Side-by-side · Research reference

MOTS-cvsPE 22-28

Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.

AAnimal-StrongHUMAN-REVIEWED16/68 cited

BAnimal-StrongHUMAN-REVIEWED16/47 cited

MOTS-c

Mitokine · Mitochondria-Encoded

5–10 mgWeekly doseLee 2015

AnimalEvidence levelLee 2015 Reynolds 2021

Min–hrsHalf-life

SQ · Variable · 2–3×/week

PE 22-28

TREK-1 Antagonist · Pre-Clinical

0.12 nMTREK-1 IC50Djillani 2017

7 AAPeptide lengthDjillani 2017

AnimalEvidence stage

IP · SQ · Once Daily (animal models)Djillani 2017 Pietri 2019

01Mechanism of Action

Parameter

MOTS-c

PE 22-28

Primary target

Mitochondrial 12S rRNA sORF → folate-AICAR-AMPK axisLee 2015

TREK-1 two-pore-domain potassium channelDjillani 2017 Ma 2020

Pathway

Folate cycle inhibition → ↑AICAR → AMPK phosphorylation → PGC-1α upregulationLee 2015 Kim 2018

TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity

Downstream effect

Enhanced fatty acid oxidation, GLUT4-mediated glucose uptake, mitochondrial bioenergetics, anti-inflammationLee 2015

Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017 Cong 2023 Wu 2021

Feedback intact?

Stress-responsive, AMPK-dependent nuclear translocationKim 2018

N/A — direct ion channel blockade; not receptor-mediated endocrine axis

Origin

Endogenous 16-AA mitokine; mtDNA-encoded; declines with age; upregulated by exerciseReynolds 2021

Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017 Mazella 2018

Antibody development

—

Not reported in animal studies

02Dosage Protocols

Parameter

MOTS-c

PE 22-28

Standard dose

5–10 mg / weekLee 2015

Experimental, extrapolated from animal data. No human RCT-derived dose.

—

Frequency

2–3× per week

Short half-life may necessitate more frequent dosing for saturation.

Once daily

Sustained antidepressant effect over 7+ days.

Lower / starter dose

2.5–5 mg / week

Recommended due to limited human data.

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Evidence basis

Animal + anecdotalLee 2015 Reynolds 2021 A first-in-human phase 1 study 2021

Phase 1a/1b CB4211 analog trial completed 2021; no native MOTS-c RCT published.

Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017 Qi 2018 Wu 2021

Duration

4–12 weeks (experimental)

Optimal cycle length unknown.

—

Reconstitution

Bacteriostatic water, 1–2 mL

10 mg/mL at 1 mL.

—

Timing

Pre-workout or fasted state preferred

Activity-context amplifies AMPK response.

—

Half-life

Minutes to hours (estimated)

Systemically unstable; native MOTS-c PK in humans not fully characterised.

—

Animal dose (antidepressant)

—

0.3–3 µg/kg IP

Effective in forced swim test, tail suspension test, CUMS models.

Animal dose (neuroprotection)

—

0.03 µg/kg IPPietri 2019

Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.

Onset (animal)

—

Within hours (acute); full effect 4–7 days

Duration (animal)

—

7–28 days testedQi 2018 Pietri 2019

Comparison to fluoxetine

—

PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7

Chronic administration shows superior long-term efficacy.

Human equivalent (extrapolated)

—

Not established — no clinical trials

Allometric scaling from rodent data unavailable.

03Metabolic / Fat Loss Evidence

Parameter

MOTS-c

PE 22-28

Primary fat target

Diet-induced / metabolic obesity; systemic fat utilization

—

Quantified reduction

Significant HFD fat gain ↓Lee 2015

Murine models, dose-dependent (5 & 15 mg/kg).

—

IGF-1 impact

No direct IGF-1 pathway; AMPK-mediated

—

Effect on lean mass

High dose significantly ↑ lean mass in mice

—

Insulin sensitivity

Reversed HFD insulin resistance in 7 days (mice)Lee 2015

—

Triglycerides

AMPK-driven FA oxidation suggests TG benefit (not directly measured)

—

Glucose metabolism

Improved glucose tolerance; GLUT4 upregulationLee 2015

—

Effect reversibility

Unknown — no long-term follow-up data

—

Context dependency

No effect in normal-chow mice; requires metabolic stressReynolds 2021

—

Key publication

Lee Cell Metab 2015 · Reynolds Nat Commun 2021 · Kim Cell Metab 2018Lee 2015 Reynolds 2021 Kim 2018

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04Side Effects & Safety

Parameter

MOTS-c

PE 22-28

Injection site reaction

Mild irritation (reported)

—

Fluid retention / Edema

Not reported

—

Glucose intolerance

Improves glucose toleranceLee 2015

—

Cardiovascular

Heart palpitations (anecdotal); cardiac hypertrophy reversed in diabetic rats

—

Cancer risk

Contradictory data — some models suggest pro-proliferative effects

—

CNS / Neurological

Insomnia, headache (anecdotal reports)

—

GI symptoms

Nausea, stomach discomfort (reported)

—

Antibody formation

No data (no long-term human trials)

—

Pregnancy / OB

Avoid — insufficient safety data

—

Evidence quality

Phase 1 analog (CB4211); preclinical; anecdotal humanA first-in-human phase 1 study 2021

—

Toxicity (animal)

—

No adverse effects reported at therapeutic doses

Cardiovascular (theoretical)

—

TREK-1 expressed in cardiac tissue; arrhythmia risk unclear

Weight change

—

Not reported in animal studies

Neurological

—

No seizures or behavioral abnormalities noted

Long-term safety

—

Unknown — longest animal study 28 days

Absolute Contraindications

MOTS-c

·Pregnancy / breastfeeding (insufficient data)

PE 22-28

·Human use — no clinical safety data available

Relative Contraindications

MOTS-c

·Active cancer or cancer predisposition
·AMPK pathway deficiency (efficacy nullified)
·Use with cancer-promoting medications (theoretical)

PE 22-28

·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)

05Administration Protocol

Parameter

MOTS-c

PE 22-28

1. Reconstitution

Add 1–2 mL bacteriostatic water. At 10 mg/vial, 1 mL gives 10 mg/mL concentration. Roll gently to dissolve.

Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.

2. Injection site

Subcutaneous — abdomen, thigh, or deltoid. Rotate sites to avoid lipohypertrophy. Pinch fat layer.

Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017

3. Timing

Pre-workout or fasted state preferred — metabolic context amplifies AMPK response. 2–3× per week.

Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.

4. Storage

Lyophilised: room temp, protected from light. Reconstituted: refrigerate, use within 21–30 days. Short systemic stability.

Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.

5. Needle

27–31G insulin syringe. Short needle (4–6 mm) for SQ delivery. Clean technique mandatory.

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06Stack Synergy

MOTS-c

+ Ipamorelin

Moderate

View Ipamorelin →

MOTS-c activates AMPK/PGC-1α for mitochondrial efficiency and fatty acid oxidation; ipamorelin stimulates GH for anabolic recovery and sleep depth. Pathways are complementary — MOTS-c handles metabolic flexibility and glucose handling while ipamorelin drives recovery and body recomposition through GH. Theoretical synergy is high; clinical data is lacking.

MOTS-c: 5 mg SQ · pre-workout (2–3×/wk)
Ipamorelin: 200–300 mcg SQ · pre-sleep (daily)
Primary benefit: Metabolic flexibility + GH recovery + ROS reduction

PE 22-28

— no documented stacks