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

Kumagai H, Kim SJ, Miller B, Zempo H, Tanisawa K, Natsume T, Lee SH, Wan J, Leelaprachakul N, Kumagai ME, Ramirez R 2nd, Mehta HH and 23 more

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Cao K, Oh TJ, Wohlschlegel JA, 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

iScience19 Oct 2024Cited by 13 (Europe PMC)

PMID39559755PMCIDPMC11570452DOI10.1016/j.isci.2024.111212PepBankPUB-39559755

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Summary

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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

8 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In mice, MOTS‑c administration prevented skeletal muscle atrophy.
In plain wordsIn mice, giving MOTS‑c prevented loss of skeletal muscle.
Peptide
MOTS-c
Outcome
DecreaseSkeletal muscle atrophy
Study
mousen: not reported in source
Mice
Outcome group
Muscle injury and repair · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity.
Show in the study text Report a problemFND-3955975503
02AnimalAnimal study (in vivo)Efficacy outcome
In mice, MOTS‑c administration enhanced muscle glucose uptake.
In plain wordsIn mice, giving MOTS‑c increased glucose uptake by muscle.
Peptide
MOTS-c
Outcome
IncreaseMuscle glucose uptake
Study
mousen: not reported in source
Mice
Outcome group
Glycemic control · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity.
Show in the study text Report a problemFND-3955975504
03AnimalAnimal study (in vivo)Mechanism
In mice, the effects of MOTS‑c on muscle atrophy and glucose uptake were blunted by suppressing CK2 activity.
In plain wordsIn mice, the muscle benefits of MOTS‑c were weaker when CK2 was suppressed.
Peptide
MOTS-c
Outcome
No significant changeMOTS-c effects with CK2 activity suppressed
Study
mousen: not reported in source
Mice
Comparator
Suppressed CK2 activity
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity.
Show in the study text Report a problemFND-3955975505
04AnimalAnimal study (in vivo)Mechanism
In mice, systemically administered MOTS‑c bound to CK2 in fat and muscle.
In plain wordsIn mice, MOTS‑c given to the whole body bound to CK2 in fat and muscle.
Peptide
MOTS-c
Outcome
Not applicableBinding to CK2 in fat and muscle
Study
mousen: not reported in source
Mice
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated · systemicAs given in this study (mouse).
Source sentences
Summary
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.
Show in the study text Report a problemFND-3955975506
05AnimalAnimal study (in vivo)Mechanism
In mice, systemically administered MOTS‑c stimulated CK2 activity in muscle.
In plain wordsIn mice, MOTS‑c raised CK2 activity in muscle.
Peptide
MOTS-c
Outcome
IncreaseCK2 activity in muscle
Study
mousen: not reported in source
Mice
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated · systemicAs given in this study (mouse).
Source sentences
Summary
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.
Show in the study text Report a problemFND-3955975507
06AnimalAnimal study (in vivo)Mechanism
In mice, systemically administered MOTS‑c suppressed CK2 activity in fat.
In plain wordsIn mice, MOTS‑c lowered CK2 activity in fat.
Peptide
MOTS-c
Outcome
DecreaseCK2 activity in fat
Study
mousen: not reported in source
Mice
Outcome group
Receptor activity and mechanism · Metabolic and weight
Studied dose
Dose not stated · systemicAs given in this study (mouse).
Source sentences
Summary
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.
Show in the study text Report a problemFND-3955975508
07LabIn vitro (cell-free)Activity measurement
In cell-free systems, MOTS‑c bound directly to CK2.
In plain wordsIn lab tests without cells, MOTS‑c bound directly to the CK2 enzyme.
Peptide
MOTS-c
Outcome
Not applicableBinding to CK2
Study
n: not reported in source
Cell-free system
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c directly binds to CK2 and activates it in cell-free systems.
Show in the study text Report a problemFND-3955975501
08LabIn vitro (cell-free)Activity measurement
In cell-free systems, MOTS‑c activated CK2.
In plain wordsIn lab tests without cells, MOTS‑c switched on the CK2 enzyme.
Peptide
MOTS-c
Outcome
IncreaseCK2 activation
Study
n: not reported in source
Cell-free system
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
MOTS-c directly binds to CK2 and activates it in cell-free systems.
Show in the study text Report a problemFND-3955975502

Studies that did not test the peptide alone4

In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking MOTS-c.

09HumanNot a test of MOTS-c aloneObservational studyOther
Male carriers of the K14Q MOTS‑c variant had a higher risk of sarcopenia, in an age- and physical-activity-dependent manner.
In plain wordsMen carrying the K14Q MOTS‑c variant were linked to a higher risk of muscle loss, depending on age and activity.
Peptide
MOTS-c
Outcome
IncreaseSarcopenia risk in male K14Q MOTS-c carriers
Study
n: not reported in source
Outcome group
Exercise and physical function · Musculoskeletal
Source sentences
Summary
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.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3955975510
10HumanNot a test of MOTS-c aloneObservational studyOther
Male carriers of the K14Q MOTS‑c variant had a higher risk of type 2 diabetes, in an age- and physical-activity-dependent manner.
In plain wordsMen carrying the K14Q MOTS‑c variant were linked to a higher risk of type 2 diabetes, depending on age and activity.
Peptide
MOTS-c
Outcome
IncreaseType 2 diabetes risk in male K14Q MOTS-c carriers
Study
n: not reported in source
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
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.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3955975511
11HumanNot a test of MOTS-c aloneObservational studyOther
Female carriers of the K14Q MOTS‑c variant had an age-specific reduced risk of type 2 diabetes.
In plain wordsWomen carrying the K14Q MOTS‑c variant were linked to a lower risk of type 2 diabetes at specific ages.
Peptide
MOTS-c
Outcome
DecreaseType 2 diabetes risk in female K14Q MOTS-c carriers
Study
n: not reported in source
Outcome group
Glycemic control · Metabolic and weight
Source sentences
Summary
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.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3955975512
12LabNot a test of MOTS-c aloneOther designActivity measurement
The naturally occurring K14Q MOTS‑c variant had reduced binding to CK2 and did not activate it or elicit its effects.
In plain wordsA natural variant of MOTS‑c bound CK2 less and did not switch it on.
Peptide
MOTS-c
Outcome
DecreaseK14Q MOTS-c variant binding to CK2 and activation
Study
n: not reported in source
Comparator
Standard MOTS-c
Outcome group
Receptor activity and mechanism · Musculoskeletal
Source sentences
Summary
Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects.
In this study, MOTS-c was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MOTS-c.
Show in the study text Report a problemFND-3955975509

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
10 Oct 2026, 08:19 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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Terms as the source lists them.

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