Mouse LPS-induced septic cardiomyopathy study demonstrating that exogenous MOTS-c reduces cardiac inflammatory cytokine expression, circulating myocardial injury markers (CK-MB, troponin), mitochondrial dysfunction, and cardiomyocyte apoptosis in endotoxemia, through AMPK-dependent anti-inflammatory and cardioprotective mechanisms. Establishes MOTS-c efficacy in a bacteremic cardiac model. Provides preclinical evidence for MOTS-c as a therapeutic candidate in septic cardiomyopathy—one of the primary drivers of death in sepsis where current treatments are purely supportive—through AMPK-mediated suppression of LPS-triggered myocardial inflammation and mitochondrial dysfunction.
Abstract
Septic cardiomyopathy is associated with mechanisms such as excessive inflammation, oxidative stress, regulation of calcium homeostasis, endothelial dysfunction, mitochondrial dysfunction, and cardiomyocyte death, and there is no effective treatment at present. MOTS-c is a mitochondria-derived peptide (MDP) encoded by mitochondrial DNA (mtDNA) that protects cells from stresses in an AMPK-dependent manner. In the present study, we aim to explore the protective effect of MOTS-c on lipopolysaccharide (LPS)-induced septic cardiomyopathy. LPS is used to establish a model of septic cardiomyopathy. Our results demonstrate that MOTS-c treatment reduces the mRNA levels of inflammatory cytokines (,,, and) in cardiomyocytes and the levels of circulating myocardial injury markers, such as CK-MB and TnT, alleviates cardiomyocyte mitochondrial dysfunction and oxidative stress, reduces cardiomyocyte apoptosis, activates cardioprotection-related signaling pathways, including AMPK, AKT, and ERK, and inhibits the inflammation-related signaling pathways JNK and STAT3. However, treatment with the AMPK pathway inhibitor compound C (CC) abolishes the positive effect of MOTS-c on LPS stress. Collectively, our research suggests that MOTS-c may attenuate myocardial injury in septic cardiomyopathy by activating AMPK and provides a new idea for therapeutic strategies in septic cardiomyopathy.