MOTS‑c is a tiny protein that can hook onto an enzyme called CK2 and turn it on in muscle, which helps keep muscles from shrinking and makes them take up more sugar. In mice, giving MOTS‑c stopped muscle loss and improved glucose use, but only when CK2 was active. A common human version of MOTS‑c (K14Q) doesn’t bind CK2 well and is linked to higher risk of muscle loss and type‑2 diabetes in men, suggesting genetics may affect how well the peptide works.

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.