Animal only
This study investigated whether MOTS-c, a small peptide encoded within mitochondrial DNA, could protect the heart from ischemia-reperfusion (IR) injury. Using the Langendorff isolated heart perfusion model in female Wistar rats (n=6 per group), researchers subjected hearts to 30 minutes of global ischemia followed by 60 minutes of reperfusion. MOTS-c was administered either before ischemia or at the start of reperfusion. The study evaluated cardiac mechanical function, oxidative stress, mitochondrial enzyme activities, membrane potential, mitochondrial DNA (mtDNA) copy number, and regulatory gene expression across two distinct mitochondrial subpopulations — subsarcolemmal and interfibrillar mitochondria. IR injury significantly impaired cardiac recovery, increased oxidative stress, reduced electron transport chain activity, and decreased mtDNA copy number and regulatory gene expression. MOTS-c treatment was associated with improved post-ischemic mechanical recovery, reduced oxidative stress, partial preservation of mitochondrial enzyme activity and membrane potential, and attenuation of mtDNA loss. Protective effects were seen in both mitochondrial subpopulations, though the magnitude varied. Key limitations include the exclusive use of an isolated ex vivo animal model, small group sizes, a single sex, and uncharacterized signaling mechanisms underlying the observed effects.
Molecular biology reports · Jun 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could improve survival of ischemic tissue flaps used in reconstructive surgery — a context where distal necrosis due to poor blood flow remains a significant clinical challenge. Using a rat ischemic flap model, researchers employed a broad range of techniques including RNA sequencing, tissue clearing, laser speckle contrast imaging, laser Doppler blood flow analysis, histological staining, Western blotting, ELISA, immunofluorescence, and adeno-associated virus (AAV)-mediated gene overexpression. The study also used human umbilical vein endothelial cells (HUVECs) for in vitro experiments. The authors report that MOTS-c treatment was associated with improved blood perfusion, enhanced angiogenesis, and better collagen remodeling in ischemic flaps. Mechanistically, the study found that MOTS-c appeared to suppress phosphorylation of PLA2G4A (cytosolic phospholipase A2) via the MAPK1/ERK2–MAPK3/ERK1–NF-κB signaling cascade, thereby reducing lysosomal membrane permeabilization (LMP), decreasing endothelial pyroptosis, and enhancing autophagy. AAV-mediated PLA2G4A overexpression in vivo was used to confirm this pathway. Key limitations include the absence of human clinical data and the complexity of the multi-modal experimental design, which makes it difficult to isolate individual mechanistic contributions.
Autophagy · Jun 2026DOI ↗ Animal only
This study investigated whether MOTS-c, a mitochondrial-derived peptide with metabolic and exercise-mimicking properties, could attenuate skeletal muscle loss in cancer cachexia. In vitro, differentiated myotubes treated with MOTS-c showed increased PGC-1α mRNA expression (~85%) and enhanced AMPK phosphorylation (~103%), suggesting activation of mitochondrial biogenesis and energy-sensing pathways. In vivo, male mice implanted with Colon-26 (C26) carcinoma cells developed significant systemic wasting (~9% body weight loss). Daily MOTS-c treatment did not prevent total body weight loss or fat mass loss in these tumor-bearing mice, but it did significantly preserve skeletal muscle mass — notably rescuing quadriceps weight (~12% vs. C26 vehicle controls). Mechanistically, MOTS-c appeared to modulate FOXO signaling and reduce atrogene expression (MuRF1 and Atrogin-1), key mediators of muscle protein breakdown, while promoting mitochondrial biogenesis markers. The authors conclude that MOTS-c partially protects against cachexia-associated muscle deterioration. Key limitations include the exclusive use of male mice, an animal-only in vivo model, and the authors' own acknowledgment that human studies are needed to validate these findings.
Frontiers in medicine · May 2026DOI ↗ Animal only
This study investigated whether the mitochondrial-derived peptide MOTS-c could protect the neonatal heart from hyperoxia-induced injury. Using neonatal mice exposed to 85% oxygen as an in vivo model and the rat cardiomyocyte cell line H9C2 as an in vitro model, researchers found that hyperoxia caused cardiac hypertrophy, fibrosis, and dysfunction, alongside reduced circulating MOTS-c levels. Administration of MOTS-c was reported to markedly reduce these pathological changes and restore cardiac function in the mouse model. Mechanistically, the study found that hyperoxia activates a KEAP1–PGAM5–AIFM1 signaling axis, triggering a ROS-specific form of programmed cell death called oxeiptosis. MOTS-c appeared to interact directly with KEAP1, preserving its binding to PGAM5 and thereby preventing nuclear translocation of AIFM1, the downstream executioner of oxeiptosis. Overexpression of KEAP1 abolished MOTS-c's protective effects, supporting KEAP1 as a key target. Limitations include exclusive reliance on animal and cell-line models with no human data, a relatively narrow mechanistic focus, and the absence of long-term outcome measures. These findings are preclinical and require validation in human studies before clinical conclusions can be drawn.
Life sciences · May 2026DOI ↗ Animal only
This study investigated an engineered variant of the mitochondria-derived peptide MOTS-c, called R13A-MOTS-c, designed to overcome the poor cellular permeability of the wild-type peptide. The researchers substituted arginine at position 13 with alanine to increase hydrophobicity, then characterized the modified peptide's uptake mechanism, showing through competition assays and knockdown experiments that it enters cells via the LAT1 amino acid transporter. In vitro, R13A-MOTS-c was reported to reduce inflammatory markers, oxidative damage, and mitochondrial dysfunction in mouse lung epithelial (MLE-12) cells exposed to radiation. In vivo, C57BL/6 mice receiving thoracic irradiation (20 Gy) and treated with intraperitoneal R13A-MOTS-c showed attenuated pulmonary inflammation, oxidative stress, and mitochondrial impairment compared to controls. The proposed mechanism centers on Nrf2 pathway activation, supported by evidence of increased nuclear Nrf2 translocation and upregulation of downstream target genes; protective effects were lost when LAT1 or Nrf2 was inhibited or knocked out. Key limitations include exclusive use of animal and cell models with no human data, a single radiation dose and treatment regimen tested, and the need for further pharmacokinetic and safety characterization before clinical translation.
Redox biology · May 2026DOI ↗ Animal only
This animal study investigated whether MOTS-c, a 16-amino acid mitochondrial-derived peptide, influences adrenal gland physiology in adult male Wistar rats. Sixteen rats received either continuous subcutaneous MOTS-c or saline for 24 hours via micro-osmotic pumps. The researchers used qRT-PCR, immunohistochemistry, ELISA, and RNA sequencing to assess adrenal tissue responses. The study first confirmed that endogenous MOTS-c expression was higher in the zona fasciculata/reticularis compared to the zona glomerulosa. MOTS-c treatment did not alter classical steroidogenic gene expression or circulating corticosterone and aldosterone levels. However, RNA sequencing identified 39 differentially expressed genes, most notably a 4.3-fold upregulation of the purinergic receptor P2ry4. The authors interpreted these findings as evidence that MOTS-c "primes" adrenocortical cells for steroidogenic responsiveness—via calcium signaling, lipid metabolism modulation, stress-response protein downregulation, and mitophagy inhibition—without directly stimulating basal hormone synthesis. Key limitations include the exclusive use of male rats, the short 24-hour treatment window, small sample size (n=16), and the absence of functional stimulation challenges (e.g., ACTH) to test the proposed "readiness" hypothesis.
Folia histochemica et cytobiologica · Mar 2026DOI ↗ Animal only
This study examined the effects of graviola (Annona muricata L.) oil extract (GOE) supplemented at three doses (200, 400, and 600 mg/kg feed) on growth performance and circadian rhythm profiles of several biomarkers in 48 male Anatolian Merino lambs over a 60-day feeding trial. Blood samples were collected at four time points across the day (07:00, 13:00, 19:00, and 01:00) on multiple study days to capture circadian variation. Measured biomarkers included Apelin (an adipokine), cardiac troponin I (cTnI), the circadian clock protein BMAL1, the mitochondria-derived peptide MOTS-c, and brown adipose mitochondrial carrier protein 1 (BMCP1), all assessed via ELISA. The 400 mg/kg dose was associated with the greatest linear improvement in live weight gain and with modulation of BMAL1, MOTS-c, and BMCP1 peaking at 19:00. The 600 mg/kg dose showed the most favorable results for Apelin and cTnI at certain time points. Limitations include the exclusive use of a single animal species, a relatively small sample size, lack of human relevance, and the observational nature of biomarker interpretation within a non-randomized animal production context.
BMC veterinary research · Mar 2026DOI ↗