ECM-derived exerkines COL1A2-pep1 attenuate cardiac remodeling by enhancing mitophagy through the mtDNA-cGAS-STING pathway
H Ci, L Chen, X Zhong, L Jin, G Zhou, Z Cai, L Li, X Wang, L ShenAbstract
Introduction
Regular exercise is considered an effective intervention for ameliorating pathological cardiac remodeling. Studies have shown that the protective effects of exercise are related to the release of "exerkines" induced by physical activity. However, the key exerkines mediating this cardioprotective effect remain to be elucidated.
Purpose
This study aims to identify novel exercise-derived small peptides with cardioprotective effects using a human plasma peptidomics screening platform, and to elucidate their protective roles and underlying molecular mechanisms in pathological cardiac remodeling.
Methods
Healthy males engaged in regular exercise were enrolled as subjects, and a human plasma peptidomics platform was established using mass spectrometry. For the in vivo experiments, mice in the exercise group were subjected to a 4-week treadmill running regimen, and peptide interventions were administered via subcutaneous osmotic pumps. Cardiac structure and function were evaluated using echocardiography and histological staining. For the in vitro experiments, techniques including Western Blot and immunofluorescence were utilized to detect mitophagy flux, oxidative stress levels, and cytosolic mtDNA leakage in neonatal rat ventricular myocytes (NRVMs). AlphaFold2 molecular modeling was employed to predict the interaction between the peptide and the target protein, which was subsequently verified by co-immunoprecipitation.
Results
Peptidomic analysis revealed that COL1A2-pep1, a novel peptide derived from the extracellular matrix (ECM), was significantly upregulated by over 30-fold in the plasma of the exercising cohort. Exogenous administration of COL1A2-pep1 effectively alleviated Ang II-induced cardiac hypertrophy and fibrosis. Mechanistic studies demonstrated that COL1A2-pep1 directly binds to the catalytic domain of the cytosolic DNA sensor cGAS, significantly inhibiting cGAS activation and the downstream STING-IRF3-mediated inflammatory response. Further investigation revealed that the targeted inhibition of cGAS by COL1A2-pep1 restored ATP production in cardiomyocytes and activated the PINK1/Parkin signaling pathway, thereby enhancing mitophagy flux. This effectively cleared damaged mitochondria and prevented further cytosolic mtDNA leakage. Notably, cardiomyocyte-specific overexpression of cGAS in vivo significantly abrogated the effects of COL1A2-pep1 in restoring mitophagy and protecting the heart.
Conclusion
This study demonstrates that COL1A2-pep1 directly binds to and antagonizes the cGAS sensor to promote PINK1/Parkin-mediated mitophagy, thereby inhibiting mtDNA leakage and ultimately alleviating pathological cardiac remodeling. This research provides a novel therapeutic strategy and potential intervention targets for the prevention and treatment of pathological cardiac remodeling.Mechanism diagram