Key result
PALMD is a novel Z-line-associated protein that stabilizes NEXN and mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults.
Why the study?
A comprehensive proteomic atlas of cardiomyocyte Z-line-associated components remained incomplete despite Z-lines being core ultrastructural organizers modulating cardiac pathogenesis.
In vivo proximity proteomics identified PALMD as a novel Z-line-associated protein that mitigates isoproterenol-induced cardiac injury by stabilizing NEXN, highlighting a potential target for myocardial protection.
Highlights PALMD as potential myocardial protector in models; hypothesis-generating and should not yet alter practice.
Summary Z-lines are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-line-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-line proteome in vivo. We found palmdelphin (PALMD) as a novel Z-line-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed transverse tubules (T-tubules) and their association with sarcoplasmic reticulum, which formed the Z-line-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with disrupted localization of T-tubule markers caveolin-3 (CAV3) and junctophilin-2 (JPH2) and the reduction of nexilin (NEXN) protein, a crucial Z-line-associated protein that is essential for both Z-line and JMC structures and functions. PALMD was found to interact with NEXN and enhance its protein stability while the Nexn mRNA level was not affected. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis. Highlights In vivo proximity proteomics uncover novel Z-line components that are undetected in in vitro proximity proteomics in cardiomyocytes. PALMD is a novel Z-line-associated protein that is dispensable for baseline cardiomyocyte function in vivo. PALMD mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults. PALMD stabilizes NEXN, an essential Z-line-associated regulator of the junctional membrane complex and cardiac systolic function.
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Guo et al. (2023) studied Isoproterenol-induced cardiac injury. PALMD knockout or overexpression vs. Wildtype or control AAV was evaluated on Cardiac function, fibrosis, and Z-line/JMC organization. PALMD is a novel Z-line-associated protein that stabilizes NEXN and mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults.
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