Cardiac specific PGC-1α knockout in mice induced 92 significantly altered molecular features in the heart, but no significant metabolic alterations in plasma, liver, or skeletal muscle.
Cardiac-specific PGC-1α deletion in mice induces local metabolic remodeling and fatal heart failure without causing systemic metabolic alterations.
Aims: Heart failure (HF) is associated with drastic changes in metabolism leading to a cardiac energy deficiency well as maladaptive changes in multiple other tissues. It is still unclear which of these changes originates from cardiomyocyte metabolic remodelling or whether they are induced secondarily by systemic factors. Our aim here was to induce cardiac restricted metabolic changes mimicking those seen in HF and to characterize the associated metabolite changes in the heart, circulation, and peripheral tissues. Methods and results: We generated a cardiac specific PGC-1α knockout mice (KO) to specifically induce metabolic dysregulation typically accompanied by HF and performed a non-targeted LC-MS metabolite profiling analysis of heart, plasma, liver, and skeletal muscle to identify metabolites associated with cardiac specific metabolic remodelling. The KO animals developed a progressive cardiomyopathy with cardiac dilatation leading to fatal HF. At 17 weeks of age, when significant remodelling had occurred but before the onset of HF, isolated PGC-1α deficient cardiomyocytes had suppressed glucose and fatty acid oxidation as well as blunted anaerobic metabolism. KO hearts displayed a distinctive metabolite profile with 92 significantly altered molecular features including metabolite changes in energy metabolism, phospholipid metabolism, amino acids, and oxidative stress signalling. Some of the metabolite changes correlated with the specific parameters of cardiac function. We did not observe any significant alterations in the metabolomes of the other measured tissues or in plasma. Conclusions: Heart specific PGC-1α KO induces metabolic, functional, and structural abnormalities leading to dilating cardiomyopathy and HF. The metabolic changes were limited to the cardiac tissue indicating that cardiomyocyte metabolic remodelling is not sufficient to evoke the body wide metabolic alterations usually associated with HF.
Kärkkäinen et al. (Sat,) conducted a other in Heart failure. Cardiac specific PGC-1α knockout was evaluated on Metabolite profile changes in heart, plasma, liver, and skeletal muscle. Cardiac specific PGC-1α knockout in mice induced 92 significantly altered molecular features in the heart, but no significant metabolic alterations in plasma, liver, or skeletal muscle.