AMPK GLUT4 AICAR; MOTS-c is a mitochondrial-derived peptide that acts as a metabolic hormone, primarily targeting skeletal muscle and fat. Its cellular mechanism involves inhibition of the folate-methionine cycle, leading to AICAR accumulation and AMPK activation. [1]
MOTS‑c (human) acetate targets the AMPK pathway. It induces the accumulation of the endogenous AMP analog AICAR, which activates AMP‑activated protein kinase (AMPK). AMPK activation leads to increased expression of GLUT4, promoting glucose uptake and improving insulin sensitivity. MOTS‑c also increases cellular NAD+ levels.

MOTS-c suppresses the folate cycle at the 5Me-THF level, which causes AICAR [5-aminoimidazole-4-carboxamide ribonucleotide] to build up. Nucleotide precursors, or NAD+, are likewise increased in cells by MOTS-c[1]. A mitochondrial signal called MOTS-c promotes the absorption of glucose by cells while inhibiting respiration. Rather of being broken down by glycolysis, the glucose that is taken up in response to MOTS-c is directed to the anabolic pentose phosphate pathway (PPP), which supplies carbon sources for the synthesis of purines. Furthermore, MOTS-c raises the amount of a β-oxidation intermediate, lowers intracellular levels of essential and non-essential fatty acids, and increases carnitine shuttles, which carry activated fatty acids into mitochondria for β-oxidation, all of which point to improved lipid utilization. Myocytes that consistently overexpress MOTS-c also show increased glucose uptake[1].

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In myocytes that stably overexpress MOTS-c, increased glucose uptake was observed. [1]
MOTS-c treatment in vitro increased cellular NAD⁺ levels and increased levels of carnitine shuttles (which transport activated fatty acids into mitochondria for β-oxidation), increased a β-oxidation intermediate, and reduced intracellular levels of essential and non-essential fatty acids, suggesting enhanced lipid utilization. [1]
MOTS-c treatment in vitro routed glucose taken up to the anabolic pentose phosphate pathway (PPP), providing carbon sources for purine synthesis, rather than being metabolized through glycolysis. [1]

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In vitro, MOTS‑c (human) acetate induces the accumulation of AMP analog AICAR, increasing activation of AMPK and expression of its downstream GLUT4. It induces glucose uptake and improves insulin sensitivity. The peptide also increases cellular NAD+ levels.

In mice given MOTS-c injections, skeletal muscle AMPK is activated and its downstream glucose transporter GLUT4 is elevated. In addition, MOTS-c might function as a possible mitochondrial signal that mediates a mitohormesis response brought on by exercise, promoting physiological adaptation and heightened exercise tolerance[1]. Skeletal muscle and fat seem to be MOTS-c's main target organs. As mice age, their levels of MOTS-c in their skeletal muscle and bloodstream decrease in tandem with the age-dependent emergence of insulin resistance. Age-dependent skeletal muscle insulin resistance is effectively reversed in older rats (12 mo.) by systemic injections that raise MOTS-c levels[1].

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Acute systemic treatment of MOTS-c by intraperitoneal injection in mice significantly reduced non-fasting glucose levels and significantly improved glucose tolerance test (GTT) responses. [1]
Hyperinsulinemic-euglycemic clamp studies demonstrated that MOTS-c regulates glucose homeostasis by targeting skeletal muscle to increase glucose clearance, but not the liver to reduce production. [1]
In aged mice (12 months), systemic MOTS-c injections reversed age-dependent skeletal muscle insulin resistance. [1]
In a high-fat diet (HFD)-induced mouse model of insulin resistance and obesity, MOTS-c prevented diet-induced obesity and insulin resistance, showing increased activation of AMPK and expression of its downstream glucose transporter in skeletal muscles. MOTS-c also caused a significant reduction in HFD-induced visceral fat and hepatic steatosis, and was associated with increased body heat production (thermal energy dissipation). HFD-fed mice treated with MOTS-c showed increased glucose utilization (higher respiratory exchange ratio, RER). [1]
Fasting mice for 48 hours significantly reduced endogenous levels of MOTS-c in skeletal muscle and plasma. MOTS-c levels in mice decline with age in skeletal muscle and in circulation, concomitant with age-dependent development of insulin resistance. [1]

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In vivo, MOTS‑c (human) acetate (0.5 mg/kg per day, i.p.) increases glucose clearance in mice fed a normal diet. It increases skeletal muscle AMPK activation and GLUT4 expression, as well as prevents high‑fat diet‑induced obesity and hyperinsulinemia in CD‑1 mice. MOTS‑c injections in mice show activation of skeletal muscle AMPK and increased levels of GLUT4.

Non‑cellular assays for MOTS‑c (human) acetate are not typically performed as it functions through intracellular signaling pathways. Its activity is assessed in cell‑based systems by measuring AMPK activation, GLUT4 expression, and glucose uptake.

In vitro cellular assays for MOTS‑c (human) acetate are performed using various cell types, including muscle cells and adipocytes. Cells are treated with the peptide, and AMPK activation is measured by Western blotting for phosphorylated AMPK. GLUT4 expression is assessed by Western blotting or qRT‑PCR. Glucose uptake is measured using radioactive or fluorescent glucose analogs.

Mouse Studies: Fasting studies: Mice were fasted for 48 hours, after which endogenous MOTS-c levels in skeletal muscle and plasma were measured. [1]
Acute treatment: Mice received intraperitoneal injections of MOTS-c to assess effects on non-fasting glucose levels and glucose tolerance test (GTT) responses. [1]
Hyperinsulinemic-euglycemic clamp: This gold-standard technique was used to measure insulin action, specifically determining that MOTS-c increases glucose clearance by skeletal muscle rather than reducing hepatic glucose production. [1]
Aged mouse study: Older mice (12 months) received systemic MOTS-c injections, which reversed age-dependent skeletal muscle insulin resistance. [1]
High-fat diet (HFD) study: Mice fed a high-fat diet were treated with MOTS-c, which prevented diet-induced obesity and insulin resistance. Parameters measured included body weight, visceral fat, hepatic steatosis, body heat production, and respiratory exchange ratio (RER). [1]

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In vivo animal experiments for MOTS‑c (human) acetate are conducted in mouse models. The peptide is administered at 0.5 mg/kg per day via intraperitoneal injection. Endpoints include glucose clearance, AMPK activation, GLUT4 expression, and prevention of high‑fat diet‑induced obesity and hyperinsulinemia.

Pharmacokinetic properties for MOTS‑c (human) acetate are not extensively detailed in available sources. The peptide has a sequence of MRWQEMGYIFYPRKLR (acetate salt). Its related CAS number for the free form is 1627580‑64‑6. As a peptide, its PK would be influenced by factors such as proteolytic degradation and clearance. It is typically administered via injection for in vivo studies.

Toxicological data for MOTS‑c (human) acetate are not extensively detailed in available sources. As a mitochondrial‑derived peptide, it is generally considered to have low toxicity. In mouse studies, the peptide is well‑tolerated at the tested doses (0.5 mg/kg per day). It is intended for research use only and not for human consumption.

[1]. MOTS-c: A Novel Mitochondrial-Derived Peptide Regulating Muscle and Fat Metabolism. Free Radic Biol Med. 2016 Nov;100:182-187.

[2]. The role of MOTS-c-mediated antioxidant defense in aerobic exercise alleviating diabetic myocardial injury. Sci Rep. 2023 Nov 13;13(1):19781.

[3]. The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test. Eur J Pharmacol. 2020 Mar 5;870:172909.

[4]. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54.

[5]. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022 Oct 9;23(19):11991.

MOTS-c (mitochondrial ORF of the twelve S c) is a 16-amino acid peptide encoded by a short open reading frame (sORF) within the mitochondrial 12S rRNA gene. It was identified in 2015 as a novel mitochondrial-derived peptide (MDP). [1]
MOTS-c is expressed in various tissues and circulates in plasma, acting as a mitochondrial hormone. Its primary target organs appear to be skeletal muscle and fat. [1]
The cellular mechanism of MOTS-c involves inhibition of the folate-methionine cycle at the level of 5Me-THF, resulting in accumulation of AICAR (a well-defined AMPK activator) and increased NAD⁺ levels, which may involve SIRT1. [1]
MOTS-c stimulates cellular glucose uptake while suppressing respiration (Crabtree effect), and glucose is routed to the pentose phosphate pathway (PPP) rather than glycolysis. [1]
MOTS-c levels decline with age in both rodents and humans, correlating with age-dependent insulin resistance. A mitochondrial polymorphism (m.1382A>C) within the MOTS-c ORF, found in the D4b2 haplogroup associated with exceptional longevity in the Japanese population, causes a Lys14Gln amino acid change that may have functional implications. [1]
MOTS-c has implications in obesity, diabetes, exercise, and longevity, representing a novel mitochondrial signaling mechanism to regulate metabolism. [1]

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MOTS‑c (human) acetate is a mitochondrial‑derived peptide that induces AICAR accumulation, AMPK activation, and GLUT4 expression. It induces glucose uptake and improves insulin sensitivity, with effects on obesity, diabetes, exercise, and longevity. It is used as a research tool for studying metabolic regulation. It is not approved for clinical use.

C103H156N28O24S2

2234.64

2174.111095

MOTS-c (human);1627580-64-6

155885767

H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH

MRWQEMGYXFYPRKLR

White to off-white solid powder

-3.9

31

29

73

153

4510

16

CCC(C)C(C(=O)NC(CC1=CC=CC=C1)C(=O)NC(CC2=CC=C(C=C2)O)C(=O)N3CCCC3C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)O)NC(=O)C(CC4=CC=C(C=C4)O)NC(=O)CNC(=O)C(CCSC)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)N)NC(=O)C(CC5=CNC6=CC=CC=C65)NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)N

WYTHCOXVWRKRAH-UHFFFAOYSA-N

InChI=1S/C101H152N28O22S2/c1-7-57(4)83(96(148)126-76(50-58-19-9-8-10-20-58)92(144)127-78(52-60-30-34-63(131)35-31-60)97(149)129-46-18-27-79(129)95(147)122-69(25-16-44-112-100(107)108)86(138)118-67(23-13-14-42-102)87(139)124-74(49-56(2)3)91(143)123-73(98(150)151)26-17-45-113-101(109)110)128-94(146)75(51-59-28-32-62(130)33-29-59)116-81(133)55-115-85(137)72(41-48-153-6)121-90(142)71(37-39-82(134)135)119-89(141)70(36-38-80(104)132)120-93(145)77(53-61-54-114-66-22-12-11-21-64(61)66)125-88(140)68(24-15-43-111-99(105)106)117-84(136)65(103)40-47-152-5/h8-12,19-22,28-35,54,56-57,65,67-79,83,114,130-131H,7,13-18,23-27,36-53,55,102-103H2,1-6H3,(H2,104,132)(H,115,137)(H,116,133)(H,117,136)(H,118,138)(H,119,141)(H,120,145)(H,121,142)(H,122,147)(H,123,143)(H,124,139)(H,125,140)(H,126,148)(H,127,144)(H,128,146)(H,134,135)(H,150,151)(H4,105,106,111)(H4,107,108,112)(H4,109,110,113)

4-[[5-amino-2-[[2-[[2-[(2-amino-4-methylsulfanylbutanoyl)amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoyl]amino]-5-[[1-[[2-[[1-[[1-[[1-[[1-[2-[[1-[[6-amino-1-[[1-[(4-carbamimidamido-1-carboxybutyl)amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid

MOTS-c (human); 1627580-64-6; MOTS-c Human Acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O :~6.25 mg/mL (~2.80 mM)
DMSO :~4 mg/mL (~1.79 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)