| Rodríguez-Esparragón 2025 Int J Mol Sci Several | Human obs. Patients with Alzheimer's disease or mild cognitive impairment and individuals with subjective cognitive decline as controls | Reported that blood and plasma transcript levels of humanin and MOTS-c, normalised to mitochondrial DNA copy number, differed significantly across groups and were lower in adults with Alzheimer's disease than in those with subjective cognitive decline. Found that plasma protein concentrations of the two peptides did not distinguish Alzheimer's disease from mild cognitive impairment. Reported in decay assays faster degradation of humanin mRNA and delayed but stable recovery of MOTS-c mRNA. | Cross-sectional case-control comparison with no group sizes reported in the abstract, controls defined as subjective cognitive decline rather than healthy individuals, and transcript-level findings not corroborated by circulating protein measurements. | Evidence tier B |
| Zicarelli 2025 Medicina (Kaunas) Endogenous MOTS-c measured | Human obs. Serum, urine and dialysate MOTS-c in chronic peritoneal dialysis patients screened for sarcopenia risk | Measured lower serum MOTS-c and higher dialysate MOTS-c in peritoneal dialysis patients at very high sarcopenia risk, and reported that serum MOTS-c correlated positively, and dialysate MOTS-c negatively, with muscle performance in physical tests. | Pilot study of 32 patients with no control group and cross-sectional sampling; sarcopenia risk was screened by questionnaire rather than confirmed diagnostically, and multiple correlations were tested. | Evidence tier B |
| Kumagai 2024 iScience Several | Human obs. Cell-free CK2 assays, mice given MOTS-c, and human carriers of the K14Q MOTS-c variant | Reported that MOTS-c binds and activates CK2 in cell-free systems, and that in mice administered MOTS-c was associated with less skeletal muscle atrophy and greater muscle glucose uptake, effects blunted when CK2 activity was suppressed. In human carriers, the K14Q variant was associated with higher sarcopenia and type 2 diabetes risk in men in an age- and physical-activity-dependent way, and with an age-specific lower type 2 diabetes risk in women. | The human analysis is observational with no sample size reported in the abstract; animal work does not state sex or group sizes; tissue-specific conclusions are inferred from a single kinase target. | Evidence tier B |
| Kim 2024 Biomedicines MT-RNR1 / K14Q variant | Human obs. m.1382A>C (K14Q) genotype and sarcopenia measures in community-dwelling Korean adults aged 65 years and older | Found higher appendicular skeletal muscle mass, lean mass and handgrip strength in older Korean men carrying the C allele than in A-allele carriers, with the differences persisting after covariate adjustment. No significant genotype differences were found in women or in blood lipids and mental health measures. | Cross-sectional, single-ethnicity sample with few C-allele carriers; many outcomes tested; muscle mass estimated rather than imaged directly. | Evidence tier B |
| Zempo 2021 Aging (Albany NY) Several | Human obs. Meta-analysis of three Asian cohorts genotyped for m.1382A>C, plus high-fat-fed mice given MOTS-c or K14Q-MOTS-c and cell experiments | Reported that males but not females carrying the C allele of the m.1382A>C variant, which produces K14Q-MOTS-c, had a higher prevalence of type 2 diabetes, with the association concentrated in men in the lowest physical-activity tertile. In high-fat-fed male mice, administered MOTS-c was associated with lower weight and improved glucose tolerance while K14Q-MOTS-c was not, and K14Q-MOTS-c showed diminished insulin-sensitising activity in cells. | Genetic associations are observational and restricted to East Asian cohorts, the physical-activity interaction is based on self-reported tertiles, and the supporting animal work used male mice of a single strain with female mice reported as unaffected. | Evidence tier B |
| D'Souza 2020 Aging (Albany NY) Endogenous MOTS-c measured | Human obs. Plasma and skeletal muscle of healthy young, middle-aged and older men | In healthy men, circulating MOTS-c was lower with age, while middle-aged and older men had about 1.5-fold higher skeletal muscle MOTS-c expression than young men. Muscle MOTS-c was associated with slow-type muscle markers and, in older men, with muscle quality, and was not associated with ARE-related gene expression. | Men only; cross-sectional design; group sizes not reported in the abstract. | Evidence tier B |
| Liu 2019 Am J Physiol Renal Physiol Endogenous MOTS-c measured | Human obs. Skeletal muscle and serum from patients with stage 5 chronic kidney disease and age-matched controls | Found lower MOTS-c in both skeletal muscle and serum of patients with stage 5 CKD than in controls, whereas circulating humanin was higher and muscle humanin lower. Reduced muscle MDP levels were associated with lower mitochondrial density and evidence of oxidative stress. | Cross-sectional comparison; sample size not reported in the abstract; restricted to advanced CKD. | Evidence tier B |
| Wang 2026 Biochem Pharmacol MOTS-c administered | Animal db/db mice with diabetic nephropathy and HK-2 human proximal tubular cells with LARS1 overexpression | Reported that administered MOTS-c was associated with preserved urinary albumin-to-creatinine ratio, less tubular injury, less lipid deposition and less macrophage accumulation in db/db mice. Reported lower p16, gammaH2AX and SA-beta-gal signal and lower LARS1 with increased LC3-mediated lipid droplet clearance, with LARS1 overexpression in HK-2 cells and an autophagy inhibitor in mice reversing these changes. | Group sizes and sex not reported in the abstract; a single genetic diabetes model and one human tubular cell line; mechanism relies on a non-selective autophagy inhibitor. | Evidence tier C |
| Liu 2026 ACS Nano MOTS-c administered | Animal Aged C57BL/6 mice with sarcopenia and cultured muscle cells exposed to a MOTS-c/black phosphorus nanocomposite (BP-PEG-MOTS-c) | Reported that a muscle-targeted nanocomposite combining MOTS-c with black phosphorus nanosheets was associated with less muscle loss and dysfunction in aged mice and in cultured muscle cells with age-related sarcopenia. Found accompanying normalisation of mitochondrial function and lower lipid peroxidation in the same models. Reported RNA-seq evidence of activated PI3K/AKT/Nrf2 signalling and suppressed ROS/p38 MAPK signalling, and described biocompatibility results in toxicity assays. | Single mouse strain and males only, group sizes not reported in the abstract, effects attributed to a composite construct without a MOTS-c-only comparison arm described, and surrogate mitochondrial and signalling endpoints. | Evidence tier C |
| Kong 2025 Exp Mol Med Several | Animal Aged C57BL/6 mouse pancreatic islets, S961-treated C57BL/6 mice and nonobese diabetic mice; circulating MOTS-c in people with type 2 diabetes | Reported that MOTS-c levels decreased with aging and senescence in pancreatic islet cells in mice. Found that treating isolated aged C57BL/6 mouse islets with MOTS-c reduced islet senescence alongside changes in nuclear gene expression and senescence-related metabolites, and that MOTS-c treatment reduced islet senescence and glucose intolerance in S961-treated C57BL/6 mice and in nonobese diabetic mice. Measured circulating MOTS-c in people and found lower levels in those with type 2 diabetes than in healthy controls. | Animal group sizes and the size and composition of the human comparison are not reported in the abstract; the human component is cross-sectional and correlational, and senescence endpoints are surrogate markers rather than diabetes outcomes. | Evidence tier C |