Melatonin ameliorates sepsis-induced myocardial dysfunction by promoting autophagy via SIRT1-mediated TFEB deacetylation.

Abstract

Sepsis-induced myocardial dysfunction (SIMD) is an acute cardiac dysfunction syndrome associated with sepsis but independent of ischemia, serving as a critical contributor to cardiogenic shock, refractory shock and mortality. Current clinical treatments remain far from achieving satisfactory outcomes. Our previous study found that serum melatonin levels were significantly lower in septic patients compared to healthy volunteers. Building on this finding, the present study further confirmed in septic mice via cecal ligation and puncture procedures that exhibited significantly decreased melatonin levels in both serum and cardiac tissues. Exogenous melatonin supplementation was observed to reduce inflammatory cytokine release and ameliorate cardiac dysfunction. These findings collectively suggest that melatonin exerts protective effects against SIMD. However, the precise molecular mechanisms underlying melatonin's ameliorative effects on SIMD remain incompletely understood. Current evidence indicates that impaired autophagic flux represents one of the key pathogenic mechanisms in SIMD, a finding supported by our preliminary omics analyses. We discovered that melatonin's amelioration of SIMD is mediated through enhanced autophagic flux. Mechanistically, we discovered that melatonin increases transcription factor EB (TFEB) content by enhancing silent information regulator 1 (SIRT1) protein levels, thereby modulating autophagy-related proteins to restore impaired autophagic flux during SIMD. Notably, SIRT1-mediated deacetylation of TFEB inhibits its ubiquitination-dependent proteasomal degradation, thereby stabilizing TFEB protein level and enhancing cardiomyocyte autophagy. This study unveils a novel mechanism whereby melatonin enhances autophagic flux through the SIRT1/TFEB axis, ultimately ameliorating SIMD. These findings provide a theoretical foundation for developing new clinical therapeutic strategies against SIMD.