Evidence

MOTS-c human studies and clinical trials

Human research on MOTS-c is mostly observational: blood and muscle levels measured in cohorts. The registered intervention trials and what they will measure.

By the MOTS-C Peptide editorial teamLast reviewed Sources: editorially approved

Short answer

No published study in this index reports outcomes from giving MOTS-c to people. 77 human studies are indexed, and none of them administered the peptide: they measured the MOTS-c that participants already produced. One Phase 2a trial of administered MOTS-c was recruiting at the time of writing [NCT07505745].

What the human research consists of

Human MOTS-c studies are overwhelmingly observational. A typical design draws blood from two or more groups, measures MOTS-c with an immunoassay and asks whether the groups differ. Published comparisons include people with and without type 2 diabetes, kidney failure, sleep apnoea and cardiovascular disease, along with age and exercise comparisons in healthy volunteers.

Human observational
77

77 indexed records. Open this set in the evidence explorer.

Registered trials

Trial records below are taken from ClinicalTrials.gov and are reproduced as the registry holds them. A registered trial is a plan, not a result.

Trials giving MOTS-c or an analogue

Registered trials in which MOTS-c or a MOTS-c analogue is administered
Registry IDWhat is givenDesignStatusResults
NCT03998514CB4211 (analogue)Nonalcoholic Fatty Liver DiseasePHASE1, randomized, triple maskingn = 88 (actual)completedstarted 2018-07-09None posted
NCT07505745MOTS-cPrediabetes, Insulin Resistance, Overweight/ObesityPHASE2, randomized, quadruple maskingn = 120 (estimated)recruitingstarted 2026-02-02None posted

The Phase 2a trial lists change in an oral-glucose-tolerance-derived insulin sensitivity index and treatment-emergent adverse events as its primary outcomes, with estimated completion in 2028 [NCT07505745]. The earlier Phase 1 programme tested CB4211, a MOTS-c analogue and therefore a different molecule; it completed in 2021 and posted no results to the registry [NCT03998514].

Trials that only measure MOTS-c

A further 4 registered studies mention MOTS-c as something they measure, not something they give. They are listed here so that search results pointing to “MOTS-c clinical trials” can be read correctly.

  • NCT04027712: Platelet Reactivity, B-amyloid, MOTS-c and Mortality of Type II Diabetics With CAD (unknown).
  • NCT03878706: The Cardiovascular Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their Combination (recruiting).
  • NCT07438002: Analysis of Effects of High-intensity Physical Exercise in Subjects With Dialyzed Chronic Kidney Disease and in Conservative Treatment (recruiting).
  • NCT07678073: Comparison of the Effects of General Anesthesia and Combined Spinal-Epidural Anesthesia on Ferroptosis, Humanin and MOTS-c Levels in Renal Transplantation (recruiting).

What regulators found

FDA’s 2026 evaluation searched PubMed, Embase, the Cochrane Database, FAERS, DailyMed, Drugs@FDA and professional references. It concluded that there is a lack of clinical and nonclinical safety information, that the agency was particularly concerned about the absence of human data by any route, and that its evaluation did not identify information on MOTS-c administered in humans [FDA 2026]. Its searches of the adverse-event database through March 2025 retrieved no reports.

The strongest human findings in the index

Ranked by study design rather than by how striking the result was. Every record links to its own page with the sample size, controls and stated limitations.

Human MOTS-c studies ranked by evidence tier
StudyModelWhat was reportedLimitationsTier
Zhang 2026
Antioxidants (Basel)
Endogenous MOTS-c measured
Human obs.
Healthy young males stratified as elite track and field athletes, recreationally active and sedentary; serum MOTS-c and fitness testing
Measured progressively higher serum MOTS-c from sedentary to recreationally active to elite athlete groups of young males. Reported strong positive correlations of serum MOTS-c with peak oxygen uptake, superoxide dismutase, back muscle endurance and post-fatigue force, a strong inverse correlation with post-exercise malondialdehyde, and no significant correlation with handgrip strength.Very small groups of 10 young males each; cross-sectional design precludes causal inference; multiple strong correlations in a small sample risk overfitting.Evidence tier B
Suliman 2026
Antioxidants (Basel)
Related mitochondrial peptide
Human obs.
Adults with kidney failure undergoing living-donor kidney transplantation and controls; serum AGEs, RAGE isoforms and MDPs by ELISA
Measured higher advanced glycation end-products and lower mitochondrial-derived peptides, including MOTS-c, in adults with chronic kidney disease compared with controls. Reported that MOTS-c was inversely associated with advanced glycation end-products and with the AGEs/sRAGE ratio, while humanin was independently associated with AGEs and sRAGE measures.Cross-sectional design with MOTS-c one of several peptides measured; single-centre transplantation cohort; ELISA-based peptide quantification without orthogonal confirmation.Evidence tier B
Horwath 2026
Exp Physiol
Endogenous MOTS-c measured
Human obs.
Adults with cerebral palsy using running frames and typically developing adults and adolescents; plasma MDPs before and after endurance exercise
Measured plasma MOTS-c, humanin and SHMOOSE in adults with cerebral palsy and typically developing participants and found comparable basal levels despite lower muscle mass and peak oxygen uptake in the cerebral palsy group. Reported no or only modest changes in circulating MDPs after an acute endurance exercise bout, with no differences between groups.Small group sizes not reported in the abstract; single post-exercise sampling point; in-house ELISA without external validation and heterogeneous exercise modes between groups.Evidence tier B
Sonay 2026
J Clin Med
Endogenous MOTS-c measured
Human obs.
Patients with Hashimoto's thyroiditis and age- and sex-matched healthy controls; circulating MOTS-c
Measured lower circulating MOTS-c in patients with Hashimoto's thyroiditis than in matched controls, with inverse correlations with body mass index, fasting glucose, HbA1c, HOMA-IR, thyroid-stimulating hormone, C-reactive protein and thyroid autoantibodies. Reported that Hashimoto's thyroiditis and HOMA-IR were independent determinants of lower MOTS-c in regression analysis.Cross-sectional design cannot establish direction; single-centre sample measured by ELISA at one time point; medication and iodine status largely unaccounted for beyond levothyroxine use.Evidence tier B
Sączek 2026
Kidney Blood Press Res
Endogenous MOTS-c measured
Human obs.
Kidney transplant recipients and age-matched controls; serum nardilysin and MOTS-c by ELISA
Measured higher serum nardilysin and MOTS-c in kidney transplant recipients than in age-matched controls over a median follow-up of about 29 months. Reported no significant associations between MOTS-c and cardiometabolic features, and a non-significant trend toward lower allograft loss risk with higher MOTS-c, while nardilysin was inversely associated with prevalent cardiovascular disease.MOTS-c was a secondary marker alongside nardilysin; single-centre observational design with a small control group and few outcome events; residual confounding likely.Evidence tier B
Musolino 2026
Int Urol Nephrol
Endogenous MOTS-c measured
Human obs.
Stable peritoneal dialysis patients; MOTS-c measured in serum, urine and peritoneal dialysate
Measured MOTS-c in serum, urine and dialysate of peritoneal dialysis patients and reported that higher urinary MOTS-c was associated with lower advanced oxidation protein products and with higher pulse wave velocity and left ventricular systolic function. Reported that higher dialysate MOTS-c was associated with lower pulse wave velocity and lower blood pressure.Small single-centre pilot with no control group and cross-sectional correlations only; multiple comparisons across three compartments without adjustment.Evidence tier B
Peng 2026
Biomedicines
Endogenous MOTS-c measured
Human obs.
Patients with acute myocardial infarction undergoing percutaneous coronary intervention; peripheral and intracoronary serum MOTS-c
Measured lower postoperative peripheral serum MOTS-c in patients with myocardial ischemia-reperfusion injury than in those without, while preoperative peripheral and intracoronary levels did not differ. Reported that postoperative peripheral MOTS-c was an independent factor in multivariable regression, with an area under the curve of 0.648 for discriminating injury.Small single-centre cross-sectional sample; modest discrimination; no longitudinal or repeated sampling, and residual confounding by procedural factors is likely.Evidence tier B
Filibeli 2026
Arch Endocrinol Metab
Several
Human obs.
Adolescents aged 12-18 with polycystic ovary syndrome and controls; serum ELISA and m.1382A>C sequencing
Measured serum MOTS-c in adolescents with and without polycystic ovary syndrome and found higher mean levels in the PCOS group that did not reach statistical significance. Reported no significant association between MOTS-c levels and anthropometric or metabolic parameters, and all participants carried the wild-type A/A genotype at m.1382A>C.Cross-sectional case-control design; the genotype analysis was uninformative because no variant carriers were found; single-centre adolescent sample.Evidence tier B
Kutuk 2026
Sci Rep
Endogenous MOTS-c measured
Human obs.
Women with polycystic ovary syndrome and age- and BMI-matched controls; serum ELISA and vastus lateralis biopsies
Measured lower circulating MOTS-c concentrations and lower skeletal muscle MOTS-c expression in women with polycystic ovary syndrome than in matched controls. Reported that serum MOTS-c was inversely associated with total testosterone and total cholesterol in this cohort.Cross-sectional case-control design cannot establish direction; muscle expression was assessed only in a subgroup; single-centre sample of women with weak correlation coefficients.Evidence tier B
Yoon 2026
J Clin Transl Endocrinol
Endogenous MOTS-c measured
Human obs.
Lean adult controls and adults with obesity scheduled for bariatric surgery; adipose tissue from lean kidney donors and participants with obesity
Found higher circulating MOTS-c in adults with obesity than in lean adults, with BMI and HOMA-IR each independently predicting higher levels and a nonlinear relationship with HOMA-IR. Reported that adipose tissue MOTS-c expression did not differ between groups and did not correlate with circulating MOTS-c. Measured no change in circulating MOTS-c 6 months after bariatric surgery despite lower BMI in the 10 participants followed.Small exploratory sample with only 10 participants followed after surgery, cross-sectional group comparison, adipose tissue controls drawn from kidney donors rather than the lean comparison group, and no sex-stratified analysis reported.Evidence tier B

Notable examples include an age comparison of circulating and muscle MOTS-c in healthy men [D'Souza et al. 2020], exercise-associated changes [Reynolds et al. 2021], and a genotype study of the m.1382A>C variant against type 2 diabetes prevalence [Zempo et al. 2021]. Browse all of them in the evidence explorer.

Frequently asked questions

Are there human clinical trials of MOTS-c?

One Phase 2a randomised, placebo-controlled trial of administered MOTS-c in adults with prediabetes was recruiting at the time of writing, with estimated completion in 2028 and no results posted. No completed trial of MOTS-c itself has published outcomes.

Has MOTS-c been given to people in a published study?

No published study in this index reports giving MOTS-c to human participants. Reviewing the substance in 2026, FDA stated that its evaluation did not identify information on the use of MOTS-c-related substances administered in humans.

What do the human MOTS-c studies actually measure?

Almost all of them measure the MOTS-c a person already produces, usually in blood, and compare levels between groups such as people with and without a condition. These are observational comparisons, not tests of giving the peptide.

What was CB4211?

CB4211 is an analogue of MOTS-c developed by CohBar. Its Phase 1a/1b trial in healthy volunteers and people with fatty liver disease completed in 2021 with no results posted to the registry. An analogue is a different molecule from MOTS-c itself.

Does lower MOTS-c in a disease mean giving MOTS-c would help?

No. An association of that kind cannot show direction or cause. Lower levels may be a consequence of the condition, a marker of something else, or unrelated. Only an intervention trial can answer the question.

References

  1. D'Souza RF, Woodhead JST, Hedges CP et al. (2020). Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). PubMed 32182209 · doi:10.18632/aging.102944 · Study record[Human obs., tier B]
  2. Reynolds JC, Lai RW, Woodhead JST et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. PubMed 33473109 · doi:10.1038/s41467-020-20790-0 · Study record[Animal, tier C]
  3. Zempo H, Kim SJ, Fuku N et al. (2021). A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). PubMed 33468709 · doi:10.18632/aging.202529 · Study record[Human obs., tier B]
  4. ClinicalTrials.gov (2026-04-01). MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity (NCT07505745). Source[retrieved 2026-11-11]
  5. ClinicalTrials.gov (2021-05-11). A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease (NCT03998514). Source[retrieved 2026-11-11]
  6. U.S. Food and Drug Administration (2026-05-11). FDA Briefing Document: MOTS-c-Related Bulk Drug Substances (MOTS-c (free base) and MOTS-c acetate). Source[retrieved 2026-11-11]