GO:1901897 regulation of relaxation of cardiac muscle: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1901897 describes any process that modulates the frequency, rate or extent of cardiac muscle relaxation, a critical determinant of diastolic filling and cardiac output.
• Relaxation requires active detachment of myosin from actin, calcium reuptake into the sarcoplasmic reticulum, and dephosphorylation of contractile proteins by protein phosphatases.
• Myosin isoform composition and myosin-binding protein C (MYBPC3) directly influence the kinetics of force generation and relaxation in human cardiac muscle.
• The micropeptide DWORF, encoded by a long noncoding RNA, regulates the sarcoplasmic reticulum calcium pump SERCA and thereby accelerates cardiac relaxation.
• Dysregulation of cardiac relaxation underlies diastolic heart failure, hypertrophic cardiomyopathy, and hypoxia-induced cardiac dysfunction.
• CRISPR-based knockout, point mutation, and knock-in models enable precise dissection of genes controlling relaxation in cardiomyocytes and animal models.
Description
Regulation of relaxation of cardiac muscle (GO:1901897) is a biological process that modulates the frequency, rate, or extent of cardiac muscle relaxation, the phase during which the heart muscle returns to its resting state after contraction. This process is essential for proper diastolic filling and cardiac output, and its dysregulation is a hallmark of diastolic heart failure and other cardiomyopathies. Cardiac relaxation is not a passive event; it requires active calcium handling, myosin detachment, and dephosphorylation of contractile proteins. Understanding the molecular players that regulate relaxation is therefore critical for developing therapies that target diastolic dysfunction. Recent studies have identified key regulators including the micropeptide DWORF, myosin-binding protein C, and protein phosphatases, which fine-tune the speed and extent of relaxation. This article synthesizes current knowledge on the mechanisms, genes, and research methods used to study GO:1901897, with a focus on how CRISPR-based models can accelerate discovery.
regulation of relaxation of cardiac muscle At A Glance
| GO ID | GO:1901897 |
|---|---|
| GO term | regulation of relaxation of cardiac muscle |
| Ontology | biological_process |
| Synonym | None |
| Major function | Modulates the frequency, rate or extent of cardiac muscle relaxation, influencing diastolic filling and cardiac output |
| Key regulators | SERCA2a, DWORF, MYBPC3, protein phosphatases (PP1, PP2A), myosin isoforms |
| Associated diseases | Diastolic heart failure, hypertrophic cardiomyopathy, hypoxia-induced cardiac dysfunction |
| Research methods | CRISPR knockout/knock-in, calcium imaging, cryo-electron tomography, proteomics |
What Is GO:1901897?
According to the Gene Ontology, GO:1901897 (regulation of relaxation of cardiac muscle) is defined as any process that modulates the frequency, rate or extent of relaxation of cardiac muscle. In other words, it encompasses all molecular and cellular events that control how quickly and completely the heart muscle relaxes after a contraction, including calcium reuptake, myosin-actin detachment, and post-translational modifications of contractile proteins.
Why Is regulation of relaxation of cardiac muscle Important in Cell Biology?
Regulation of cardiac muscle relaxation is fundamental to normal heart function because it determines the duration of diastole and thus ventricular filling. Impaired relaxation is a primary cause of diastolic heart failure, which accounts for nearly half of all heart failure cases. Moreover, relaxation is dynamically regulated by calcium handling, myosin isoform switching, and phosphorylation events, making it a rich target for therapeutic intervention. Understanding GO:1901897 at the molecular level can reveal new drug targets and biomarkers for cardiac disease.
• Diastolic heart failure is characterized by impaired cardiac relaxation, leading to reduced ventricular filling and elevated filling pressures.
• Hypoxia and high-altitude exposure alter cardiac output regulation, partly through effects on relaxation kinetics.
• Myosin isoform composition (e.g., alpha vs. beta myosin heavy chain) directly affects the speed of force generation and relaxation.
• Myosin-binding protein C (MYBPC3) mutations are a leading cause of hypertrophic cardiomyopathy and are linked to altered relaxation.
• The micropeptide DWORF enhances SERCA activity, accelerating calcium reuptake and relaxation, and represents a potential therapeutic target.
• Protein phosphatases PP1 and PP2A dephosphorylate contractile proteins and are critical for the relaxation phase.
• Epigenetic regulation of cardiac fibrosis can indirectly affect relaxation by altering ventricular stiffness.
• Nucleus mechanosensing in cardiomyocytes integrates mechanical signals to modulate gene expression related to relaxation.
• Insect flight muscle and cardiac muscle share dual regulation mechanisms, offering comparative insights into relaxation control.
• CRISPR screening can identify novel regulators of cardiac relaxation, accelerating target discovery.
What Happens During regulation of relaxation of cardiac muscle?
Calcium reuptake into the sarcoplasmic reticulum
In simple terms: After a heart muscle cell contracts, calcium must be quickly pumped back into storage to allow the muscle to relax.
The sarcoplasmic reticulum calcium ATPase (SERCA2a) is the primary pump responsible for removing calcium from the cytosol during relaxation. Its activity is regulated by phospholamban and the micropeptide DWORF, which enhance SERCA function and accelerate relaxation. This calcium reuptake is a rate-limiting step for cardiac relaxation and is modulated by beta-adrenergic signaling.
Myosin-actin detachment and cross-bridge cycling
In simple terms: For the muscle to relax, the molecular motors (myosin) must let go of the thin filaments (actin).
Relaxation requires detachment of myosin heads from actin filaments, a process influenced by myosin isoform composition and regulatory proteins such as myosin-binding protein C (MYBPC3). Cryo-electron tomography has revealed that MYBPC3 links myosin and actin filaments, modulating cross-bridge kinetics and thus relaxation speed. Myosin isoform-dependent effects of compounds like omecamtiv mecarbil further demonstrate the importance of myosin regulation in relaxation.
Dephosphorylation of contractile proteins by phosphatases
In simple terms: Phosphate groups added during contraction must be removed to reset the system for relaxation.
Protein phosphatases, particularly PP1 and PP2A, dephosphorylate key contractile proteins such as troponin I and myosin light chain, promoting relaxation. Bokník et al. demonstrated that protein phosphatases play a crucial role in the regulation of cardiac inotropy and relaxation, with inhibition of phosphatases prolonging relaxation.
Mechanosensing and nuclear signaling
In simple terms: Heart muscle cells can sense mechanical forces and adjust their gene expression to control relaxation.
Nucleus mechanosensing in cardiomyocytes involves the transmission of mechanical signals from the sarcomere to the nucleus, influencing gene expression programs that regulate relaxation and hypertrophy. This process is mediated by linker of nucleoskeleton and cytoskeleton (LINC) complex proteins and can affect calcium handling and myofilament properties.
Epigenetic and fibrotic remodeling
In simple terms: Long-term changes in gene activity and scar tissue formation can stiffen the heart and slow relaxation.
Epigenetic regulation of cardiac fibrosis, including DNA methylation and histone modifications, can alter the expression of genes involved in extracellular matrix deposition. Increased fibrosis reduces ventricular compliance and impairs relaxation, linking epigenetic mechanisms to GO:1901897.
Key Genes Involved in GO:1901897 regulation of relaxation of cardiac muscle
The following genes and proteins are central to the regulation of cardiac muscle relaxation, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SERCA2a (ATP2A2) | Calcium reuptake into sarcoplasmic reticulum | Rate-limiting for relaxation; target of DWORF and phospholamban |
| DWORF | Micropeptide that enhances SERCA activity | Accelerates relaxation; potential therapeutic target |
| MYBPC3 | Myosin-binding protein C, modulates cross-bridge kinetics | Mutations cause hypertrophic cardiomyopathy; affects relaxation |
| MYH7 | Beta-myosin heavy chain isoform | Isoform composition affects force generation and relaxation speed |
| MYH6 | Alpha-myosin heavy chain isoform | Isoform composition affects force generation and relaxation speed |
| PPP1CA | Protein phosphatase 1 catalytic subunit | Dephosphorylates contractile proteins; regulates relaxation |
| PPP2CA | Protein phosphatase 2A catalytic subunit | Dephosphorylates contractile proteins; regulates relaxation |
| PLN | Phospholamban, inhibits SERCA2a | Regulates SERCA activity and relaxation |
| TNNT2 | Troponin T, thin filament regulatory protein | Phosphorylation state affects relaxation |
| TNNI3 | Troponin I, thin filament regulatory protein | Phosphorylation by PKA accelerates relaxation |
| MYL2 | Myosin regulatory light chain | Phosphorylation modulates cross-bridge cycling |
| ACTC1 | Cardiac actin | Thin filament component; mutations affect relaxation |
| LMNA | Lamin A/C, nuclear envelope protein | Mechanosensing and nuclear signaling |
| SUN1 | LINC complex protein | Nucleus mechanosensing in cardiomyocytes |
| SYNE1 | Nesprin-1, LINC complex protein | Nucleus mechanosensing in cardiomyocytes |
| COL1A1 | Collagen type I, extracellular matrix | Fibrosis impairs relaxation |
| COL3A1 | Collagen type III, extracellular matrix | Fibrosis impairs relaxation |
| HDAC4 | Histone deacetylase 4 | Epigenetic regulation of cardiac fibrosis |
How Is regulation of relaxation of cardiac muscle Regulated?
The regulation of cardiac muscle relaxation is itself tightly controlled by multiple signaling pathways. Beta-adrenergic stimulation activates protein kinase A (PKA), which phosphorylates phospholamban, troponin I, and myosin-binding protein C, thereby accelerating calcium reuptake and cross-bridge detachment to enhance relaxation. Conversely, protein phosphatases PP1 and PP2A dephosphorylate these targets, modulating the duration and extent of relaxation. Calcium/calmodulin-dependent protein kinase II (CaMKII) also phosphorylates phospholamban and ryanodine receptors, influencing calcium handling and relaxation. Additionally, epigenetic mechanisms such as histone acetylation and DNA methylation regulate the expression of genes involved in fibrosis and hypertrophy, indirectly affecting relaxation. Mechanosensing pathways involving the LINC complex transmit mechanical stretch signals to the nucleus, altering gene expression programs that control relaxation.
regulation of relaxation of cardiac muscle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MYBPC3 | Hypertrophic cardiomyopathy | Knock-in mouse or human iPSC-derived cardiomyocytes with patient mutation |
| ATP2A2 (SERCA2a) | Diastolic heart failure | Overexpression or knockout in cardiomyocytes to assess relaxation kinetics |
| DWORF | Diastolic dysfunction | Knockout and overexpression models to test effects on SERCA activity |
| PPP1CA | Heart failure with altered relaxation | Cardiomyocyte-specific knockout or point mutation to modulate phosphatase activity |
| COL1A1 | Cardiac fibrosis | Knockout or knockdown in cardiac fibroblasts to reduce fibrosis |
Diastolic heart failure
Diastolic heart failure, also known as heart failure with preserved ejection fraction (HFpEF), is characterized by impaired cardiac relaxation and increased ventricular stiffness. This condition leads to elevated filling pressures and reduced cardiac output, particularly during exercise. Dysregulation of calcium handling, increased fibrosis, and altered myosin isoform expression contribute to impaired relaxation in HFpEF. Targeting regulators of relaxation, such as SERCA2a and DWORF, is a promising therapeutic strategy.
Hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is often caused by mutations in sarcomeric genes, particularly MYBPC3 and MYH7. These mutations alter cross-bridge kinetics and calcium sensitivity, leading to impaired relaxation and diastolic dysfunction. Cryo-electron tomography has revealed structural changes in MYBPC3 that affect its interaction with myosin and actin, providing mechanistic insights into HCM. CRISPR-based models of MYBPC3 mutations are valuable for studying HCM pathogenesis.
Hypoxia-induced cardiac dysfunction
Hypoxia, such as that experienced at high altitude, alters cardiac output regulation and can impair relaxation. Siebenmann et al. reviewed the effects of hypoxia on cardiac output, highlighting changes in heart rate, stroke volume, and diastolic function. These adaptations involve complex interplay between calcium handling, myosin isoform expression, and autonomic regulation, making relaxation a key target for understanding hypoxia-related cardiac dysfunction.
Cardiac fibrosis and stiffness
Cardiac fibrosis, driven by excessive deposition of extracellular matrix proteins such as collagen, increases ventricular stiffness and impairs relaxation. Epigenetic regulation of fibrosis, including histone modifications and DNA methylation, modulates the expression of pro-fibrotic genes. Targeting epigenetic enzymes like HDAC4 may offer therapeutic avenues to improve relaxation in fibrotic heart disease.
From regulation of relaxation of cardiac muscle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of DWORF impair cardiac relaxation? | DWORF knockout mouse or human iPSC-derived cardiomyocytes |
| How do MYBPC3 mutations affect cross-bridge kinetics? | Knock-in mouse carrying patient mutation or CRISPR-edited iPSC-cardiomyocytes |
| Can SERCA2a overexpression rescue diastolic dysfunction? | Cardiomyocyte-specific overexpression in mouse models of heart failure |
| What is the role of PP1 in relaxation? | Cardiomyocyte-specific PP1 knockout or point mutation (e.g., phosphorylation site) |
| Does mechanosensing regulate relaxation gene expression? | LINC complex knockout (LMNA, SUN1) in cardiomyocytes |
| Can epigenetic modifiers improve relaxation in fibrosis? | HDAC4 knockout or overexpression in cardiac fibroblasts and cardiomyocytes |
How to Study the regulation of relaxation of cardiac muscle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcium imaging | Calcium transient decay kinetics | Assess relaxation speed in cardiomyocytes |
| Sarcomere shortening assay | Cell shortening and re-lengthening | Measure contractility and relaxation in edited cells |
| Cryo-electron tomography | Myofilament structure and interactions | Study MYBPC3 and myosin arrangement |
| Phosphoproteomics | Phosphorylation states of contractile proteins | Evaluate phosphatase/kinase effects |
| CRISPR knockout screening | Gene essentiality for relaxation | Identify novel regulators |
| RNA-seq | Transcriptional changes | Assess gene expression after CRISPR editing |
| Western blot | Protein expression and phosphorylation | Validate knockout or overexpression |
| Immunofluorescence | Subcellular localization | Study LINC complex and mechanosensing |
Calcium imaging and contractility assays
Calcium imaging using fluorescent indicators (e.g., Fura-2, Fluo-4) in isolated cardiomyocytes allows direct measurement of calcium transient decay kinetics, a proxy for relaxation. Combined with edge-detection systems for sarcomere shortening, these methods quantify relaxation speed and extent. Such assays are essential for validating the effects of CRISPR edits in genes like SERCA2a or DWORF.
Cryo-electron tomography and structural biology
Cryo-electron tomography of intact cardiac muscle provides near-atomic resolution of myofilament organization and the interaction between myosin, actin, and MYBPC3. This technique has revealed how MYBPC3 links filaments and modulates cross-bridge kinetics, offering mechanistic insights into relaxation. It is particularly useful for studying structural consequences of point mutations introduced by CRISPR.
Proteomics and phosphoproteomics
Mass spectrometry-based proteomics and phosphoproteomics can quantify changes in protein abundance and phosphorylation states of contractile proteins and calcium-handling proteins. This is valuable for assessing how CRISPR-mediated knockout or knock-in of phosphatases (e.g., PP1) or kinases alters the relaxation machinery.
CRISPR library screening and bioinformatics
Genome-wide CRISPR knockout or activation screens in cardiomyocytes can identify novel regulators of relaxation. Combined with bioinformatics analysis of transcriptomic and proteomic data, these screens accelerate target discovery. For example, screens could uncover micropeptides like DWORF or epigenetic modifiers that affect relaxation.
How CRISPR Can Be Used to Study GO:1901897 regulation of relaxation of cardiac muscle
Knockout
CRISPR knockout of genes such as DWORF, SERCA2a, or PP1 in cardiomyocytes or animal models can reveal their necessity for normal relaxation. For example, DWORF knockout mice show impaired calcium reuptake and prolonged relaxation, validating its role in GO:1901897. Knockout of phosphatases can similarly alter relaxation kinetics.
Point Mutation
Introducing precise point mutations (e.g., phosphorylation site mutations in troponin I or phospholamban) using CRISPR base editing or homology-directed repair allows dissection of regulatory phosphorylation events. Such models help determine how specific residues modulate relaxation without confounding effects of complete protein loss.
Knock-in
Knock-in of disease-associated mutations, such as MYBPC3 mutations found in hypertrophic cardiomyopathy, creates physiologically relevant models. These can be introduced into human iPSC-derived cardiomyocytes or mice to study impaired relaxation and test therapeutic interventions.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression of genes like SERCA2a or DWORF can enhance relaxation and rescue diastolic dysfunction in disease models. Overexpression studies have shown that increasing SERCA2a activity accelerates calcium reuptake and improves relaxation.
How EDITGENE Supports regulation of relaxation of cardiac muscle Research
Researchers studying regulation of relaxation of cardiac muscle-related genes often need to determine whether a candidate gene is causally involved in relaxation or is merely a biomarker. EDITGENE provides end-to-end CRISPR services to create precisely engineered cell and animal models, enabling functional validation of genes identified through screens or omics studies.
Contact EDITGENE today to design your custom CRISPR model for regulation of relaxation of cardiac muscle research.
Frequently Asked Questions About regulation of relaxation of cardiac muscle
What is GO:1901897?
GO:1901897 is a Gene Ontology term for regulation of relaxation of cardiac muscle, defined as any process that modulates the frequency, rate or extent of cardiac muscle relaxation.
What genes are involved in regulation of relaxation of cardiac muscle?
Key genes include ATP2A2 (SERCA2a), DWORF, MYBPC3, MYH7, PPP1CA, PPP2CA, PLN, TNNT2, and TNNI3, among others.
How does calcium reuptake affect cardiac relaxation?
Calcium reuptake into the sarcoplasmic reticulum by SERCA2a is a rate-limiting step for relaxation; its activity is enhanced by DWORF and inhibited by phospholamban.
What is the role of myosin-binding protein C in relaxation?
MYBPC3 links myosin and actin filaments, modulating cross-bridge kinetics and thus the speed of relaxation; mutations cause hypertrophic cardiomyopathy.
Which phosphatases regulate cardiac relaxation?
Protein phosphatases PP1 and PP2A dephosphorylate contractile proteins such as troponin I, promoting relaxation.
How can CRISPR be used to study cardiac relaxation?
CRISPR knockout, point mutation, knock-in, and overexpression models allow functional dissection of genes controlling relaxation in cardiomyocytes and animal models.
What diseases are associated with impaired cardiac relaxation?
Diastolic heart failure, hypertrophic cardiomyopathy, and hypoxia-induced cardiac dysfunction are linked to impaired relaxation.
What methods are used to measure cardiac relaxation?
Calcium imaging, sarcomere shortening assays, cryo-electron tomography, and phosphoproteomics are commonly used.
What is DWORF and how does it affect relaxation?
DWORF is a micropeptide encoded by a long noncoding RNA that enhances SERCA activity, accelerating calcium reuptake and relaxation.
Can overexpression of SERCA2a improve relaxation?
Yes, overexpression of SERCA2a or DWORF has been shown to enhance calcium reuptake and improve relaxation in models of heart failure.
Conclusion
Regulation of relaxation of cardiac muscle (GO:1901897) is a complex biological process essential for normal cardiac function. It involves coordinated calcium reuptake, myosin-actin detachment, phosphatase activity, and mechanosensing. Dysregulation of this process contributes to major cardiac diseases, including diastolic heart failure and hypertrophic cardiomyopathy. CRISPR-based models offer powerful tools to dissect the genetic and molecular underpinnings of relaxation, and EDITGENE provides comprehensive services to support such research. By targeting key regulators like SERCA2a, DWORF, and MYBPC3, new therapeutic strategies for cardiac disease may emerge.
References
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- 4. Bullard B et al.. 2019. Through thick and thin: dual regulation of insect flight muscle and cardiac muscle compared.. J Muscle Res Cell Motil 40(2):99-110 PMID: 31292801
- 5. Coscarella IL et al.. 2023. Nucleus Mechanosensing in Cardiomyocytes.. Int J Mol Sci 24(17) PMID: 37686151
- 6. Scellini B et al.. 2024. Myosin Isoform-Dependent Effect of Omecamtiv Mecarbil on the Regulation of Force Generation in Human Cardiac Muscle.. Int J Mol Sci 25(18) PMID: 39337273
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- 8. Huang X et al.. 2023. Cryo-electron tomography of intact cardiac muscle reveals myosin binding protein-C linking myosin and actin filaments.. J Muscle Res Cell Motil 44(3):165-178 PMID: 37115473
