GO:0090075 relaxation of muscle: Calcium Handling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0090075 relaxation of muscle is the biological process that reduces the extent of muscle contraction, often by lowering cytoplasmic Ca2+ or by dephosphorylating myosin light chain.
• In striated muscle, relaxation kinetics depend on sarcomeric determinants such as SERCA-mediated Ca2+ reuptake and thin-filament regulation.
• In smooth muscle, cGMP and beta-adrenergic signaling promote relaxation through calcium-independent pathways that decrease myosin light chain phosphorylation.
• Impaired muscle relaxation is a measurable phenotype in myopathies and can be assessed using motor cortical stimulation.
• Progressive muscle relaxation is a behavioral intervention studied in clinical populations, but it is distinct from the cellular process GO:0090075.
• Researchers study relaxation of muscle using calcium imaging, force measurements, phosphoproteomics, and CRISPR-engineered cell and animal models.
Description
Relaxation of muscle (GO:0090075) is a fundamental biological process that reverses contraction, allowing muscles to return to a low-force state. It is essential for normal movement, airway patency, vascular tone, and cardiac filling. At the cellular level, relaxation requires the removal of calcium from the cytoplasm, often through the action of Ca2+ ATPases that pump calcium into the sarcoplasmic reticulum lumen, and in some muscles it also involves calcium-independent pathways that reduce myosin light chain phosphorylation. Understanding this process is critical because defects in relaxation contribute to myopathies, airway hyperresponsiveness, and other disorders. This article integrates the QuickGO definition of GO:0090075 with verified PubMed literature to provide a research-grade overview of its mechanisms, key genes, disease links, and experimental methods.
relaxation of muscle At A Glance
| GO ID | GO:0090075 |
|---|---|
| GO term | relaxation of muscle |
| Ontology | biological_process |
| Synonym | none |
| Major function | Reduction of muscle contraction via calcium removal and/or decreased myosin light chain phosphorylation |
| Key cellular event | Ca2+ reuptake into sarcoplasmic reticulum lumen by Ca2+ ATPases |
| Alternative pathway | Calcium-independent decrease in myosin light chain phosphorylation |
| Relevant tissues | Striated muscle, smooth muscle (airway, vascular, gastrointestinal) |
| Disease relevance | Myopathies, airway hyperresponsiveness, and other contractile disorders |
What Is GO:0090075?
GO:0090075 relaxation of muscle is defined as a process in which the extent of muscle contraction is reduced. This can occur through multiple mechanisms, including the removal of calcium from the cytoplasm to the sarcoplasmic reticulum lumen via Ca2+ ATPases, and in some muscles through calcium-independent pathways that decrease the phosphorylation state of myosin light chain.
Why Is relaxation of muscle Important in Cell Biology?
Relaxation of muscle is as important as contraction for normal physiology; it determines the timing and extent of muscle force decline and is required for functions such as cardiac filling, airway dilation, and smooth muscle quiescence. Defects in relaxation can lead to impaired motor function in myopathies and contribute to airway diseases where smooth muscle fails to relax adequately. Moreover, understanding the molecular pathways of relaxation has therapeutic implications, as beta-adrenergic agonists and cGMP-mediated signaling are used to promote smooth muscle relaxation in clinical settings.
• Enables muscle return to resting state after contraction, essential for coordinated movement.
• Regulates airway diameter; impaired relaxation contributes to bronchoconstriction.
• Controls vascular tone through cGMP-mediated smooth muscle relaxation.
• Required for cardiac relaxation and proper filling during diastole.
• Dysregulated relaxation is a feature of myopathies and can be detected by motor cortical stimulation.
• Calcium-independent pathways provide additional targets for therapeutic modulation.
• Progressive muscle relaxation as a behavioral technique is studied in clinical populations, though distinct from cellular GO:0090075.
• Relaxation mechanisms are conserved across striated and smooth muscle but use different regulatory proteins.
• Experimental models of relaxation aid drug discovery for asthma and cardiovascular diseases.
• Quantitative assays of relaxation kinetics inform diagnosis and treatment monitoring.
What Happens During relaxation of muscle?
Calcium removal from the cytoplasm
In simple terms: Calcium is pumped out of the main cell fluid to stop contraction.
A central event in muscle relaxation is the removal of calcium from the cytoplasm to the sarcoplasmic reticulum lumen through the action of Ca2+ ATPases, such as SERCA. This reduces cytoplasmic Ca2+ concentration, leading to dissociation of calcium from troponin C and subsequent inhibition of actomyosin cross-bridge cycling in striated muscle.
Sarcomeric determinants of relaxation kinetics
In simple terms: The speed of relaxation depends on the properties of the contractile proteins themselves.
In striated muscle, relaxation kinetics are influenced by sarcomeric determinants including myosin isoform composition, thin filament regulation, and the rate of cross-bridge detachment. These intrinsic properties set the maximum rate of force decline independent of calcium removal.
Calcium-independent pathways in smooth muscle
In simple terms: Some muscles relax without needing calcium changes, by turning off the myosin motor.
In some muscles, calcium-independent pathways also play a role in muscle relaxation by decreasing the phosphorylation state of myosin light chain. For example, cGMP-mediated signaling activates myosin light chain phosphatase, reducing myosin light chain phosphorylation and promoting relaxation even at constant calcium levels.
Beta-adrenergic relaxation of airway smooth muscle
In simple terms: Adrenaline-like signals relax airway muscles through multiple molecular switches.
Beta-adrenergic agonists relax airway smooth muscle by raising cAMP, which activates protein kinase A and leads to phosphorylation of multiple targets that reduce calcium sensitivity and promote myosin light chain dephosphorylation. This pathway is a key therapeutic mechanism in asthma treatment.
cGMP-mediated smooth muscle relaxation
In simple terms: Nitric oxide signals relax blood vessels by making cGMP.
cGMP-mediated smooth muscle relaxation involves activation of cGMP-dependent protein kinase (PKG), which reduces cytoplasmic calcium and decreases calcium sensitivity of the contractile apparatus, partly through myosin light chain phosphatase activation. This pathway is central to vascular smooth muscle relaxation.
Key Genes Involved in GO:0090075 relaxation of muscle
The following genes and proteins are central to the process of relaxation of muscle, based on their roles in calcium handling, myosin light chain phosphorylation, and signaling pathways.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ATP2A1 | SERCA1 calcium pump in fast-twitch skeletal muscle | Mutations cause Brody myopathy with impaired relaxation |
| ATP2A2 | SERCA2 calcium pump in cardiac and slow-twitch muscle | Key regulator of cardiac relaxation and calcium reuptake |
| MYH7 | Beta-myosin heavy chain in cardiac muscle | Sarcomeric determinant of relaxation kinetics |
| MYH2 | Fast myosin heavy chain in skeletal muscle | Influences cross-bridge cycling rate and relaxation speed |
| TNNT3 | Fast skeletal muscle troponin T | Thin filament regulation of calcium sensitivity |
| TNNI2 | Fast skeletal muscle troponin I | Inhibitory subunit affecting relaxation |
| MYL2 | Regulatory myosin light chain in cardiac muscle | Phosphorylation modulates contraction and relaxation |
| MYL9 | Smooth muscle myosin regulatory light chain | Phosphorylation state determines smooth muscle relaxation |
| MYLK | Myosin light chain kinase | Phosphorylates myosin light chain to promote contraction; inhibition aids relaxation |
| PPP1R12A | Myosin light chain phosphatase regulatory subunit | Target of cGMP/PKG to promote relaxation |
| PRKG1 | cGMP-dependent protein kinase I | Mediates cGMP-induced smooth muscle relaxation |
| ADRB2 | Beta-2 adrenergic receptor | Mediates beta-adrenergic relaxation of airway smooth muscle |
| ADCY5 | Adenylyl cyclase type 5 | Produces cAMP for beta-adrenergic relaxation |
| PRKACA | cAMP-dependent protein kinase A catalytic subunit | Phosphorylates targets to reduce calcium sensitivity |
| CALM1 | Calmodulin | Calcium sensor regulating myosin light chain kinase and other targets |
| ATP2B1 | Plasma membrane calcium ATPase | Extrudes calcium to lower cytoplasmic levels during relaxation |
| SLC8A1 | Sodium-calcium exchanger | Contributes to calcium removal in some muscles |
| NOS3 | Endothelial nitric oxide synthase | Produces NO to activate cGMP-mediated relaxation |
How Is relaxation of muscle Regulated?
Relaxation of muscle is regulated at multiple levels. In striated muscle, the rate of calcium reuptake by SERCA pumps is a primary determinant, and SERCA activity is modulated by phospholamban and sarcolipin. In smooth muscle, cGMP and cAMP signaling pathways regulate myosin light chain phosphatase activity and calcium sensitivity, providing calcium-independent control. Beta-adrenergic stimulation increases cAMP, activating PKA, which phosphorylates several targets to promote relaxation. Additionally, cGMP produced by soluble guanylate cyclase in response to nitric oxide activates PKG, which reduces intracellular calcium and decreases calcium sensitivity.
relaxation of muscle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ATP2A1 | Brody myopathy with impaired relaxation | Knockout or point-mutation in skeletal muscle cells |
| ADRB2 | Asthma and airway hyperresponsiveness | Knockout or overexpression in airway smooth muscle cells |
| PRKG1 | Hypertension and smooth muscle dysfunction | Knockout or point-mutation in vascular smooth muscle cells |
| MYL9 | Smooth muscle contractile disorders | Phospho-mutant knock-in in smooth muscle cells |
| ATP2A2 | Cardiac diastolic dysfunction | Knockout or overexpression in cardiomyocytes |
Myopathies with impaired relaxation
Impaired muscle relaxation is a hallmark of certain myopathies, such as Brody disease, which is caused by mutations in ATP2A1 encoding SERCA1. Detecting impaired muscle relaxation in myopathies can be performed using motor cortical stimulation, which provides a functional readout of relaxation kinetics.
Airway hyperresponsiveness and asthma
In asthma, airway smooth muscle fails to relax adequately, leading to bronchoconstriction. Beta-adrenergic relaxation of airway smooth muscle is a key therapeutic target, and impaired beta-adrenergic signaling can contribute to disease severity.
Cardiovascular disorders
Defective relaxation of cardiac and vascular smooth muscle contributes to diastolic dysfunction and hypertension. cGMP-mediated smooth muscle relaxation is critical for vascular tone, and alterations in this pathway are implicated in cardiovascular disease.
Behavioral relaxation interventions
Progressive muscle relaxation is a behavioral technique used in clinical populations such as ulcerative colitis, dementia caregivers, schizophrenia, and cancer patients, but it is distinct from the cellular process GO:0090075.
From relaxation of muscle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ATP2A1 impair muscle relaxation? | ATP2A1 knockout in skeletal muscle cell line or mouse |
| Does a point mutation in MYL9 alter relaxation kinetics? | MYL9 phospho-mutant knock-in in smooth muscle cells |
| Does overexpression of PRKG1 enhance cGMP-mediated relaxation? | PRKG1 overexpression in vascular smooth muscle cells |
| Does tagging SERCA2 affect its localization and function? | Tagged knock-in of ATP2A2 in cardiomyocytes |
| Does ADRB2 knockout reduce beta-adrenergic relaxation? | ADRB2 knockout in airway smooth muscle cells |
| Can CRISPR library screening identify new regulators of relaxation? | Genome-wide knockout library in muscle cells followed by functional assay |
How to Study the relaxation of muscle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcium imaging | Cytoplasmic Ca2+ concentration | Assessing SERCA function during relaxation |
| Force transduction | Muscle force and relaxation rate | Drug screening for relaxants |
| Phosphoproteomics | Myosin light chain phosphorylation | Studying calcium-independent relaxation |
| Motor cortical stimulation | Relaxation kinetics in vivo | Diagnosing myopathies |
| CRISPR knockout screening | Gene requirement for relaxation | Identifying novel regulators |
| RNA-seq | Transcriptional changes | Profiling gene expression during relaxation |
| Proteomics | Protein abundance and modifications | Validating targets |
Calcium imaging
Calcium imaging using fluorescent indicators measures changes in cytoplasmic Ca2+ concentration during relaxation, providing direct readout of calcium removal.
Force measurements
Force measurements on isolated muscle strips or single cells quantify relaxation kinetics and sensitivity to pharmacological agents.
Phosphoproteomics
Phosphoproteomics identifies changes in myosin light chain phosphorylation and other signaling events during smooth muscle relaxation.
Motor cortical stimulation
Motor cortical stimulation can detect impaired muscle relaxation in patients with myopathies, offering a clinical diagnostic tool.
How CRISPR Can Be Used to Study GO:0090075 relaxation of muscle
Knockout
CRISPR knockout of genes such as ATP2A1 or ADRB2 can abolish or reduce muscle relaxation, allowing researchers to test causality.
Point Mutation
Point mutations can be introduced into genes like MYL9 to mimic phosphorylation-defective states and study their impact on relaxation.
Knock-in
Knock-in of tagged versions of SERCA2 or PRKG1 enables live-cell imaging and biochemical isolation of protein complexes involved in relaxation.
Overexpression
Overexpression of relaxation-promoting genes such as PRKG1 or ATP2A2 can enhance relaxation and serve as a gain-of-function model.
How EDITGENE Supports relaxation of muscle Research
Researchers studying relaxation of muscle-related genes often need to determine whether a candidate gene is causally involved in calcium handling, myosin light chain phosphorylation, or signaling pathways. EDITGENE provides a comprehensive suite of CRISPR services to generate precisely engineered cell and animal models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for relaxation of muscle research.
Frequently Asked Questions About relaxation of muscle
What is relaxation of muscle GO:0090075?
GO:0090075 is a biological process in which the extent of muscle contraction is reduced, often through calcium removal or decreased myosin light chain phosphorylation.
What genes are involved in relaxation of muscle?
Key genes include ATP2A1, ATP2A2, MYL9, MYLK, PRKG1, ADRB2, and others involved in calcium handling and myosin regulation.
How does calcium removal cause muscle relaxation?
Calcium is pumped into the sarcoplasmic reticulum by Ca2+ ATPases, reducing cytoplasmic calcium and stopping contraction.
What is calcium-independent muscle relaxation?
It is relaxation that occurs without changes in calcium, often by decreasing myosin light chain phosphorylation through phosphatases.
Which diseases involve impaired muscle relaxation?
Brody myopathy, asthma, and cardiovascular disorders can involve impaired relaxation.
How can I study relaxation of muscle in the lab?
Methods include calcium imaging, force measurements, phosphoproteomics, and motor cortical stimulation.
What is the role of cGMP in muscle relaxation?
cGMP activates PKG, which reduces calcium sensitivity and promotes myosin light chain dephosphorylation, leading to relaxation.
Can CRISPR be used to study relaxation of muscle?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models can be used to test gene function in relaxation.
What is progressive muscle relaxation?
It is a behavioral technique for reducing psychological stress, distinct from the cellular process GO:0090075.
How does beta-adrenergic signaling relax airway smooth muscle?
Beta-agonists raise cAMP, activating PKA, which reduces calcium sensitivity and promotes relaxation.
Conclusion
Relaxation of muscle (GO:0090075) is a vital biological process that reverses contraction through calcium removal and calcium-independent pathways. Its dysregulation contributes to myopathies, asthma, and cardiovascular diseases, making it a key area of research. Advances in CRISPR genome editing and functional assays enable precise interrogation of the genes and pathways involved, offering opportunities for therapeutic development.
References
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- 2. Baykal D et al.. 2024. The effects of progressive muscle relaxation exercise on dementia caregivers.. Geriatr Nurs 59:491-497 PMID: 39146639
- 3. Poggesi C et al.. 2005. Sarcomeric determinants of striated muscle relaxation kinetics.. Pflugers Arch 449(6):505-17 PMID: 15750836
- 4. Carvajal JA et al.. 2000. Molecular mechanism of cGMP-mediated smooth muscle relaxation.. J Cell Physiol 184(3):409-20 PMID: 10911373
- 5. Kotlikoff MI et al.. 1996. Molecular mechanisms of beta-adrenergic relaxation of airway smooth muscle.. Annu Rev Physiol 58:115-41 PMID: 8815788
- 6. Vancampfort D et al.. 2013. Progressive muscle relaxation in persons with schizophrenia: a systematic review of randomized controlled trials.. Clin Rehabil 27(4):291-8 PMID: 22843353
- 7. Molenaar JP et al.. 2023. Detecting impaired muscle relaxation in myopathies with the use of motor cortical stimulation.. Neuromuscul Disord 33(5):396-404 PMID: 37030055
- 8. Noruzi Zamenjani M et al.. 2019. The effect of progressive muscle relaxation on cancer patients' self-efficacy.. Complement Ther Clin Pract 34:70-75 PMID: 30712748
