Exercise-derived peptide confers protection against septic cardiomyopathy by enhancing CCAAT/enhancer binding protein β-mediated autophagy.

Septic cardiomyopathy (SC) is a sepsis-mediated cardiovascular complication characterized by cardiac dysfunction. Emerging evidence indicated that exercise training confers protection against SC; however, the underlying mechanisms are not yet fully understood. In this study, we identified a novel exercise-derived peptide, apolipoprotein A1 peptide (named ApoA1tide), through mouse plasma peptidomic screening. Subsequent experiments revealed that ApoA1tide mitigated lipopolysaccharide (LPS)-induced SC in murine models, as evidenced by enhanced cardiac function, prolonged survival, and improved myocardial structure. Moreover, ApoA1tide was found to inhibit inflammatory responses, cardiomyocyte apoptosis, and oxidative stress in mice subjected to LPS induction. Correspondingly, in vitro experiments demonstrated that ApoA1tide suppressed LPS-induced apoptosis and oxidative stress in neonatal rat cardiac myocytes (NRCMs). Additionally, ApoA1tide enhanced autophagic activity in both LPS-induced mice and NRCMs. Mechanistically, RNA sequencing identified CCAAT/enhancer-binding protein β (C/EBPβ) as the primary target of ApoA1tide. The expression of C/EBPβ was upregulated following ApoA1tide treatment. Overexpression of C/EBPβ in NRCMs resulted in increased expression of autophagy-related genes, including LC3B, Atg3, Atg4b, and Atg7. Conversely, Knockdown of C/EBPβ eliminated the enhancement of autophagy induced by ApoA1tide, along with the protective effects of ApoA1tide on cardiac functionality, cardiomyocyte apoptosis, oxidative stress, and inflammation. These findings indicate that ApoA1tide exerts its protective effects against SC by enhancing C/EBPβ-mediated autophagy. Our study provides a novel therapeutic strategy for SC.