Key result
RYR2 depletion in mouse cardiomyocytes triggered ultrastructural and transcriptomic defects associated with severe ER stress and ATF4 activation, perturbing cardiomyocyte maturation.
Why the study?
Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the underlying mechanisms remained unclear.
RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation, and its dysfunction perturbs maturation primarily through ATF4-mediated ER stress.
RYR2 mutagenesis clarifies maturation mechanisms in models; leaves open clinical relevance for human cardiomyocyte therapies.
AIMS: Calcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem. METHODS AND RESULTS: We performed Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4. CONCLUSION: RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.
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Guo et al. (2022) studied Cardiomyocyte maturation and RYR2 dysfunction. Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 was evaluated on Ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. RYR2 depletion in mouse cardiomyocytes triggered ultrastructural and transcriptomic defects associated with severe ER stress and ATF4 activation, perturbing cardiomyocyte maturation.
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