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Mtc2.5
MOTS-c Research
Mostly mechanism / observationalLimited safety
13 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most MOTS-c studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from mixed-quality meta-analyses and randomised trials published 2015–2024.
Based on 13 studies · 1 meta-analysis
Confidence
Moderate
By outcome
Longevity & aging
Mostly mechanism / observational10 studies
Glucose & metabolic
Mostly mechanism / observational4 studies
Exercise & physical performance
Mostly mechanism / observational3 studies
Active research area
5 studies in the last 5 years · Latest meta-analysis: 2024
20152024
1Animal2015
Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation.
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J. · Cell Metab (2015)
Discovery paper: identifies MOTS-c, a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA, that regulates insulin sensitivity and metabolic homeostasis
Cellular action is inhibition of the folate cycle and de novo purine biosynthesis, leading to AMPK activation, with skeletal muscle as the primary target
MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity
MOTS-c... translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner.
Kim KH, Son JM, Benayoun BA, Lee C. · Cell Metab (2018)
Mechanistic cell study showing MOTS-c translocates to the nucleus and regulates nuclear gene expression in an AMPK-dependent manner under metabolic stress
Under glucose restriction, MOTS-c regulated genes with antioxidant response elements (ARE) and interacted with the stress transcription factor NRF2 (NFE2L2)
Frames a bi-genomic 'mitonuclear' communication mechanism — a mitochondrial-encoded factor controlling the nuclear genome
Mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice... In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation.
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D. · Nat Commun (2021)
In mice, MOTS-c treatment enhanced physical performance across young, middle-aged and old animals, and late-life intermittent dosing (3×/week) increased physical capacity and healthspan
MOTS-c regulated nuclear genes related to metabolism and proteostasis and modulated skeletal-muscle metabolism and myoblast stress adaptation
Human component is observational: exercise induced endogenous MOTS-c in skeletal muscle and circulation — not an interventional trial of administered MOTS-c
MOTS-c treatment significantly alleviated bone loss... MOTS-c increased phosphorylated AMPK levels, and compound C, an AMPK inhibitor, could partially abrogate the effects of the MOTS-c on osteoclastogenesis.
Ming W, Lu G, Xin S, Huanyu L, Yinghao J, Xiaoying L. · Biochem Biophys Res Commun (2016)
Mouse ovariectomy osteoporosis model; MOTS-c injected at 5 mg/kg/day for 12 weeks
MOTS-c significantly reduced bone loss on micro-CT and inhibited RANKL-induced osteoclast differentiation
Effect depended on AMPK: MOTS-c raised phosphorylated AMPK and the AMPK inhibitor compound C partially abrogated the benefit
Circulating MOTS-c level was significantly reduced in diabetic individuals but was increased significantly in obesity patients.
Zhou Q, Yin S, Lei X, Tian Y, Lin D, Wang L, Chen Q. · Diabetol Metab Syndr (2024)
Systematic review and meta-analysis (602 participants) of circulating blood MOTS-c concentration across physiological and pathological metabolic states (PROSPERO CRD42021248167)
Plasma MOTS-c was significantly reduced in diabetes but increased in obesity, and positively correlated with total cholesterol and LDL-c
Synthesizes OBSERVATIONAL associations between endogenous circulating MOTS-c and metabolic status — not a trial of administered MOTS-c
Among MDPs, mitochondrial ORF of the 12S rRNA type-c (MOTS-c) is the most associated with exercise... Systemic MOTS-c administration increases exercise performance by boosting skeletal muscle stress responses.
Yoon TK, Lee CH, Kwon O, Kim MS. · Diabetes Metab J (2022)
Review of MOTS-c within exercise-related mitohormesis (the beneficial response to low-level mitochondrial stress)
Summarizes that MOTS-c rises in skeletal muscle, circulation and hypothalamus with exercise, and that exogenous MOTS-c boosts performance and adipose thermogenesis in animal studies
Frames MOTS-c as a mediator of some salutary metabolic effects of exercise
This is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human... eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels.
Ramanjaneya M, Jerobin J, Bettahi I, Bensila M, Aye M, Siveen KS. · Clin Endocrinol (Oxf) (2019)
Human observational/physiology study in PCOS and healthy subjects using intralipid infusion + hyperinsulinaemic-euglycaemic clamp, with plasma MOTS-c measured by ELISA
Intralipid significantly raised plasma MOTS-c (to ~232% basal in controls, ~349% in PCOS); insulin infusion blunted the lipid-induced rise
Notably, eight weeks of moderate exercise training did NOT change circulating MOTS-c in either group — a null human finding
Circulating MOTS-c reduced with age, but older (70-81 y) and middle-aged (45-55 y) men had ~1.5-fold higher skeletal muscle MOTS-c expression than young (18-30 y).
D'Souza RF, Woodhead JST, Hedges CP, Zeng N, Wan J, Kumagai H. · Aging (Albany NY) (2020)
Human observational study of plasma and skeletal-muscle MOTS-c across young, middle-aged and older healthy men
Circulating MOTS-c declined with age, while muscle MOTS-c expression was higher in older/middle-aged men and tracked slow-type myofiber markers
In older men, muscle MOTS-c was associated with better muscle quality (leg-press load relative to thigh cross-sectional area)
Increased β-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow-up.
Ikonomidis I, Katogiannis K, Kyriakou E, Taichert M, Katsimaglis G, Tsoumani M. · J Thromb Thrombolysis (2020)
Prospective observational cohort of 121 type 2 diabetics after coronary revascularization (plus a 90-patient external validation cohort); MOTS-c measured by blood assay
Low MOTS-c (< 167 ng/ml) independently predicted major adverse cardiac events over 2 years (relative risk 3.8), additive to high on-clopidogrel platelet reactivity
An association/prognostic-marker study of endogenous circulating MOTS-c, not an interventional trial of administered MOTS-c