GO:0055119 relaxation of cardiac muscle: Physiology, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0055119 relaxation of cardiac muscle is defined as the process in which the extent of cardiac muscle contraction is reduced.
• Cardiac relaxation is driven by a fall in cytosolic Ca2+ and by the detachment of myosin heads from actin, returning the sarcomere to a low-force state.
• Phosphorylation of cardiac troponin I by PKA accelerates the rate of cardiac muscle relaxation and is a key regulatory switch.
• The super-relaxed state of myosin, in which myosin heads are folded back onto the thick filament, contributes to the low-energy relaxed state of cardiac muscle.
• Passive viscoelastic properties of cardiac muscle, including calcium-dependent effects, also shape the relaxation phase independently of active force.
• The human cardiac myosin filament has been resolved at atomic resolution, providing a structural framework for understanding relaxation.
Description
Relaxation of cardiac muscle (GO:0055119) is the biological process in which the extent of cardiac muscle contraction is reduced. It is the essential diastolic counterpart to contraction, allowing the heart to refill with blood and to reset the contractile apparatus for the next beat. At the cellular level, relaxation depends on the removal of cytosolic Ca2+ by the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and the Na+/Ca2+ exchanger, the dissociation of Ca2+ from troponin C, and the subsequent re-inhibition of the thin filament by troponin I. The process is not merely passive: phosphorylation of cardiac troponin I by protein kinase A increases the rate of cardiac muscle relaxation, demonstrating that relaxation is actively regulated. In addition, the myosin heads can enter a super-relaxed state in which ATP turnover is very low, contributing to the energy-sparing relaxed state of the thick filament. Structural studies of the human cardiac myosin filament have revealed the atomic details of the relaxed conformation, providing a framework for understanding how mutations may alter relaxation. Because impaired relaxation underlies diastolic dysfunction and heart failure with preserved ejection fraction, researchers need robust models to dissect the molecular players in this process.
relaxation of cardiac muscle At A Glance
| GO ID | GO:0055119 |
|---|---|
| GO term | relaxation of cardiac muscle |
| Ontology | biological_process |
| Synonym | none |
| Major function | Reduction of the extent of cardiac muscle contraction, enabling diastolic filling and sarcomere resetting |
| Key trigger | Fall in cytosolic Ca2+ and dissociation of Ca2+ from troponin C |
| Key regulatory switch | Phosphorylation of cardiac troponin I by PKA increases the rate of relaxation |
| Structural basis | Atomic model of the human cardiac myosin filament reveals the relaxed conformation |
| Energy state | Super-relaxed state of myosin lowers ATP turnover in relaxed cardiac muscle |
What Is GO:0055119?
GO:0055119 relaxation of cardiac muscle is the biological process in which the extent of cardiac muscle contraction is reduced. It encompasses the molecular and cellular events that lower force production in cardiac myocytes, including the decline in cytosolic Ca2+ concentration, the dissociation of Ca2+ from the thin filament, the dephosphorylation or phosphorylation-dependent modulation of regulatory proteins, and the return of myosin heads to a folded, low-activity conformation.
Why Is relaxation of cardiac muscle Important in Cell Biology?
Relaxation of cardiac muscle is essential for normal diastolic function, because the heart must relax and refill before each contraction. Defects in relaxation contribute to diastolic dysfunction, heart failure with preserved ejection fraction, and hypertrophic cardiomyopathy, where mutations in sarcomeric proteins alter Ca2+ handling and myofilament regulation. Understanding the molecular mechanisms of relaxation, including the role of troponin I phosphorylation and the super-relaxed state of myosin, is therefore critical for developing targeted therapies. Moreover, passive viscoelastic properties of cardiac muscle, which are calcium-dependent, influence the relaxation phase and are relevant to myocardial stiffness. Structural knowledge of the cardiac myosin filament provides a template for interpreting disease mutations that may impair relaxation.
• Relaxation of cardiac muscle is required for diastolic filling and normal cardiac output.
• Impaired relaxation is a hallmark of heart failure with preserved ejection fraction and diastolic dysfunction.
• Phosphorylation of cardiac troponin I accelerates relaxation and is a key regulatory mechanism.
• The super-relaxed state of myosin reduces energy consumption in the relaxed heart.
• Mutations in sarcomeric proteins can alter relaxation and contribute to hypertrophic cardiomyopathy.
• Calcium-dependent passive viscoelasticity of cardiac muscle affects the relaxation phase.
• Understanding relaxation mechanisms aids in the development of inotropic and lusitropic drugs.
• Structural models of the cardiac myosin filament enable structure-function studies of relaxation.
• Relaxation is a dynamic process that can be studied with genetically encoded Ca2+ indicators and force measurements.
• Comparative studies of insect flight muscle and cardiac muscle reveal dual regulation of relaxation.
What Happens During relaxation of cardiac muscle?
Calcium removal and troponin switching
In simple terms: Relaxation starts when calcium is pumped out of the cell, so the contractile proteins can switch off.
During relaxation, cytosolic Ca2+ is rapidly removed by the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and the Na+/Ca2+ exchanger, causing Ca2+ to dissociate from troponin C. This dissociation reverses the conformational change in the thin filament that had allowed myosin to bind actin, thereby reducing force. The rate of Ca2+ decline is a major determinant of the speed of relaxation.
Troponin I phosphorylation and relaxation rate
In simple terms: Adding a phosphate group to troponin I makes the heart muscle relax faster.
Phosphorylation of cardiac troponin I by protein kinase A increases the rate of cardiac muscle relaxation. This modification reduces the affinity of troponin C for Ca2+ and accelerates the dissociation of Ca2+ from the thin filament, thereby speeding the transition to the relaxed state. This mechanism is important for the lusitropic effect of beta-adrenergic stimulation.
Super-relaxed state of myosin
In simple terms: Myosin heads can fold back and save energy when the muscle is relaxed.
In relaxed cardiac muscle, myosin heads can adopt a super-relaxed state in which they are folded back onto the thick filament and exhibit very low ATP turnover. This state is thought to conserve energy and to maintain the thick filament in a ready-but-inactive conformation. The super-relaxed state has been characterized in myofibrils from cardiac muscle and is regulated by factors such as phosphorylation of myosin binding protein C.
Passive viscoelasticity and calcium-dependent mechanics
In simple terms: Even without active force, the heart muscle has passive stiffness that changes with calcium.
Calcium increases cardiac muscle viscoelasticity independent of active force development, indicating that passive mechanical properties are dynamically regulated. Theoretical analysis of power-law stress relaxation and calcium-dependent passive mechanics in cardiac muscle suggests that these passive properties contribute to the overall relaxation behavior. These findings highlight that relaxation is not solely determined by active cross-bridge cycling.
Structural basis of the relaxed thick filament
In simple terms: The detailed 3D structure of the cardiac myosin filament shows how it is organized when relaxed.
Atomic models of the human cardiac muscle myosin filament have revealed the precise arrangement of myosin heads in the relaxed state. Three-dimensional reconstructions of vertebrate cardiac muscle myosin filaments provide further structural insights into the relaxed conformation. These structures help explain how mutations in myosin and associated proteins may perturb relaxation.
Key Genes Involved in GO:0055119 relaxation of cardiac muscle
The following genes and proteins are central to the process of relaxation of cardiac muscle, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| TNNT2 | Cardiac troponin T, part of the thin filament regulatory complex | Mutations linked to hypertrophic cardiomyopathy and altered relaxation |
| TNNI3 | Cardiac troponin I, inhibits actomyosin ATPase and is phosphorylated to accelerate relaxation | Phosphorylation by PKA increases relaxation rate |
| TNNC1 | Cardiac troponin C, binds Ca2+ to trigger contraction | Ca2+ binding and release kinetics determine relaxation onset |
| MYH7 | Beta-myosin heavy chain, forms the thick filament | Mutations cause hypertrophic cardiomyopathy and may affect super-relaxed state |
| MYBPC3 | Myosin binding protein C, stabilizes the thick filament | Phosphorylation regulates super-relaxed state and relaxation |
| ACTC1 | Cardiac actin, thin filament component | Mutations linked to cardiomyopathy and altered relaxation |
| ATP2A2 | SERCA2a, pumps Ca2+ into the sarcoplasmic reticulum | Determines rate of Ca2+ removal and relaxation speed |
| PLN | Phospholamban, inhibits SERCA2a | Phosphorylation relieves inhibition and accelerates relaxation |
| RYR2 | Ryanodine receptor 2, releases Ca2+ from SR | Leak or altered gating affects relaxation |
| NPPA | Atrial natriuretic peptide | Marker of cardiac stress and diastolic dysfunction |
| NPPB | B-type natriuretic peptide | Marker of heart failure and impaired relaxation |
| MYL2 | Regulatory myosin light chain | Phosphorylation modulates myosin head conformation |
| MYL3 | Essential myosin light chain | Structural component of the thick filament |
| TTN | Titin, giant sarcomeric protein | Contributes to passive stiffness and relaxation |
| CASQ2 | Calsequestrin 2, Ca2+ buffer in SR | Affects Ca2+ storage and release during relaxation |
| CALM1 | Calmodulin, Ca2+ sensor | Regulates Ca2+ signaling and relaxation |
How Is relaxation of cardiac muscle Regulated?
Relaxation of cardiac muscle is regulated by beta-adrenergic signaling, which activates protein kinase A (PKA). PKA phosphorylates cardiac troponin I, reducing the Ca2+ affinity of troponin C and accelerating relaxation. PKA also phosphorylates phospholamban, relieving its inhibition of SERCA2a and increasing the rate of Ca2+ reuptake into the sarcoplasmic reticulum. In addition, phosphorylation of myosin binding protein C modulates the super-relaxed state of myosin, influencing the energy cost of relaxation. Calcium-dependent passive viscoelasticity further fine-tunes the mechanical relaxation phase.
relaxation of cardiac muscle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TNNI3 | Diastolic dysfunction due to altered phosphorylation | Knock-in of phospho-null or phospho-mimetic TNNI3 |
| MYH7 | Hypertrophic cardiomyopathy with impaired relaxation | Point mutation knock-in of MYH7 |
| MYBPC3 | Hypertrophic cardiomyopathy and altered super-relaxed state | Knockout or knock-in of MYBPC3 |
| ATP2A2 | Heart failure with reduced SERCA2a activity | Overexpression of ATP2A2 in cardiomyocytes |
| PLN | Impaired relaxation due to phospholamban inhibition | Knockout of PLN or phospho-mimetic knock-in |
Diastolic dysfunction and heart failure with preserved ejection fraction
Impaired relaxation of cardiac muscle is a central feature of diastolic dysfunction and heart failure with preserved ejection fraction. Defects in Ca2+ handling, such as reduced SERCA2a activity or increased phospholamban inhibition, slow the decline of cytosolic Ca2+ and prolong relaxation. Phosphorylation of cardiac troponin I is also altered in these conditions, contributing to impaired lusitropy.
Hypertrophic cardiomyopathy
Mutations in sarcomeric genes such as MYH7, MYBPC3, TNNT2, and TNNI3 can alter relaxation by affecting myosin head conformation, thin filament regulation, or the super-relaxed state. Structural studies of the cardiac myosin filament help explain how these mutations may perturb the relaxed state.
Altered passive mechanics and myocardial stiffness
Calcium-dependent passive viscoelasticity and power-law stress relaxation contribute to myocardial stiffness, which is increased in some cardiac diseases. These passive properties are independent of active force and may represent therapeutic targets for improving relaxation.
From relaxation of cardiac muscle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TNNI3 phosphorylation slow relaxation? | TNNI3 phospho-null knock-in mouse |
| Does a MYH7 mutation alter the super-relaxed state? | MYH7 point mutation knock-in in hiPSC-cardiomyocytes |
| Does overexpression of SERCA2a accelerate relaxation? | ATP2A2 overexpression in cardiomyocytes |
| Does MYBPC3 haploinsufficiency impair relaxation? | MYBPC3 knockout mouse |
| Does calcium-dependent passive stiffness change with TTN mutations? | TTN knockout or truncation knock-in |
| Can a tagged knock-in of MYL2 reveal myosin head conformation? | MYL2 fluorescent knock-in |
How to Study the relaxation of cardiac muscle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Ca2+ imaging | Cytosolic Ca2+ transients | Assessing relaxation speed in cardiomyocytes |
| Force measurement | Active and passive force | Studying relaxation kinetics in muscle strips |
| Phospho-specific Western blot | Phosphorylation of TNNI3 and PLN | Evaluating PKA-mediated relaxation regulation |
| Cryo-EM | Atomic structure of myosin filament | Determining relaxed conformation |
| Stress-relaxation test | Passive viscoelasticity | Quantifying calcium-dependent stiffness |
| Super-relaxed state assay | ATP turnover of myosin | Measuring energy state of relaxed muscle |
| Mass spectrometry | Phosphoproteomics | Identifying relaxation-related phosphorylation sites |
Calcium imaging and force measurements
Relaxation can be studied by measuring cytosolic Ca2+ transients with genetically encoded indicators and simultaneously recording force in isolated cardiomyocytes or muscle strips. The rate of Ca2+ decline and force relaxation are key parameters.
Phosphorylation analysis
Phosphorylation of cardiac troponin I and phospholamban can be assessed by Western blotting with phospho-specific antibodies or by mass spectrometry. These methods reveal the regulatory state of relaxation.
Structural biology
Cryo-electron microscopy and X-ray crystallography have been used to determine the atomic structure of the cardiac myosin filament in the relaxed state. These structures provide a framework for understanding how mutations affect relaxation.
Passive mechanics and viscoelasticity
Passive viscoelastic properties can be measured using stress-relaxation protocols and analyzed with power-law models. These methods quantify calcium-dependent passive mechanics independent of active force.
How CRISPR Can Be Used to Study GO:0055119 relaxation of cardiac muscle
Knockout
CRISPR knockout of genes such as TNNI3, MYBPC3, or PLN can be used to determine their requirement for normal relaxation. Loss-of-function models help establish causality between a gene and relaxation defects.
Point Mutation
Point mutations identified in hypertrophic cardiomyopathy patients, such as in MYH7 or TNNT2, can be introduced by CRISPR to study their effects on relaxation. These models allow precise structure-function analysis.
Knock-in
Knock-in of phospho-null or phospho-mimetic variants of TNNI3 can test the role of phosphorylation in accelerating relaxation. Similarly, tagged knock-in of MYL2 can visualize myosin head conformation in live cells.
Overexpression
Overexpression of ATP2A2 (SERCA2a) or its regulator PLN can be achieved by CRISPR-mediated knock-in of a strong promoter or by lentiviral delivery. These models test whether increasing Ca2+ reuptake accelerates relaxation.
How EDITGENE Supports relaxation of cardiac muscle Research
Researchers studying relaxation of cardiac muscle-related genes often need to determine whether a candidate gene is causally involved in the relaxation process or is merely a bystander. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell and animal models, enabling rigorous functional studies of cardiac relaxation mechanisms.
Contact EDITGENE today to design your custom CRISPR model for relaxation of cardiac muscle research.
Frequently Asked Questions About relaxation of cardiac muscle
What is GO:0055119 relaxation of cardiac muscle?
GO:0055119 is the biological process in which the extent of cardiac muscle contraction is reduced, enabling diastolic filling.
What genes are involved in relaxation of cardiac muscle?
Key genes include TNNT2, TNNI3, TNNC1, MYH7, MYBPC3, ATP2A2, PLN, and RYR2, among others.
How does calcium removal cause cardiac muscle relaxation?
Calcium is pumped back into the sarcoplasmic reticulum by SERCA2a and extruded by the Na+/Ca2+ exchanger, causing Ca2+ to dissociate from troponin C and reducing force.
What is the role of troponin I phosphorylation in relaxation?
Phosphorylation of cardiac troponin I by PKA increases the rate of cardiac muscle relaxation by reducing Ca2+ affinity.
What is the super-relaxed state of myosin?
It is a state in which myosin heads are folded back onto the thick filament and exhibit very low ATP turnover, conserving energy during relaxation.
How is relaxation of cardiac muscle studied experimentally?
Researchers use Ca2+ imaging, force measurements, phospho-specific Western blots, cryo-EM, and stress-relaxation tests.
What diseases are linked to impaired cardiac relaxation?
Diastolic dysfunction, heart failure with preserved ejection fraction, and hypertrophic cardiomyopathy are linked to impaired relaxation.
Can CRISPR be used to study relaxation of cardiac muscle?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models can be used to dissect gene function in relaxation.
What is the structural basis of the relaxed cardiac myosin filament?
Atomic models of the human cardiac myosin filament reveal the arrangement of myosin heads in the relaxed state.
How does passive viscoelasticity affect cardiac relaxation?
Calcium-dependent passive viscoelasticity and power-law stress relaxation contribute to the overall relaxation behavior independent of active force.
Conclusion
Relaxation of cardiac muscle (GO:0055119) is a finely regulated biological process essential for normal heart function. It involves Ca2+ removal, troponin I phosphorylation, the super-relaxed state of myosin, and passive viscoelastic properties. Dysregulation of these mechanisms contributes to diastolic dysfunction and heart failure, making them important therapeutic targets. Continued research using advanced CRISPR models and structural techniques will further elucidate the molecular details of relaxation.
References
- 1. Bers DM. 2002. Cardiac excitation-contraction coupling.. Nature 415(6868):198-205 PMID: 11805843
- 2. Baker AJ et al.. 2025. Ca(2+) increases cardiac muscle viscoelasticity independent of active force development.. Biophys J 124(16):2698-2707 PMID: 40652326
- 3. Ježek F et al.. 2025. Theoretical analysis of power-law stress relaxation and calcium-dependent passive mechanics in cardiac muscle.. J Physiol 603(19):5369-5385 PMID: 40846493
- 4. Zhang R et al.. 1995. Cardiac troponin I phosphorylation increases the rate of cardiac muscle relaxation.. Circ Res 76(6):1028-35 PMID: 7758157
- 5. 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
- 6. Walklate J et al.. 2022. Exploring the super-relaxed state of myosin in myofibrils from fast-twitch, slow-twitch, and cardiac muscle.. J Biol Chem 298(3):101640 PMID: 35090895
- 7. Al-Khayat HA et al.. 2013. Atomic model of the human cardiac muscle myosin filament.. Proc Natl Acad Sci U S A 110(1):318-23 PMID: 23251030
- 8. Zoghbi ME et al.. 2008. Three-dimensional structure of vertebrate cardiac muscle myosin filaments.. Proc Natl Acad Sci U S A 105(7):2386-90 PMID: 18252826
