MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Gudiksen A, Hansen CC, van der Stede T, Daugaard AH, Schmidt JH, Ringholm S, Merimi M, Al-Obaidi FR, Kristoffersen AT, Zole E, Regenberg B, Kjøbsted R, Wojtaszewski J, Hellsten Y, Pilegaard H

Free radical biology & medicine9 Jan 2026Cited by 3 (Europe PMC)

PMID41520850DOI10.1016/j.freeradbiomed.2026.01.002PepBankPUB-41520850

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Summary

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

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

Results from this study8

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

01AnimalAnimal study (in vivo)Activity measurement
In mice, MOTS‑c administration augmented skeletal muscle mitochondrial bioenergetic performance.
In plain wordsIn mice, MOTS‑c improved how well muscle mitochondria produce energy.
Peptide
MOTS-c
Outcome
IncreaseSkeletal muscle mitochondrial bioenergetic performance
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK).
Show in the study text Report a problemFND-4152085001
02AnimalAnimal study (in vivo)Mechanism
In two transgenic mouse strains, the MOTS‑c effect on muscle mitochondrial bioenergetics depended on both PGC-1α and AMPK.
In plain wordsIn mice, the muscle energy effect of MOTS‑c needed both PGC-1α and AMPK.
Peptide
MOTS-c
Outcome
Not applicableDependence of bioenergetic effect on PGC-1α and AMPK
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Receptor activity and mechanism · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK).
Show in the study text Report a problemFND-4152085002
03AnimalAnimal study (in vivo)Other
In mice, MOTS‑c produced no apparent change in mitochondrial respiratory protein content.
In plain wordsIn mice, MOTS‑c did not clearly change the amount of respiratory proteins in mitochondria.
Peptide
MOTS-c
Outcome
No significant changeMitochondrial respiratory protein content
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume.
Show in the study text Report a problemFND-4152085003
04AnimalAnimal study (in vivo)Mechanism
In mice, MOTS‑c treatment lowered mitochondrial reactive oxygen species emission.
In plain wordsIn mice, MOTS‑c treatment lowered the release of reactive oxygen species from mitochondria.
Peptide
MOTS-c
Outcome
DecreaseMitochondrial reactive oxygen species emission
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress.
Show in the study text Report a problemFND-4152085004
05AnimalAnimal study (in vivo)Mechanism
In mice, MOTS‑c treatment lowered ROS-related protein damage.
In plain wordsIn mice, MOTS‑c treatment lowered protein damage linked to reactive oxygen species.
Peptide
MOTS-c
Outcome
DecreaseROS-related protein damage
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress.
Show in the study text Report a problemFND-4152085005
06AnimalAnimal study (in vivo)Mechanism
In mice, RNA-sequencing suggested that MOTS‑c treatment acts subtly across redox handling, mitochondrial integrity and OXPHOS efficiency.
In plain wordsIn mice, gene data suggest MOTS‑c has small effects across several mitochondrial functions.
Peptide
MOTS-c
Outcome
Not applicableMuscle gene expression after MOTS-c (RNA-sequencing)
Study
mousen: not reported in source
Transgenic mouse strains (PGC-1α and AMPK dependence)
Outcome group
Mitochondrial function · Musculoskeletal
Studied dose
Dose not stated
Source sentences
Summary
RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics.
Show in the study text Report a problemFND-4152085006

Natural levels measured2

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

07HumanEndogenous levelOther designOther
In humans doing one-legged knee extensor exercise, interstitial levels of the body's own MOTS‑c were increased.
In plain wordsIn people doing one-legged knee exercise, the body's own MOTS‑c levels in muscle fluid were higher.
Peptide
MOTS-c
Outcome
IncreaseInterstitial MOTS-c during one-legged knee extensor exercise
Study
n: not reported in source
Outcome group
Exercise and physical function · Musculoskeletal
Source sentences
Summary
Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans.
This result measures the body's own MOTS-c. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4152085007
08HumanEndogenous levelOther designOther
In humans doing one-legged knee extensor exercise, the arterio-venous difference of MOTS‑c did not change.
In plain wordsIn people doing one-legged knee exercise, the body's own MOTS‑c did not change between artery and vein of the muscle.
Peptide
MOTS-c
Outcome
No significant changeArterio-venous difference of MOTS-c across exercising muscle
Study
n: not reported in source
Outcome group
Exercise and physical function · Musculoskeletal
Source sentences
Summary
Despite increased interstitial MOTS-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans.
This result measures the body's own MOTS-c. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-4152085008

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

Subjects

Terms as the source lists them.

Publication types

Journal Article

MeSH terms

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