seiei College (JP)
- Waseda University (JP)
- Tokai University (JP)
- University of California, Los Angeles (US)
- Saga University (JP)
- Juntendo University (JP)
- University of Tsukuba (JP)
- Meiji Yasuda Life Foundation of Health and Welfare (JP)
- J. F. Oberlin University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Tohoku University (JP)
- Fukuoka University (JP)
- Corresponding author
- Cohen, Pinchas
- ORCID
- Kumagai, Hiroshi
- Kim, Su-Jeong
- Miller, Brendan
- Zempo, Hirofumi
- Tanisawa, Kumpei
- Wan, Junxiang
- Mehta, Hemal H.
- Oh, Tae Jung
- Wohlschlegel, James A.
- Sha, Jihui
- Nishida, Yuichiro
- Fuku, Noriyuki
- Dobashi, Shohei
- Takaragawa, Mizuki
- Yoshihara, Toshinori
- Kawakami, Ryoko
- Torii, Suguru
- Midorikawa, Taishi
- Oka, Koichiro
- Hara, Megumi
- Iwasaka, Chiharu
- Yamada, Yosuke
- Higaki, Yasuki
- Tanaka, Keitaro
- Yen, Kelvin
- Cohen, Pinchas
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 27
- Issue
- 11
- Pages
- 111212
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC11570452
- OpenAlex
- W4403561659
- Cited by
- 15
- References
- 65
- Citations by year
- 2026: 10 · 2025: 4 · 2024: 1
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (21K17693, 18K17982, 19H04065, 17K13241, S1511017)
- National Institutes of Health (R01CA231219, 17015018, P30AG068345, R01AG068405, R01HL158691, RF1AG061834, R01AG069698, P01AG055369, 221S0001)
- Japan Society for the Promotion of Science (16H06277, 22H04923, 18390182, 20249038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- MOTS-c, casein kinase 2, skeletal muscle atrophy, muscle glucose uptake, sarcopenia, type 2 diabetes, protein-protein interaction, tissue-specific signaling, sex differences, muscle metabolism
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