Poster abstracts
Poster number 98 submitted by Bennett Yunker
Local Protein Synthesis: A New Dimension in Cardiac Regulation and Remodeling
Bennett Yunker (Biophysics Graduate Program), Juan IE Mariangelo (Department of Physiology and Cell Biology), Anastasia Pokrass (Department of Physiology and Cell Biology), Vladimir Bogdanov (Department of Physiology and Cell Biology), Roman Kalinin (Department of Physiology and Cell Biology)
Abstract:
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, underscoring the need for a paradigm-shift towards research advancing our fundamental knowledge.1-2 Recent discoveries demonstrate that cardiomyocytes utilize local protein synthesis (LPS) through the sarcoplasmic reticulum (SR) for synthesizing key excitation-contraction coupling (ECC) proteins, a process distinct from classical protein biogenesis.3-4 Our data confirms SR-centric translation machinery, including ribosomes and ER-specific translocon (Sec61a), directly localized at the SR membrane. Stimulated emission depletion (STED) microscopy and proximity ligation assays (PLA) further validate the precise colocalization of newly synthesized RyR2 protein, ribosomes, and Sec61a at cardiomyocyte Z-lines. Additionally, we observed rapid translational responses (<1 hr) to neurohormonal stimulation (e.g., epinephrine), particularly concentrated at intercalated discs, independent of transcriptional regulation. This suggests neurohormonal signals dynamically regulate ECC protein synthesis locally, mediated by calcium (Ca²⁺) dynamics rather than transcriptional changes. We hypothesize that this neurohormonal-LPS axis represents a vital mechanism for immediate and compartment-specific cardiac regulation, disrupted in pathological hypertrophy. Our findings establish a novel cardiac regulatory mechanism, offering significant potential for targeted therapeutic strategies addressing heart failure through the modulation of localized ECC protein synthesis.
References:
1. Lindstrom, Megan et al. “Global Burden of Cardiovascular Diseases and Risks Collaboration, 1990-2021.” Journal of the American College of Cardiology (2022): doi:10.1016/j.jacc.2022.11.001
2. Benjamin, Emelia J et al. “Heart Disease and Stroke Statistics-2018 Update.” Circulation (2018): doi:10.1161/CIR.0000000000000558
3. Bogdanov, Vladimir et al. “Distributed synthesis of sarcolemmal and sarcoplasmic reticulum membrane proteins in cardiac myocytes.” Basic research in cardiology (2021): doi:10.1007/s00395-021-00895-3
4. Sandmann, Christopher et al. “Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.” BioRXiv (2024): https://doi.org/10.1101/2024.09.20.614189
Keywords: Local Protein Synthesis, Cardiac Regulation, Heart Failure