TB-500 vs MOTS-c: Actin-Binding Repair Fragment vs Mitochondrial Metabolic Peptide

Q: Does TB-500 have any human trial data?

Not on the TB-500 heptapeptide that we have identified. The human studies people cite used full-length thymosin beta-4 (RegeneRx's RGN-137 and RGN-259), which is a different molecule.

Q: Are TB-500 and MOTS-c banned in sport?

Yes. WADA's 2026 Prohibited List bans thymosin beta-4 and its derivatives, naming TB-500, under S2, and names MOTS-c under S4 as an AMPK activator. Both are prohibited at all times.

> Research disclaimer: This article summarizes peer-reviewed literature and public regulatory records for informational and research purposes only. It is not medical advice. TB-500 and MOTS-c sold online are research chemicals, not FDA-approved drugs. Nothing here is a dosing protocol, an efficacy claim, or a recommendation for human or veterinary use.

Quick answer: TB-500 and MOTS-c are often stocked side by side and sometimes sold as a "recovery plus performance" pairing, but they come from different parts of the cell and have almost nothing in common mechanistically. TB-500, as usually sold, is the acetylated heptapeptide Ac-LKKTETQ, matching residues 17–23 of thymosin β4 (Tβ4), the stretch that binds actin. Its research story is about cell migration, blood-vessel growth, and tissue repair, and most of the evidence comes from the full-length protein in animal models. MOTS-c is a 16-amino-acid peptide encoded inside the mitochondrial genome, in the 12S rRNA gene. Its research story is about metabolism: insulin sensitivity, skeletal muscle, and the folate–purine–AMPK pathway. A MOTS-c analog (CB4211) has been through a small phase 1a/1b human study; the TB-500 heptapeptide has not been tested in humans in any trial we've identified. Both are on WADA's 2026 Prohibited List, and neither is FDA-approved.

---

Why These Two Get Compared

The comparison comes from the market more than the science. Both peptides moved through the 2026 FDA compounding review together, both got favorable but advisory votes from the same committee in July 2026, and both appear in vendor catalogs aimed at athletes and people interested in healthy aging. In forums, TB-500 gets filed under "healing" and MOTS-c under "metabolic" or "longevity," and the natural question is whether one does the other's job or whether they overlap.

The short version is that they answer different research questions. If your question is about a tendon, a wound, or a vascular repair model, the TB-500 and Tβ4 literature is where to look. If your question is about glucose handling, fat oxidation, exercise capacity, or age-related metabolic decline, MOTS-c is the molecule with data. The rest of this article explains why, and what the evidence actually supports for each.

Where Each Peptide Comes From

TB-500: a fragment of an actin-buffering protein

Thymosin β4 is a 43-amino-acid protein found in most nucleated cells. Inside the cell, it binds monomeric G-actin and keeps a ready pool available for the cytoskeleton. The commercial "TB-500" heptapeptide reproduces residues 17–23 (LKKTETQ), the central actin-binding motif. It's a synthetic fragment; the body isn't known to produce that seven-residue piece on its own as a signaling molecule. Our mechanism of action guide goes deeper on the actin story, and our fragment vs full-length article explains why results from the 43-residue protein shouldn't be assumed to transfer to the fragment.

MOTS-c: a peptide encoded by mitochondrial DNA

Mitochondria have their own small genome, and for most of the history of molecular biology it was thought to encode only 13 proteins plus the RNAs needed to make them. In 2015, Changhan Lee, Pinchas Cohen, and colleagues at the University of Southern California reported a short open reading frame inside the mitochondrial 12S rRNA gene that encodes a 16-amino-acid peptide. They named it MOTS-c, for "mitochondrial open reading frame of the 12S rRNA-c" (Lee et al., Cell Metabolism, 2015). It joined humanin as one of a small family of "mitochondrial-derived peptides."

That origin matters for how you read the literature. MOTS-c is something the body makes, and its levels can be measured in blood and muscle. Studies discuss endogenous MOTS-c changing with age and exercise, which is a kind of evidence that simply doesn't exist for a synthetic fragment like TB-500.

How They Act

| | TB-500 (Ac-LKKTETQ) | MOTS-c |
|---|---|---|
| Origin | Synthetic fragment of thymosin β4 (residues 17–23) | Endogenous peptide encoded in mitochondrial 12S rRNA |
| Length | 7 residues | 16 residues |
| Core activity in the literature | Actin binding; cell migration; angiogenesis; tissue repair | Folate cycle and de novo purine synthesis inhibition, leading to AMPK activation; insulin sensitivity |
| Primary target tissue in key papers | Wounds, tendons, heart, cornea (mostly full-length Tβ4 work) | Skeletal muscle |
| Human data on the exact molecule | None identified for the heptapeptide | None published for native MOTS-c in a controlled trial; an analog (CB4211) completed phase 1a/1b |
| WADA 2026 | Prohibited at all times (S2, "Thymosin-β4 and its derivatives e.g. TB-500") | Prohibited at all times (S4, AMPK activators, MOTS-c named) |

TB-500: migration and vessels

The case for thymosin β4 in tissue repair rests mostly on animal work with the full protein. Malinda and colleagues reported that Tβ4 sped up healing of full-thickness wounds in rats, with more re-epithelialization, collagen deposition, and new vessel growth (J Invest Dermatol, 1999). Later studies tied those effects to cell migration and angiogenesis, and to cardiac repair models. How much the 17–23 fragment reproduces on its own is a thinner question; our angiogenesis research page covers what's known.

What TB-500's literature doesn't really address is systemic metabolism. There's no body of work showing that Tβ4 or its fragment changes insulin sensitivity, fuel preference, or exercise capacity in the way MOTS-c papers do.

MOTS-c: muscle metabolism and AMPK

Lee and colleagues' 2015 paper laid out the core mechanism. In cells, MOTS-c inhibited the folate cycle and the de novo purine synthesis pathway tethered to it. That raised levels of AICAR, an intermediate that activates AMP-activated protein kinase (AMPK), the cell's main energy-stress sensor. In mice, MOTS-c treatment prevented both diet-induced obesity and age-dependent insulin resistance, and skeletal muscle appeared to be its main target organ.

Two later papers extended that picture:

Nuclear signaling. Kim and colleagues showed that under metabolic stress, MOTS-c moves from the cytoplasm into the nucleus in an AMPK-dependent way, binds chromatin, and regulates nuclear genes, including antioxidant response element (ARE) targets, interacting with the stress-responsive transcription factor NRF2 (Cell Metabolism, 2018). That made MOTS-c one of the first examples of a mitochondrial-encoded factor directly regulating the nuclear genome.

Exercise and aging. Reynolds and colleagues reported that MOTS-c treatment improved treadmill performance in young, middle-aged, and old mice. In 22-month-old mice, treated animals ran about twice as long and roughly 2.16 times as far as untreated controls. Intermittent treatment started late in life improved physical capacity and healthspan measures. In humans, the same paper found that exercise raised endogenous MOTS-c levels in skeletal muscle and in circulation (Nature Communications, 2021).

That last finding is the reason MOTS-c is sometimes described as an "exercise mimetic." It's worth being precise: the performance results are in mice given the peptide by injection, while the human finding is that exercise increases the body's own MOTS-c. Those are different claims.

> Sourcing note for researchers: confirm identity before anything else. A 7-residue fragment and a 16-residue peptide have very different molecular masses, so the certificate of analysis should make it obvious which one is in the vial. Our peptide buying guide lists what a COA should show, and our third-party testing guide explains how to read one.

The Human Data, Read Carefully

MOTS-c: an analog in a small phase 1a/1b study

CohBar developed CB4211, described by the company as an improved analog of MOTS-c, for nonalcoholic steatohepatitis (NASH) and obesity. Its phase 1a/1b trial (NCT03998514) was randomized, double-blind, and placebo-controlled. Phase 1a tested single and multiple ascending doses in 65 healthy adults. Phase 1b gave a once-daily subcutaneous dose or placebo for four weeks to 20 adults with obesity and nonalcoholic fatty liver disease.

CohBar's August 2021 topline release reported that the study met its primary endpoint of safety and tolerability, with no serious adverse events; the only adverse events in more than 10% of CB4211 subjects were mostly mild to moderate injection-site reactions. On exploratory endpoints, ALT fell 21% with CB4211 versus a 4% rise with placebo, AST fell 28% versus 11%, and glucose fell 6% versus no change. Liver fat, the measure most relevant to the target disease, fell by a similar amount in both groups.

Three cautions apply. CB4211 is an analog, not native MOTS-c. Phase 1b enrolled 11 people on drug and 9 on placebo for four weeks. And the efficacy measures were exploratory. This is early safety data on a related molecule, not evidence that MOTS-c sold as a research chemical does anything in people.

TB-500: no trials of the fragment

We haven't identified any human trial of the Ac-LKKTETQ heptapeptide. The human studies people cite for "TB-500" used full-length thymosin β4, such as RegeneRx's RGN-137 (topical, for wounds and epidermolysis bullosa) and RGN-259 (eye drops, for dry eye and neurotrophic keratopathy). Our human clinical trials overview walks through what those trials did and didn't find. FDA's own safety-risk listing for the fragment states that the agency has not identified any human exposure data for drug products containing it.

So, on paper, MOTS-c is a step ahead on human data, but only through an analog, in a tiny short study, measuring something unrelated to tissue repair.

Safety and Open Questions

Neither peptide has a well-characterized human safety profile in the form sold online.

Shared manufacturing concerns. FDA's review of peptides for compounding repeatedly flags immunogenicity risk, aggregation, and peptide-related impurities as general concerns for synthetic peptides of this kind. Those concerns apply to research-grade product of either molecule regardless of the biology.

TB-500 specifics. Because Tβ4 promotes cell migration and angiogenesis, theoretical questions about tumor growth come up repeatedly; our cancer and tumor research page summarizes that literature without overstating it. Our side effects and safety page covers the rest.

MOTS-c specifics. Its main documented actions are metabolic. In a research setting, that raises practical questions about glucose handling, especially alongside other agents that affect insulin sensitivity. The 2021 CohBar data showed a small glucose drop in people with obesity and fatty liver; how native MOTS-c behaves in lean or diabetic subjects in controlled conditions isn't established.

Neither molecule has long-term human data. Any claim that one is "safer" than the other goes beyond the evidence.

Regulatory and Anti-Doping Status in 2026

FDA approval. Neither TB-500 nor MOTS-c is an FDA-approved drug.

Compounding. On April 15, 2026, FDA said it would remove 12 peptides, including the thymosin β4 fragment, from its Category 2 list of bulk substances that raise significant safety concerns. On July 23, 2026, FDA's Pharmacy Compounding Advisory Committee voted 8–6, with one abstention, to recommend adding TB-500 to the 503A bulks list. At the same meeting it voted 7–5, with two abstentions, to recommend adding MOTS-c (both free base and acetate). In both cases FDA's scientific review staff had recommended against listing. The votes are advisory, and listing still requires rulemaking. Our 503A compounding article explains the process.

Sport. WADA's 2026 Prohibited List, in force since January 1, 2026, prohibits "Thymosin-β4 and its derivatives e.g. TB-500" under S2 (peptide hormones, growth factors, related substances, and mimetics) and names MOTS-c under S4 among activators of AMPK, alongside AICAR. Both are banned at all times, in and out of competition. Our drug testing research page has more on detection.

Choosing a Research Focus

If you're deciding which literature to build on, the useful question isn't "which peptide is better," it's "which biological system am I studying?"

Tissue repair models (tendon, ligament, skin wound, corneal injury, cardiac injury): the Tβ4 literature is relevant, with the caveat that most of it uses the full-length protein.

Metabolic models (diet-induced insulin resistance, fuel preference, age-related decline in exercise capacity): MOTS-c has the mechanistic papers and the only human-adjacent data, via CB4211.

Combined designs: studies that pair the two are, as far as we can find, absent from the peer-reviewed literature. Vendor "stack" pages pairing them aren't evidence of any interaction, positive or negative. If you're designing such work, both arms and the combination need their own controls.

Frequently Asked Questions

Is MOTS-c the same kind of peptide as TB-500?

No. MOTS-c is a 16-residue peptide the body makes from a gene inside mitochondrial DNA, and its studied actions are metabolic, through the folate–purine–AMPK pathway. TB-500 is a synthetic 7-residue fragment matching residues 17–23 of thymosin β4, studied for actin binding, cell migration, and tissue repair.

Has MOTS-c been tested in humans?

Native MOTS-c has not been reported in a controlled clinical trial that we've found. An analog, CB4211, completed a phase 1a/1b study: 65 healthy adults in phase 1a and 20 adults with obesity and fatty liver in a four-week phase 1b. It was reported as well tolerated with no serious adverse events, and exploratory liver enzymes and glucose fell versus placebo, while liver fat fell similarly in both groups.

Does TB-500 have any human trial data?

Not on the TB-500 heptapeptide that we've identified. The human studies people cite used full-length thymosin β4 (RegeneRx's RGN-137 and RGN-259), which is a different molecule.

Are TB-500 and MOTS-c banned in sport?

Yes. WADA's 2026 Prohibited List bans thymosin β4 and its derivatives, naming TB-500, under S2, and names MOTS-c under S4 as an AMPK activator. Both are prohibited at all times.

What is the FDA status of TB-500 and MOTS-c in 2026?

Neither is FDA-approved. On July 23, 2026, FDA's Pharmacy Compounding Advisory Committee voted 8–6 (one abstention) to recommend adding TB-500 to the 503A bulks list and 7–5 (two abstentions) to recommend adding MOTS-c, against FDA staff recommendations. The votes are advisory, and listing would still require rulemaking.

Before You Source a Lot

Check identity first. TB-500 and MOTS-c differ by nine residues and have clearly different molecular masses, so the certificate of analysis should leave no doubt about which one you have. Apollo Peptide Sciences publishes third-party COA documentation for its TB-500 lots. Compare the reported mass and sequence against what your protocol calls for. The peptide buying guide has the broader sourcing checklist.

---

Sources: Lee C et al., "The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance," Cell Metab 2015; Kim KH et al., "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress," Cell Metab 2018; Reynolds JC et al., "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis," Nat Commun 2021; ClinicalTrials.gov NCT03998514 (CB4211 phase 1a/1b); CohBar press release, Aug. 10, 2021; Malinda KM et al., J Invest Dermatol 1999 (thymosin β4 wound healing); FDA, "Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks" (content current as of Apr. 22, 2026); Hyman, Phelps & McNamara FDA Law Blog, "PCAC Approves Four Bulk Drug Substances for the 503A List," July 2026; WADA, 2026 Prohibited List (S2.3, S4.4).