176 Chapter 7 alterations within the ER-mitochondrial compartment and only GCaPM6f was associated with significantly improved force development in PLN-R14del EHTs.72 Recently, a SR localized micropeptide called dwarf open reading frame (DWORF) was discovered to have the opposite function of PLN. DWORF overexpression in homozygous R14del mice did prevent abnormal S/ ER cluster formation but did not result in an additional increase in calcium reuptake due to an already enhanced calcium reuptake.108 Both findings argue that aberrant S/ER formation is the key mechanism, rather than targeting the super-inhibition of SERCA2a, in the development of PLN-R14del cardiomyopathy. Together, altered PLN protein conformation could affect the localization and interaction of proteins crucial for ER/mitochondria integrity. By the reduction of protein toxicity, cardiomyocyte cell loss, fibrosis, and cardiac dysfunction could be prevented. As the main function of PLN is the regulation of calcium by the modulation of SERCA, multiple therapeutic strategies have been tested to modulate calcium handling. The CaMKII inhibitor KN93 reversed the proarrhythmic phenotype in myocytes of PLN-R14del mice, consequently suggesting its anti-arrhythmic application and especially potentially preventing SCD.100,108100 On the contrary, Metoprolol (β-blocker) significantly decreased the heart rate and showed no increase in the survival rate of PLN-R14del mice.62 Given the molecular effects of β-blocker are not based on a modulation of CaMKII, it seems the community is open and motivated for new pharmacologic drugs for CaMKII inhibition Still, Ca2+ scavenging250 could be beneficial to improve impaired Ca2+-homeostasis and prevent arrhythmogenesis. If the PLN-R14del results in enhanced calcium reuptake, rather than the previously described super-inhibition, increasing calcium S/ER reuptake could be ineffective in PLN-R14del cardiomyopathy and need to be further evaluated before more therapeutic testing. Conversely, the option of gene correction therapy, with the potential to directly correct the mutation in the PLN gene, offers a potentially superior strategy. Nonetheless, significant obstacles, including ethical considerations and the development of effective methods for delivering gene therapy into the target cells, must be overcome. In both scenarios, implementing additional model systems, such as the porcine model, could prove highly beneficial. This is due to the high similarity between porcine and human cardiac anatomy, electrophysiology and coronary circulation.251 Consequently, potential agents could be tested using these model systems, providing greater knowledge of their mechanism of action and possible side effects. Nevertheless, the pursuit of both gene therapy and pharmacological treatment options is ongoing, to advance our understanding and improving therapeutic options for PLN-R14del cardiomyopathy.
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