201 Fatty Acid Oxidation in PLN R14del Cardiomyopathy 8 INTRODUCTION The R14del (c.40_42delAGA, p.Arg14del) pathogenic variant in the phospholamban (PLN) gene is associated with biventricular cardiomyopathy with a high risk of life-threatening ventricular arrhythmias, often presenting as dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM).1,2 It explains a large proportion of Dutch DCM and ACM patients and has also been identified in many other countries.3,4 PLN is a small phosphoprotein located in the cardiomyocyte sarcoplasmic reticulum and the nuclear membrane and is the major regulator of SERCA2a/ATP2A2 activity and calcium (Ca2+) cycling.1 We and others have shown that mechanisms within the nuclear, endoplasmic/sarcoplasmic reticulum and mitochondrial network are impaired in PLN-R14del cardiomyopathy.5–7 Despite these efforts, no effective treatment is available for PLN-R14del variant carriers to prevent disease development. Macroscopically, PLN-R14del hearts show biventricular subepicardial fibrofatty tissue replacement of the myocardium, which is characterised by extensive interstitial fibrosis, adipocyte infiltration, and islands of isolated cardiomyocytes between adipocytes.8–10 This adipocyte infiltration and fibrosis create an anatomical barrier resulting in the reentry of the electrical impulse and thereby an increased risk of fatal arrhythmias.11,12 A novel adult zebrafish plna R14del model also displays this adipocyte accumulation and mitochondrial damage in the diseased myocardium,13 while the available murine models show mitochondrial impairment in the absence of adipocyte accumulation.14,15 Mitochondrial dysfunction decreases ATP production, thereby opening the sensitive K+ channels on the sarcolemma channels, which reduces cardiomyocyte excitability and impairs electrical conduction in the heart.16 Besides altered electrical conduction, metabolic changes also affect cardiac ion channel gating, intracellular calcium handling, and fibrosis formation; all well-known aspects of PLN-R14del pathophysiology.16 However, the majority of studies have focused on calcium regulation by PLN,14,17 little effort has been put into elucidating the basis for the metabolic aberrations in human PLN-R14del cardiomyopathy. The presence of myocardial fibrofatty infiltration is accompanied by intracellular cardiomyocyte lipid abnormalities in cardiomyopathies in adults, such as those due to variants in PKP2 and PNPLA2.18,19 Several forms of childhood cardiomyopathies caused by mutations in the mitochondrial fatty acid oxidation (FAO) pathway genes, such as HADHA, HADHB, CPT2, and ACADVL, also show intracellular cardiomyocyte lipid droplet storage and adipocyte infiltration in the myocardium and other organs.20 A recent study has linked lipid droplet accumulation in PLN-R14del to the endoplasmic reticulum stress.6 However, little is known about the transcriptional regulation of this process and what (metabolic) factors influence lipid droplet accumulation. A limited number of lipid droplets, which store unutilized fatty acids (FAs) by mitochondria for energy production, are present in healthy cardiomyocytes. However, an increased lipid droplet deposition is associated with impaired FAO.21 While FAs are the primary energy source in healthy adult cardiomyocytes, diseased cardiomyocytes switch from FAO to glycolysis for energy production, resembling the energy balance of the fetal heart.22,23 Yet, this switch to
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