222 Chapter 8 R14del hiPSC-CMs, further suggesting the importance of impaired FAO as a key pathological mechanism underling PLN-R14del cardiomyopathy. Notably, we observed enhanced Ca2+ handling properties and elevated mitochondrial trifunctional protein levels (HADHA and HADHB) in PLN-R14del hiPSC-CMs after bezafibrate treatment, a PPARA-targeting agonist. Several FDA/EMA-approved PPARA agonists, including bezafibrate, have shown protective effects on cardiomyopathies by restoring the FA metabolism.39,40 However, to the best of our knowledge, we showed for the first time, the potential of bezafibrate in re-activating mitochondrial FAO and improving Ca2+ transients, which provides a novel strategic path for developing precision medicine for PLN-R14del patients, such as targeting FAO upstream regulators (i.e. PPARA). Besides FAO suppression, the activation of glycolysis-related genes was shown in murine cardiomyocytes carrying another PLN pathogenic variant (p.Arg9Cys).41 We also showed PLN-R14del hiPSC-CMs exhibited a preference for glucose utilisation. Increased glucose utilisation, which further inhibits FAO by malonyl coenzyme A-mediated inhibition, has been shown in cardiomyocytes from hypertrophic cardiomyopathies and failing hearts.33,42 The switch from FAs to glucose utilisation can be due to its faster uptake in the cells and the lower oxygen consumption.43 Like lipotoxicity, increased glucose levels can have deleterious effects on cardiomyocytes by introducing oxidative stress-related cell death and decreasing contractile force.44,45 Thus, the glucose-dependent energy metabolism is associated with the progression of cardiac dysfunction and could be an early pathological process in PLN-R14del hearts.42 Last but not least, we also observed reduced metabolic flexibility in PLN-R14del hiPSC-CMs. Healthy cardiomyocytes have the flexibility of switching substrates for energy production under different conditions.42 This metabolic flexibility is a critical factor for maintaining normal cardiac function and preventing the progression of diseased hearts.46 Impaired metabolic flexibility has also been observed in mouse cardiomyocytes with the depletion of Ryr2, which show reduced mRNA levels of key regulators in the FA metabolism (e.g. Ppargc1a, Pparα, Pparγ, and Klf15) as well as the glucose metabolism (e.g. Glut4 and Pck1).47 Therefore, restoring balanced metabolic activity is beneficial for 435 PLNR14del cardiomyopathy. It is important to note that histone acetylation and transcriptome changes in PLN-R14del versus control hearts are derived from both cardiomyocytes and nonmyocyte cell types, such as endothelial cells and fibroblasts that are abundant in the heart.48 Non-myocyte cell types in the heart also contribute to the disease progression.49 Therefore, the responsible cell type(s) or mechanisms for the adipocyte infiltration by either the activation of the already existing pool of adipocytes or transdifferentiation of (cardiac) cells into adipocytes remain unclear. However, we have previously shown that the majority of the bulk data came from cardiomyocytes when compared to 11 non-myocyte cell types in both inherited and acquired heart disease.25,26 The impaired mitochondrial FAO indicated by the bulk data was 444 validated in PLN-R14del hiPSC-CMs at transcriptional and functional levels, highlighting the possibility of FAO abnormalities as early pathological signs in PLN-R14del cardiomyocytes. Nevertheless, future studies should also focus on investigating interactions between cardiomyocytes and non-myocyte cells during the cardiac energy rearrangement
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