Sirtuin signalling governs calcium homeostasis and mitochondrial function in metabolic syndrome cardiomyocytes.

Abstract

Metabolic syndrome (MetS) is a major contributor to cardiovascular disease and is characterized by impaired Ca²⁺ handling and mitochondrial dysfunction in cardiomyocytes. However, the upstream mechanisms linking metabolic stress to these alterations remain incompletely defined. Here, we investigated whether sirtuin signalling coordinates intracellular Ca²⁺ homeostasis and mitochondrial function in a high-sucrose diet-induced mouse model of MetS. Male BALB/c mice were exposed to 32% sucrose for 24 weeks, followed by isolation of ventricular cardiomyocytes. MetS cardiomyocytes exhibited mitochondrial depolarization, increased reactive oxygen species production, elevated basal cytosolic Ca²⁺ levels, reduced Ca²⁺ transient amplitude and decreased sarcoplasmic reticulum Ca²⁺ content. These alterations were associated with reduced phospholamban phosphorylation, increased CaMKII and ryanodine receptor phosphorylation and activation of pro-apoptotic signalling. Notably, pharmacological inhibition of SIRT1 with EX527 in control cardiomyocytes recapitulated key features of the MetS phenotype, whereas SIRT1 activation with SRT1720 restored mitochondrial membrane potential, reduced reactive oxygen species production, improved Ca²⁺ handling, normalized aberrant phosphorylation of Ca²⁺-handling proteins and attenuated apoptotic signalling. Collectively, these findings identify SIRT1 as a critical integrator of mitochondrial function and Ca²⁺ homeostasis during metabolic stress, highlighting sirtuin-dependent pathways as promising therapeutic targets in metabolic cardiomyopathy.