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<p>The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose–response profile and direct cardioprotective mechanisms in myocardial ischemia–reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25–0.7&#xa0;mg/kg) delivered via Krebs–Henseleit buffer during the first 10&#xa0;min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide–protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5&#xa0;mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia–reperfusion alone, improving heart rate, left ventricular developed pressure, and rate–pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5&#xa0;mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.</p>

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Exogenous MOTS-c mitigates myocardial ischemia–reperfusion injury: experimental and in silico evidence from rat heart models

  • 期刊论文

  • 发表日期：

    2026年1月28日

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  • Saranya Sri Santhanam,
  • Srijan Jayaraman,
  • Gino A. Kurian

摘要

The mitochondrial-derived peptide MOTS-c regulates metabolic and cellular stress responses, but its dose–response profile and direct cardioprotective mechanisms in myocardial ischemia–reperfusion injury (MIRI) remain undefined. This proof-of-concept study aimed to identify the optimal cardioprotective dose of exogenous MOTS-c and delineate its multi-pathway mechanisms using an ex vivo rat heart IR model with in silico support. Isolated Langendorff-perfused rat hearts underwent 30-min global ischemia and 60-min reperfusion with or without MOTS-c (0.25–0.7 mg/kg) delivered via Krebs–Henseleit buffer during the first 10 min of reperfusion. Hemodynamics, infarct size (TTC), oxidative stress markers, inflammation, and apoptotic gene expression were quantified. Peptide–protein interactions with survival pathways were predicted computationally. MOTS-c at 0.5 mg per kg conferred maximal protection, producing a 73% reduction in infarct size compared with ischemia–reperfusion alone, improving heart rate, left ventricular developed pressure, and rate–pressure product, and lowering end-diastolic pressure. Lactate dehydrogenase release decreased by 65%. Antioxidant defenses improved with increased superoxide dismutase, catalase, and glutathione redox ratio, along with reduced lipid peroxidation. Myeloperoxidase activity normalized, pro-apoptotic genes including caspase 3, caspase 7, caspase 9, BAX, and PARP were downregulated, while cytoprotective genes including BCL2, GPX4, and FOXO were increased. Molecular docking demonstrated high-affinity interactions of MOTS-c with MAPK, mTOR, AMPK, NRF2, PI3K, and caspase 3. This ex vivo study identifies 0.5 mg/kg as the optimal dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects. Although the isolated heart model isolates direct myocardial actions, the lack of systemic influences and limited dose range necessitate broader dosing and pharmacokinetic studies before translational application.