{"gene":"MYOM1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2021,"finding":"CRISPR/Cas9 knockout of MYOM1 in human embryonic stem cell-derived cardiomyocytes demonstrated that myomesin-1 is required for sarcomere assembly, contractility regulation, and cardiomyocyte development; loss of myomesin-1 recapitulates a myocardial atrophy phenotype in vitro and impairs calcium homeostasis.","method":"CRISPR/Cas9 knockout of MYOM1 in hESCs, differentiation to cardiomyocytes, phenotypic analysis of sarcomere structure and contractility","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotypes (sarcomere assembly, contractility, calcium homeostasis) in human cardiomyocytes, single lab, multiple readouts","pmids":["33452765"],"is_preprint":false},{"year":2022,"finding":"ALPK3 (α-kinase 3) colocalized with MYOM1 and MYOM2 at both the nuclear envelope and the sarcomere M-band; loss-of-function variants in ALPK3 caused mislocalization of myomesin proteins (including MYOM1) and dysregulated additional M-band proteins involved in sarcomere protein turnover, impairing cardiomyocyte structure and function.","method":"Co-localization in hiPSC-derived cardiomyocytes and patient tissues, ALPK3 loss-of-function iPSC model, proteomic analysis","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization, loss-of-function model with defined phenotype, single lab with multiple orthogonal methods","pmids":["36321451"],"is_preprint":false},{"year":2011,"finding":"Alternative splicing of MYOM1 exon 17a is regulated by MBNL1-3, CELF1, and CELF2 (which decrease exon 17a inclusion), and is aberrantly increased in DM1 muscle due to sequestration of MBNL proteins by expanded CUG repeats; CELF1 activity on MYOM1 splicing was not affected by expanded CUG repeats.","method":"Exon array to detect aberrant splicing in DM1 patient muscle; MYOM1 minigene splicing assay in HEK293T cells with MBNL1-3, CELF1, CELF2 overexpression or CUG repeat expression","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene splicing assay with multiple regulatory factors tested, single lab, two orthogonal methods (exon array + minigene assay)","pmids":["21794030"],"is_preprint":false},{"year":2021,"finding":"SRSF5 (splicing factor) promotes the alternative splicing of Myom1 in the heart, facilitating the switch from embryonic to adult isoforms; loss of Srsf5 in mice prevented completion of this isoform switch and caused noncompaction of the ventricular myocardium with cardiac dysfunction.","method":"CRISPR-Cas9 Srsf5 knockout mice; RNA splicing analysis of Myom1 isoforms; cardiac phenotype characterization","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse model with defined splicing and cardiac phenotype, single lab, multiple readouts","pmids":["34622152"],"is_preprint":false},{"year":2020,"finding":"MuRF1 (E3 ubiquitin ligase) interacts with MYOM1 and mediates its ubiquitination in diabetic skeletal muscle; exogenous hydrogen sulphide reduces the interaction between MuRF1 and MYOM1 via MuRF1 S-sulfhydration at Cys44, thereby decreasing MYOM1 ubiquitination and degradation.","method":"Co-immunoprecipitation of MuRF1 with MYOM1, ubiquitination assay in db/db mice, S-sulfhydration analysis, H2S treatment in vivo and in C2C12 cells","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assay, S-sulfhydration at identified site, single lab with multiple methods","pmids":["32633463"],"is_preprint":false},{"year":2007,"finding":"MYOM1 (myomesin-1) and MYOM2 (M-protein) show layer-specific differential expression at the structural, mRNA, and protein levels in extraocular muscle orbital vs. global layers, with the differential M-band composition predicting increased elasticity but reduced force and eccentric contraction-mediated damage in EOMs, providing a potential mechanism for EOM sparing in Duchenne muscular dystrophy.","method":"Semiquantitative PCR, qPCR, immunohistochemistry, confocal microscopy, electron microscopy on rat EOM layers","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EM, qPCR, IHC) in single lab establishing layer-specific MYOM1 localization with functional modeling","pmids":["17325154"],"is_preprint":false},{"year":2008,"finding":"Serum response factor (SRF) is required for expression of Myom1 in the heart; conditional cardiac SRF knockout powerfully attenuated Myom1 expression along with other myofibril proteins, blocking sarcomere formation and rhythmic beating.","method":"Conditional cardiac-specific SRF knockout mouse, SRF point mutants blocking cofactor interactions, viral rescue of SRF-null ES cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined sarcomere phenotype plus mechanistic rescue experiments, single lab","pmids":["19004760"],"is_preprint":false},{"year":2015,"finding":"Loss of muscleblind-like 1 (Mbnl1) in mice results in persistence of embryonic splice isoforms of Myom1 in cardiac tissue, associated with cardiac pathology including hypertrophy, fibrosis, and sudden death.","method":"Mbnl1 deletion mouse model (Mbnl1ΔE2/ΔE2), splicing analysis of cardiac RNAs including Myom1, cardiac phenotype characterization","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Myom1 splicing change is one of many in a broad splicing regulator KO; no direct functional rescue or mechanistic follow-up specific to MYOM1","pmids":["25761764"],"is_preprint":false},{"year":2023,"finding":"The SARS-CoV-2 papain-like protease (PLpro) was shown to cleave a predicted sequence in MYOM1 in an in vitro cleavage assay.","method":"In vitro protease cleavage assay using SARS-CoV-2 PLpro on predicted MYOM1 cleavage sequence","journal":"Viruses","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro cleavage assay, no functional consequence established, single lab","pmids":["36851756"],"is_preprint":false},{"year":2022,"finding":"miR-135a directly targets MYOM1 (confirmed by dual-luciferase assay), negatively regulating its expression in LPS-treated THP-1 cells; MYOM1 depletion reversed the protective effect of miR-135a inhibition on LPS-induced cell injury.","method":"Dual-luciferase reporter assay confirming miR-135a binding to MYOM1 3'UTR; qRT-PCR and western blot for MYOM1 expression; rescue experiments in LPS-treated THP-1 cells","journal":"Acta biochimica Polonica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase assay plus rescue experiment, single lab, mechanistic context in immune cells not well established for this sarcomeric protein","pmids":["35977075"],"is_preprint":false},{"year":2026,"finding":"Calpain activation mediates degradation of MYOM1 in vandetanib-treated cardiomyocytes; calpain inhibition rescued MYOM1 protein levels and preserved myofilament structure, while calpain1 overexpression aggravated loss of contractile proteins.","method":"Calpain inhibitor treatment and calpain1 overexpression/knockdown in cardiomyocytes treated with vandetanib; western blot quantification of MYOM1 protein levels; calcium imaging","journal":"European journal of pharmaceutical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, defined calpain–MYOM1 degradation axis with gain/loss of function, but no direct in vitro cleavage reconstitution or site identification","pmids":["41765115"],"is_preprint":false}],"current_model":"MYOM1 encodes myomesin-1, a structural M-band protein that cross-links myosin filaments in the sarcomere; it is transcriptionally regulated by SRF and undergoes MBNL1/CELF- and SRSF5-regulated alternative splicing during development, its localization and stability depend on ALPK3, it is subject to MuRF1-mediated ubiquitination and calpain-mediated degradation (both modifiable by H2S/S-sulfhydration and calpain inhibition respectively), and its loss in human cardiomyocytes impairs sarcomere assembly, contractility, and calcium homeostasis, causing myocardial atrophy."},"narrative":{"mechanistic_narrative":"MYOM1 encodes myomesin-1, a structural M-band component of the sarcomere that is required for sarcomere assembly, contractile function, and calcium homeostasis in human cardiomyocytes, where its loss recapitulates a myocardial atrophy phenotype [PMID:33452765]. Myomesin-1 localizes to both the sarcomere M-band and the nuclear envelope together with the α-kinase ALPK3, which is required for correct myomesin localization and for regulating M-band protein turnover [PMID:36321451]. Expression of MYOM1 depends on the transcription factor SRF, whose cardiac loss blocks myofibril formation and rhythmic beating [PMID:19004760], while developmental embryonic-to-adult isoform switching is governed by alternative splicing controlled antagonistically by MBNL1–3 versus CELF1/CELF2 at exon 17a [PMID:21794030] and by SRSF5, whose loss prevents completion of the isoform switch and causes ventricular noncompaction [PMID:34622152]. Myomesin-1 protein abundance is set by regulated degradation: the E3 ubiquitin ligase MuRF1 binds MYOM1 and mediates its ubiquitination in catabolic muscle, an interaction reduced by H2S-driven S-sulfhydration of MuRF1 at Cys44 [PMID:32633463]. Layer-specific MYOM1/MYOM2 M-band composition in extraocular muscle correlates with altered mechanical properties [PMID:17325154].","teleology":[{"year":2007,"claim":"Established that muscle-type-specific M-band composition, including MYOM1 expression levels, tracks with distinct mechanical properties, linking myomesin content to sarcomere biomechanics.","evidence":"PCR, qPCR, immunohistochemistry, confocal and electron microscopy across rat extraocular muscle layers","pmids":["17325154"],"confidence":"Medium","gaps":["Mechanical predictions modeled, not directly measured","No causal manipulation of MYOM1 levels"]},{"year":2008,"claim":"Identified SRF as a transcriptional requirement for Myom1 expression, placing myomesin-1 downstream of the core cardiac myofibrillar gene program.","evidence":"Conditional cardiac SRF knockout mouse with cofactor-mutant and viral rescue experiments","pmids":["19004760"],"confidence":"Medium","gaps":["Direct SRF binding to the MYOM1 promoter not demonstrated","Myom1 is one of many affected myofibrillar genes"]},{"year":2011,"claim":"Defined MYOM1 exon 17a as an alternative-splicing target controlled by competing MBNL and CELF factors, explaining aberrant splicing in myotonic dystrophy via MBNL sequestration.","evidence":"Exon array of DM1 patient muscle plus MYOM1 minigene splicing assays in HEK293T with MBNL1-3/CELF1/CELF2","pmids":["21794030"],"confidence":"Medium","gaps":["Functional consequence of exon 17a inclusion on myomesin-1 protein not established","Minigene context may not reflect endogenous regulation"]},{"year":2015,"claim":"Showed that loss of Mbnl1 in vivo causes persistence of embryonic Myom1 isoforms in heart, linking splicing dysregulation to cardiac pathology.","evidence":"Mbnl1 deletion mouse with cardiac RNA splicing analysis and phenotyping","pmids":["25761764"],"confidence":"Low","gaps":["Myom1 splicing change is one of many in a broad regulator KO; no MYOM1-specific rescue","Causal contribution of Myom1 mis-splicing to phenotype unresolved"]},{"year":2020,"claim":"Identified MuRF1-mediated ubiquitination as a degradation pathway controlling MYOM1 abundance and showed it is reversible by H2S-driven S-sulfhydration of MuRF1.","evidence":"Reciprocal Co-IP, ubiquitination assay, and S-sulfhydration site mapping in db/db mice and C2C12 cells","pmids":["32633463"],"confidence":"Medium","gaps":["MYOM1 ubiquitination site not mapped","Established in skeletal/diabetic muscle; cardiac relevance untested"]},{"year":2021,"claim":"Demonstrated by loss-of-function that myomesin-1 is required for sarcomere assembly, contractility, and calcium homeostasis in human cardiomyocytes, giving the gene a defined cellular phenotype.","evidence":"CRISPR/Cas9 MYOM1 knockout in hESC-derived cardiomyocytes with structural and functional readouts","pmids":["33452765"],"confidence":"Medium","gaps":["Molecular mechanism of contractility and calcium defect not dissected","Single-lab in vitro model"]},{"year":2021,"claim":"Established SRSF5 as the splicing factor driving the embryonic-to-adult Myom1 isoform switch, connecting incomplete switching to ventricular noncompaction.","evidence":"CRISPR-Cas9 Srsf5 knockout mice with Myom1 isoform and cardiac phenotype analysis","pmids":["34622152"],"confidence":"Medium","gaps":["Whether arrested Myom1 switching alone drives noncompaction not isolated","Other SRSF5 targets contribute"]},{"year":2022,"claim":"Placed myomesin proteins downstream of ALPK3, showing ALPK3 co-localizes with MYOM1 at M-band and nuclear envelope and is required for its correct localization and M-band protein turnover.","evidence":"Co-localization in hiPSC-derived cardiomyocytes and patient tissue, ALPK3 LOF iPSC model, proteomics","pmids":["36321451"],"confidence":"Medium","gaps":["Direct ALPK3-MYOM1 physical interaction vs. indirect effect not resolved","Kinase substrate relationship undefined"]},{"year":2022,"claim":"Reported miR-135a as a direct negative regulator of MYOM1 in an immune-cell injury context, an uncharacterized setting for this sarcomeric protein.","evidence":"Dual-luciferase 3'UTR reporter, qRT-PCR/western, and rescue in LPS-treated THP-1 cells","pmids":["35977075"],"confidence":"Low","gaps":["Biological role of MYOM1 in non-muscle immune cells unexplained","Single-lab reporter and rescue without orthogonal validation"]},{"year":2023,"claim":"Showed in vitro that SARS-CoV-2 PLpro can cleave a predicted MYOM1 sequence, raising a candidate host-protein target during infection.","evidence":"In vitro protease cleavage assay on a predicted MYOM1 cleavage site","pmids":["36851756"],"confidence":"Low","gaps":["No functional consequence of cleavage established","Cleavage not demonstrated in cells"]},{"year":2026,"claim":"Defined a calpain-mediated degradation axis controlling MYOM1 protein levels in drug-induced cardiotoxicity, with calpain inhibition preserving myofilament structure.","evidence":"Calpain inhibitor and calpain1 gain/loss-of-function in vandetanib-treated cardiomyocytes with western blot and calcium imaging","pmids":["41765115"],"confidence":"Low","gaps":["No in vitro cleavage reconstitution or site identification","Direct vs. indirect calpain action not distinguished"]},{"year":null,"claim":"How myomesin-1's M-band cross-linking activity mechanistically integrates with its transcriptional, splicing, and degradation control to determine sarcomere mechanics in human disease remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MYOM1 in the human M-band lattice in the corpus","No timeline-documented Mendelian disease mutation in MYOM1 itself","Integration of regulatory inputs (SRF, splicing, MuRF1, calpain, ALPK3) into a unified control model untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,3,6]}],"complexes":["sarcomere M-band"],"partners":["MYOM2","ALPK3","MURF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52179","full_name":"Myomesin-1","aliases":["190 kDa connectin-associated protein","190 kDa titin-associated protein","Myomesin family member 1"],"length_aa":1685,"mass_kda":187.6,"function":"Major component of the vertebrate myofibrillar M band. Binds myosin, titin, and light meromyosin. This binding is dose dependent","subcellular_location":"Cytoplasm, myofibril, sarcomere, M line","url":"https://www.uniprot.org/uniprotkb/P52179/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYOM1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYOM1","total_profiled":1310},"omim":[{"mim_id":"621008","title":"MYOSIN LIGHT CHAIN KINASE FAMILY, MEMBER 4; MYLK4","url":"https://www.omim.org/entry/621008"},{"mim_id":"616832","title":"MYOMESIN 3; MYOM3","url":"https://www.omim.org/entry/616832"},{"mim_id":"603509","title":"MYOMESIN 2; MYOM2","url":"https://www.omim.org/entry/603509"},{"mim_id":"603508","title":"MYOMESIN 1; MYOM1","url":"https://www.omim.org/entry/603508"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":375.8},{"tissue":"skeletal muscle","ntpm":762.9},{"tissue":"tongue","ntpm":399.9}],"url":"https://www.proteinatlas.org/search/MYOM1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P52179","domains":[{"cath_id":"2.60.40.10","chopping":"273-371","consensus_level":"high","plddt":76.4879,"start":273,"end":371},{"cath_id":"2.60.40.10","chopping":"399-501","consensus_level":"high","plddt":72.9389,"start":399,"end":501},{"cath_id":"2.60.40.10","chopping":"514-614","consensus_level":"high","plddt":83.4317,"start":514,"end":614},{"cath_id":"2.60.40.10","chopping":"643-733","consensus_level":"high","plddt":81.0416,"start":643,"end":733},{"cath_id":"2.60.40.10","chopping":"745-832","consensus_level":"high","plddt":84.695,"start":745,"end":832},{"cath_id":"2.60.40.10","chopping":"939-1035","consensus_level":"high","plddt":82.634,"start":939,"end":1035},{"cath_id":"2.60.40.10","chopping":"1036-1139","consensus_level":"medium","plddt":81.2129,"start":1036,"end":1139},{"cath_id":"2.60.40.10","chopping":"1140-1238","consensus_level":"medium","plddt":71.8804,"start":1140,"end":1238},{"cath_id":"2.60.40.10","chopping":"1247-1356","consensus_level":"medium","plddt":82.4387,"start":1247,"end":1356},{"cath_id":"2.60.40.10","chopping":"1461-1570","consensus_level":"high","plddt":79.3494,"start":1461,"end":1570},{"cath_id":"2.60.40.10","chopping":"1572-1685","consensus_level":"medium","plddt":81.7116,"start":1572,"end":1685}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52179","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52179-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52179-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYOM1","jax_strain_url":"https://www.jax.org/strain/search?query=MYOM1"},"sequence":{"accession":"P52179","fasta_url":"https://rest.uniprot.org/uniprotkb/P52179.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52179/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52179"}},"corpus_meta":[{"pmid":"23236287","id":"PMC_23236287","title":"Recurrent 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loss of myomesin-1 recapitulates a myocardial atrophy phenotype in vitro and impairs calcium homeostasis.\",\n      \"method\": \"CRISPR/Cas9 knockout of MYOM1 in hESCs, differentiation to cardiomyocytes, phenotypic analysis of sarcomere structure and contractility\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotypes (sarcomere assembly, contractility, calcium homeostasis) in human cardiomyocytes, single lab, multiple readouts\",\n      \"pmids\": [\"33452765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALPK3 (α-kinase 3) colocalized with MYOM1 and MYOM2 at both the nuclear envelope and the sarcomere M-band; loss-of-function variants in ALPK3 caused mislocalization of myomesin proteins (including MYOM1) and dysregulated additional M-band proteins involved in sarcomere protein turnover, impairing cardiomyocyte structure and function.\",\n      \"method\": \"Co-localization in hiPSC-derived cardiomyocytes and patient tissues, ALPK3 loss-of-function iPSC model, proteomic analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization, loss-of-function model with defined phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36321451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Alternative splicing of MYOM1 exon 17a is regulated by MBNL1-3, CELF1, and CELF2 (which decrease exon 17a inclusion), and is aberrantly increased in DM1 muscle due to sequestration of MBNL proteins by expanded CUG repeats; CELF1 activity on MYOM1 splicing was not affected by expanded CUG repeats.\",\n      \"method\": \"Exon array to detect aberrant splicing in DM1 patient muscle; MYOM1 minigene splicing assay in HEK293T cells with MBNL1-3, CELF1, CELF2 overexpression or CUG repeat expression\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene splicing assay with multiple regulatory factors tested, single lab, two orthogonal methods (exon array + minigene assay)\",\n      \"pmids\": [\"21794030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SRSF5 (splicing factor) promotes the alternative splicing of Myom1 in the heart, facilitating the switch from embryonic to adult isoforms; loss of Srsf5 in mice prevented completion of this isoform switch and caused noncompaction of the ventricular myocardium with cardiac dysfunction.\",\n      \"method\": \"CRISPR-Cas9 Srsf5 knockout mice; RNA splicing analysis of Myom1 isoforms; cardiac phenotype characterization\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse model with defined splicing and cardiac phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"34622152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MuRF1 (E3 ubiquitin ligase) interacts with MYOM1 and mediates its ubiquitination in diabetic skeletal muscle; exogenous hydrogen sulphide reduces the interaction between MuRF1 and MYOM1 via MuRF1 S-sulfhydration at Cys44, thereby decreasing MYOM1 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation of MuRF1 with MYOM1, ubiquitination assay in db/db mice, S-sulfhydration analysis, H2S treatment in vivo and in C2C12 cells\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ubiquitination assay, S-sulfhydration at identified site, single lab with multiple methods\",\n      \"pmids\": [\"32633463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MYOM1 (myomesin-1) and MYOM2 (M-protein) show layer-specific differential expression at the structural, mRNA, and protein levels in extraocular muscle orbital vs. global layers, with the differential M-band composition predicting increased elasticity but reduced force and eccentric contraction-mediated damage in EOMs, providing a potential mechanism for EOM sparing in Duchenne muscular dystrophy.\",\n      \"method\": \"Semiquantitative PCR, qPCR, immunohistochemistry, confocal microscopy, electron microscopy on rat EOM layers\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EM, qPCR, IHC) in single lab establishing layer-specific MYOM1 localization with functional modeling\",\n      \"pmids\": [\"17325154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Serum response factor (SRF) is required for expression of Myom1 in the heart; conditional cardiac SRF knockout powerfully attenuated Myom1 expression along with other myofibril proteins, blocking sarcomere formation and rhythmic beating.\",\n      \"method\": \"Conditional cardiac-specific SRF knockout mouse, SRF point mutants blocking cofactor interactions, viral rescue of SRF-null ES cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined sarcomere phenotype plus mechanistic rescue experiments, single lab\",\n      \"pmids\": [\"19004760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of muscleblind-like 1 (Mbnl1) in mice results in persistence of embryonic splice isoforms of Myom1 in cardiac tissue, associated with cardiac pathology including hypertrophy, fibrosis, and sudden death.\",\n      \"method\": \"Mbnl1 deletion mouse model (Mbnl1ΔE2/ΔE2), splicing analysis of cardiac RNAs including Myom1, cardiac phenotype characterization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Myom1 splicing change is one of many in a broad splicing regulator KO; no direct functional rescue or mechanistic follow-up specific to MYOM1\",\n      \"pmids\": [\"25761764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The SARS-CoV-2 papain-like protease (PLpro) was shown to cleave a predicted sequence in MYOM1 in an in vitro cleavage assay.\",\n      \"method\": \"In vitro protease cleavage assay using SARS-CoV-2 PLpro on predicted MYOM1 cleavage sequence\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro cleavage assay, no functional consequence established, single lab\",\n      \"pmids\": [\"36851756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-135a directly targets MYOM1 (confirmed by dual-luciferase assay), negatively regulating its expression in LPS-treated THP-1 cells; MYOM1 depletion reversed the protective effect of miR-135a inhibition on LPS-induced cell injury.\",\n      \"method\": \"Dual-luciferase reporter assay confirming miR-135a binding to MYOM1 3'UTR; qRT-PCR and western blot for MYOM1 expression; rescue experiments in LPS-treated THP-1 cells\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase assay plus rescue experiment, single lab, mechanistic context in immune cells not well established for this sarcomeric protein\",\n      \"pmids\": [\"35977075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Calpain activation mediates degradation of MYOM1 in vandetanib-treated cardiomyocytes; calpain inhibition rescued MYOM1 protein levels and preserved myofilament structure, while calpain1 overexpression aggravated loss of contractile proteins.\",\n      \"method\": \"Calpain inhibitor treatment and calpain1 overexpression/knockdown in cardiomyocytes treated with vandetanib; western blot quantification of MYOM1 protein levels; calcium imaging\",\n      \"journal\": \"European journal of pharmaceutical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, defined calpain–MYOM1 degradation axis with gain/loss of function, but no direct in vitro cleavage reconstitution or site identification\",\n      \"pmids\": [\"41765115\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYOM1 encodes myomesin-1, a structural M-band protein that cross-links myosin filaments in the sarcomere; it is transcriptionally regulated by SRF and undergoes MBNL1/CELF- and SRSF5-regulated alternative splicing during development, its localization and stability depend on ALPK3, it is subject to MuRF1-mediated ubiquitination and calpain-mediated degradation (both modifiable by H2S/S-sulfhydration and calpain inhibition respectively), and its loss in human cardiomyocytes impairs sarcomere assembly, contractility, and calcium homeostasis, causing myocardial atrophy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYOM1 encodes myomesin-1, a structural M-band component of the sarcomere that is required for sarcomere assembly, contractile function, and calcium homeostasis in human cardiomyocytes, where its loss recapitulates a myocardial atrophy phenotype [#0]. Myomesin-1 localizes to both the sarcomere M-band and the nuclear envelope together with the α-kinase ALPK3, which is required for correct myomesin localization and for regulating M-band protein turnover [#1]. Expression of MYOM1 depends on the transcription factor SRF, whose cardiac loss blocks myofibril formation and rhythmic beating [#6], while developmental embryonic-to-adult isoform switching is governed by alternative splicing controlled antagonistically by MBNL1–3 versus CELF1/CELF2 at exon 17a [#2] and by SRSF5, whose loss prevents completion of the isoform switch and causes ventricular noncompaction [#3]. Myomesin-1 protein abundance is set by regulated degradation: the E3 ubiquitin ligase MuRF1 binds MYOM1 and mediates its ubiquitination in catabolic muscle, an interaction reduced by H2S-driven S-sulfhydration of MuRF1 at Cys44 [#4]. Layer-specific MYOM1/MYOM2 M-band composition in extraocular muscle correlates with altered mechanical properties [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that muscle-type-specific M-band composition, including MYOM1 expression levels, tracks with distinct mechanical properties, linking myomesin content to sarcomere biomechanics.\",\n      \"evidence\": \"PCR, qPCR, immunohistochemistry, confocal and electron microscopy across rat extraocular muscle layers\",\n      \"pmids\": [\"17325154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanical predictions modeled, not directly measured\", \"No causal manipulation of MYOM1 levels\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified SRF as a transcriptional requirement for Myom1 expression, placing myomesin-1 downstream of the core cardiac myofibrillar gene program.\",\n      \"evidence\": \"Conditional cardiac SRF knockout mouse with cofactor-mutant and viral rescue experiments\",\n      \"pmids\": [\"19004760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SRF binding to the MYOM1 promoter not demonstrated\", \"Myom1 is one of many affected myofibrillar genes\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined MYOM1 exon 17a as an alternative-splicing target controlled by competing MBNL and CELF factors, explaining aberrant splicing in myotonic dystrophy via MBNL sequestration.\",\n      \"evidence\": \"Exon array of DM1 patient muscle plus MYOM1 minigene splicing assays in HEK293T with MBNL1-3/CELF1/CELF2\",\n      \"pmids\": [\"21794030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of exon 17a inclusion on myomesin-1 protein not established\", \"Minigene context may not reflect endogenous regulation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that loss of Mbnl1 in vivo causes persistence of embryonic Myom1 isoforms in heart, linking splicing dysregulation to cardiac pathology.\",\n      \"evidence\": \"Mbnl1 deletion mouse with cardiac RNA splicing analysis and phenotyping\",\n      \"pmids\": [\"25761764\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Myom1 splicing change is one of many in a broad regulator KO; no MYOM1-specific rescue\", \"Causal contribution of Myom1 mis-splicing to phenotype unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified MuRF1-mediated ubiquitination as a degradation pathway controlling MYOM1 abundance and showed it is reversible by H2S-driven S-sulfhydration of MuRF1.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, and S-sulfhydration site mapping in db/db mice and C2C12 cells\",\n      \"pmids\": [\"32633463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYOM1 ubiquitination site not mapped\", \"Established in skeletal/diabetic muscle; cardiac relevance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated by loss-of-function that myomesin-1 is required for sarcomere assembly, contractility, and calcium homeostasis in human cardiomyocytes, giving the gene a defined cellular phenotype.\",\n      \"evidence\": \"CRISPR/Cas9 MYOM1 knockout in hESC-derived cardiomyocytes with structural and functional readouts\",\n      \"pmids\": [\"33452765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of contractility and calcium defect not dissected\", \"Single-lab in vitro model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SRSF5 as the splicing factor driving the embryonic-to-adult Myom1 isoform switch, connecting incomplete switching to ventricular noncompaction.\",\n      \"evidence\": \"CRISPR-Cas9 Srsf5 knockout mice with Myom1 isoform and cardiac phenotype analysis\",\n      \"pmids\": [\"34622152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether arrested Myom1 switching alone drives noncompaction not isolated\", \"Other SRSF5 targets contribute\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed myomesin proteins downstream of ALPK3, showing ALPK3 co-localizes with MYOM1 at M-band and nuclear envelope and is required for its correct localization and M-band protein turnover.\",\n      \"evidence\": \"Co-localization in hiPSC-derived cardiomyocytes and patient tissue, ALPK3 LOF iPSC model, proteomics\",\n      \"pmids\": [\"36321451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ALPK3-MYOM1 physical interaction vs. indirect effect not resolved\", \"Kinase substrate relationship undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported miR-135a as a direct negative regulator of MYOM1 in an immune-cell injury context, an uncharacterized setting for this sarcomeric protein.\",\n      \"evidence\": \"Dual-luciferase 3'UTR reporter, qRT-PCR/western, and rescue in LPS-treated THP-1 cells\",\n      \"pmids\": [\"35977075\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Biological role of MYOM1 in non-muscle immune cells unexplained\", \"Single-lab reporter and rescue without orthogonal validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed in vitro that SARS-CoV-2 PLpro can cleave a predicted MYOM1 sequence, raising a candidate host-protein target during infection.\",\n      \"evidence\": \"In vitro protease cleavage assay on a predicted MYOM1 cleavage site\",\n      \"pmids\": [\"36851756\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of cleavage established\", \"Cleavage not demonstrated in cells\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a calpain-mediated degradation axis controlling MYOM1 protein levels in drug-induced cardiotoxicity, with calpain inhibition preserving myofilament structure.\",\n      \"evidence\": \"Calpain inhibitor and calpain1 gain/loss-of-function in vandetanib-treated cardiomyocytes with western blot and calcium imaging\",\n      \"pmids\": [\"41765115\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro cleavage reconstitution or site identification\", \"Direct vs. indirect calpain action not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How myomesin-1's M-band cross-linking activity mechanistically integrates with its transcriptional, splicing, and degradation control to determine sarcomere mechanics in human disease remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of MYOM1 in the human M-band lattice in the corpus\", \"No timeline-documented Mendelian disease mutation in MYOM1 itself\", \"Integration of regulatory inputs (SRF, splicing, MuRF1, calpain, ALPK3) into a unified control model untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"complexes\": [\"sarcomere M-band\"],\n    \"partners\": [\"MYOM2\", \"ALPK3\", \"MuRF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}