{"gene":"CKM","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1991,"finding":"CK-M and CK-B mRNA levels are markedly decreased in the diabetic rat heart, and both are insulin-responsive: acute insulin injection increases CK-M mRNA ~1.6-fold and CK-B mRNA ~2.2-fold within 5 hours, with CK-M mRNA restored to normal within 12 h and CK-B within 48 h; chronic insulin therapy restored both to normal levels.","method":"Northern blot quantitation with specific cDNA probes in streptozotocin-diabetic rat hearts; acute and chronic insulin administration","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative Northern blot with specific probes, multiple time points and treatment conditions, single lab","pmids":["1887884"],"is_preprint":false},{"year":1991,"finding":"Sequencing of CKMM cDNA from a myotonic dystrophy (DM) patient revealed two novel polymorphisms but no translationally significant mutation, ruling out a coding-sequence defect in CKMM as a cause of DM.","method":"cDNA isolation and sequencing from skeletal muscle of a DM patient","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct cDNA sequencing, negative result rigorously established, single lab","pmids":["2016086"],"is_preprint":false},{"year":1987,"finding":"Accumulation of CK-MM (muscle-specific creatine kinase isoenzyme) is specifically and preferentially impaired in innervated, contracting cultured muscle fibers from Duchenne muscular dystrophy (DMD) patients compared to controls, while accumulation of other muscle-specific isozymes (glycogen phosphorylase, phosphoglycerate mutase, lactate dehydrogenase) is not significantly impaired.","method":"Long-term innervated contracting muscle fiber cultures from DMD patients and controls; CK-MM and other isozyme activity assays","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparison across multiple DMD and control patients, multiple isozymes as internal specificity controls, single lab","pmids":["3613854"],"is_preprint":false},{"year":1988,"finding":"Exercise-induced release into plasma is predominantly CK-MM (skeletal muscle isoform); in male rats CK-MM increased ~678% after treadmill running vs. ~114% in females, while CK-BB showed a small similar increase in both sexes (~35–41%), establishing sex-linked differences specifically in CK-MM leakage from skeletal muscle.","method":"Treadmill exercise in rats; plasma and tissue total CK activity and CK isoenzyme profile assays (including CK-MM and CK-BB); comparison between males and females","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct isoenzyme profiling in plasma and multiple muscle/tissue homogenates, sex-comparison with internal controls (CK-BB), single lab","pmids":["3174399"],"is_preprint":false},{"year":1989,"finding":"Following release from injured myocardium, the tissue isoform CK-MM3 is converted in the circulation to post-translational products MM2 and then MM1 (carboxy-terminal lysine cleavage by carboxypeptidase). The MM3/MM1 ratio peaks 2–6 hours after AMI onset, earlier than total CK or CK-MB, enabling early diagnosis; during successful reperfusion the MM3/MM1 ratio peaks earlier than without reperfusion.","method":"Serial blood sampling from AMI patients; anion-exchange liquid chromatography and high-voltage electrophoresis for CK-MM isoform quantitation; comparison of reperfused vs. non-reperfused patients","journal":"Clinics in laboratory medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clinical isoform kinetics with two orthogonal separation methods, multiple patient groups, single review/lab","pmids":["2686906"],"is_preprint":false},{"year":1987,"finding":"CK-MM isoform subtype analysis (MM3, MM2, MM1) provides earlier diagnosis of acute myocardial infarction (within first 3–9 h) than CK-MB; MM3 (tissue isoform) rises and peaks earlier than total CK or CK-MB after AMI. During successful thrombolytic reperfusion, the rate of rise of MM3 is more rapid and MM3/MM1 ratio peaks earlier than without reperfusion.","method":"Serial blood sampling at 3-h intervals in AMI and non-AMI patients; anion-exchange HPLC and modified high-voltage electrophoresis for CK-MM isoform subtypes; immunoprecipitation for CK-MB","journal":"Clinical chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal quantitation methods, controlled patient cohorts with and without reperfusion, single lab","pmids":["3815799"],"is_preprint":false},{"year":2006,"finding":"CK-MM autoantibodies are present in all human subjects tested (levels highly variable); they form immune complexes with CK-MM in plasma; the percentage of CK in immune complexes correlates with CK-MM autoantibody level at lower CK concentrations. Administration of CK-MM antibodies to mice reduced plasma CK activity following bolus CK injection by 11–32%, demonstrating that CK-MM autoantibodies modulate the rate of CK clearance from the circulation.","method":"ELISA for CK-MM autoantibodies in 25 human subjects; protein A-sepharose immune complex isolation; in vivo mouse bolus CK injection with and without CK-MM antibody administration","journal":"Muscle & nerve","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ELISA + immune complex pulldown + in vivo mouse experiment, three orthogonal approaches, single lab","pmids":["16810680"],"is_preprint":false},{"year":1995,"finding":"A patient with acute myocardial infarction showed no elevation of serum CK activity; CK-MM protein was absent from serum and myocardial tissue. Molecular analysis of cDNA and genomic DNA from the patient's myocardium revealed depressed CK-MM mRNA and a point mutation at codon 54 (Exon 2: GAC [Asp] → GGC [Gly]) on the beta-sheet of CK-MM, associated with CK-MM protein deficiency.","method":"Immunoassay for CK-MM protein in serum and tissue; cDNA and genomic DNA isolation and sequencing from myocardial tissue; mRNA quantitation","journal":"Rinsho byori. The Japanese journal of clinical pathology","confidence":"Low","confidence_rationale":"Tier 2 / Weak — single case, cDNA sequencing + protein immunoassay, no functional validation of the point mutation","pmids":["7884961"],"is_preprint":false},{"year":1991,"finding":"Monoclonal antibody-based immunoinhibition of CK-MM isoforms demonstrates that CK-MM3 (tissue isoform) is completely inhibited, MM2 is ~57% inhibited, and MM1 (serum isoform) is not inhibited. The tissue isoform is a metal-dependent enzyme (inhibited by EDTA and heat-labile). The MM3/MM1 ratio peaks ~2–6 h after AMI onset and a ratio >1.0 indicates pathological release from tissue.","method":"Immunoinhibition assay with monoclonal antibody; EDTA inhibition and heat lability tests; clinical serial sampling in AMI patients","journal":"Rinsho byori. The Japanese journal of clinical pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunoinhibition method, partial biochemical characterization (metal dependence), single lab/review","pmids":["1762189"],"is_preprint":false},{"year":2023,"finding":"CKM inhibits proliferation, promotes apoptosis, and promotes differentiation of chicken primary myoblasts (CPMs). Overexpression and RNA interference experiments showed these effects, and transcriptome sequencing of CKM-disrupted CPMs identified differentially expressed genes in myogenesis pathways, indicating CKM participates in regulation of skeletal muscle development.","method":"qPCR expression profiling; overexpression and RNAi knockdown in primary myoblasts; proliferation, apoptosis, and differentiation assays; transcriptome sequencing (RNA-seq) of CKM-disrupted CPMs","journal":"Animals : an open access journal from MDPI","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain/loss-of-function in primary cells with phenotypic readouts, single lab, chicken model only","pmids":["37508090"],"is_preprint":false},{"year":2017,"finding":"CKM Glu83Gly variant (rs11559024) is associated with ~18% lower baseline serum CK levels and ~24% lower CK variability/inducibility in carriers, indicating that this amino acid change affects constitutive CK protein levels or release from muscle; however, the variant is not associated with myalgia.","method":"Meta-analysis of longitudinal cohort (GoDARTS) and randomized clinical trial (JUPITER); genetic association with baseline CK, CK SD, and myalgia outcomes","journal":"Circulation. Cardiovascular genetics","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — genetic association study (no direct biochemical mechanism experiment), but replicated across two independent cohorts with specific phenotypic readout","pmids":["28790154"],"is_preprint":false}],"current_model":"CKM (muscle-type creatine kinase, CK-MM) is the muscle-specific isoenzyme that catalyzes reversible transfer of phosphate between creatine and ATP; it is released from injured skeletal and cardiac muscle as the MM homodimer, undergoes sequential carboxypeptidase-mediated post-translational cleavage in blood from the tissue isoform MM3 to MM2 to MM1, and its clearance is modulated by circulating CK-MM autoantibodies that form immune complexes; CK-MM mRNA expression is insulin-responsive and reduced in diabetic heart, while a Glu83Gly coding variant (rs11559024) lowers constitutive serum CK levels, and CKM loss-of-function in muscle cells inhibits proliferation and promotes differentiation."},"narrative":{"mechanistic_narrative":"CKM encodes the muscle-specific isoenzyme of creatine kinase (CK-MM), a muscle metabolic enzyme whose expression and release are tied to muscle integrity and energy metabolism [PMID:1887884, PMID:3613854]. Its mRNA is insulin-responsive: CK-M transcript levels fall markedly in diabetic rat heart and are restored toward normal by acute and chronic insulin administration [PMID:1887884]. CK-MM is a metal-dependent enzyme that, upon release from injured skeletal or cardiac muscle, circulates as the tissue isoform MM3 and undergoes sequential carboxy-terminal lysine cleavage by carboxypeptidase to MM2 and then the serum isoform MM1, with the MM3/MM1 ratio rising earlier than total CK or CK-MB and providing early detection of acute myocardial infarction and reperfusion [PMID:2686906, PMID:3815799, PMID:1762189]. Circulating CK-MM autoantibodies, present in all subjects tested, form immune complexes with CK-MM and modulate its clearance rate from plasma [PMID:16810680]. Within muscle cells, CKM regulates skeletal muscle development, inhibiting proliferation and promoting apoptosis and differentiation of primary myoblasts [PMID:37508090]. A CKM Glu83Gly coding variant (rs11559024) lowers baseline serum CK levels and CK inducibility, indicating that the amino acid sequence affects constitutive enzyme levels or release [PMID:28790154]. Beyond these findings, the catalytic mechanism, structure, and protein partners of CK-MM have not been characterized in the available corpus.","teleology":[{"year":1987,"claim":"Established that CK-MM accumulation is a specific defect in muscular dystrophy and that CK-MM subtype profiling can report on muscle pathology earlier than existing markers, motivating CK-MM as both a disease readout and a clinical tool.","evidence":"Innervated contracting DMD muscle fiber cultures with isozyme activity assays; serial AMI blood sampling with anion-exchange HPLC and electrophoresis for MM subtypes","pmids":["3613854","3815799"],"confidence":"Medium","gaps":["Mechanism by which CK-MM accumulation is selectively impaired in DMD not defined","No molecular explanation for the basis of MM3/MM1 conversion kinetics"]},{"year":1988,"claim":"Showed that exercise-induced plasma CK is predominantly the muscle MM isoform with sex-linked differences in leakage, linking serum CK levels directly to skeletal muscle release dynamics.","evidence":"Treadmill exercise in male and female rats with plasma and tissue CK isoenzyme profiling, CK-BB as internal control","pmids":["3174399"],"confidence":"Medium","gaps":["Molecular basis of sex difference in CK-MM leakage not established","Does not address membrane mechanism of release from muscle"]},{"year":1989,"claim":"Defined the post-translational processing pathway of circulating CK-MM (MM3→MM2→MM1 via carboxypeptidase) and its kinetic value for early AMI and reperfusion diagnosis.","evidence":"Serial AMI patient sampling with anion-exchange chromatography and high-voltage electrophoresis, reperfused vs non-reperfused comparison","pmids":["2686906"],"confidence":"Medium","gaps":["Identity and regulation of the responsible carboxypeptidase not pinned down here","Tissue vs circulating processing rates not separated mechanistically"]},{"year":1991,"claim":"Demonstrated CK-M mRNA is insulin-responsive, connecting CKM expression to metabolic/hormonal control in heart, and ruled out a CKM coding defect as a cause of myotonic dystrophy.","evidence":"Northern blot quantitation in streptozotocin-diabetic rat hearts with insulin treatment; cDNA sequencing from a DM patient; monoclonal antibody immunoinhibition with EDTA/heat lability tests","pmids":["1887884","2016086","1762189"],"confidence":"Medium","gaps":["Transcriptional mechanism of insulin responsiveness not defined","Metal-dependence of the tissue isoform only partially characterized"]},{"year":1995,"claim":"Linked a CK-MM coding point mutation (codon 54 Asp→Gly) to CK-MM protein deficiency, providing first genetic evidence that CKM sequence variation controls enzyme presence.","evidence":"Single AMI patient case with serum/tissue CK-MM immunoassay and cDNA/genomic DNA sequencing","pmids":["7884961"],"confidence":"Low","gaps":["Single case with no functional validation of the point mutation","Causal link between mutation and protein deficiency not established by reconstitution"]},{"year":2006,"claim":"Identified CK-MM autoantibodies as a universal modulator of CK-MM clearance, explaining inter-individual variability in circulating CK levels independent of muscle release.","evidence":"ELISA in 25 subjects, protein A-sepharose immune complex isolation, and in vivo mouse bolus CK injection with antibody administration","pmids":["16810680"],"confidence":"Medium","gaps":["Mechanism of antibody-mediated clearance (Fc receptor, organ site) not defined","Physiological/pathological relevance of autoantibody levels not established"]},{"year":2017,"claim":"Showed a common CKM coding variant (Glu83Gly) lowers baseline serum CK and its inducibility, tying genotype to constitutive enzyme level/release without a myalgia phenotype.","evidence":"Meta-analysis of GoDARTS cohort and JUPITER trial for genetic association with baseline CK, CK SD, and myalgia","pmids":["28790154"],"confidence":"Low","gaps":["Genetic association without a direct biochemical mechanism experiment","Whether the variant alters enzyme stability, activity, or release is unresolved"]},{"year":2023,"claim":"Provided functional evidence that CKM regulates myogenic cell fate, inhibiting proliferation and promoting differentiation, extending its role beyond a passive metabolic enzyme.","evidence":"Overexpression and RNAi in chicken primary myoblasts with proliferation/apoptosis/differentiation assays and transcriptome sequencing","pmids":["37508090"],"confidence":"Low","gaps":["Chicken model only, not confirmed in mammalian muscle","Molecular pathway linking CKM to myogenic gene expression not defined"]},{"year":null,"claim":"The catalytic mechanism, three-dimensional structure, direct protein partners, and the molecular basis by which CKM influences myoblast differentiation remain uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CK-MM in the timeline","No identified direct physical partners","Mechanism connecting enzyme function to muscle development unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[4,8]}],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06732","full_name":"Creatine kinase M-type","aliases":["Creatine kinase M chain","Creatine phosphokinase M-type","CPK-M","M-CK"],"length_aa":381,"mass_kda":43.1,"function":"Reversibly catalyzes the transfer of phosphate between ATP and various phosphogens (e.g. creatine phosphate). Creatine kinase isoenzymes play a central role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, brain and spermatozoa","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P06732/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CKM","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CKB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CKM","total_profiled":1310},"omim":[{"mim_id":"615671","title":"SET DOMAIN-CONTAINING PROTEIN 3; SETD3","url":"https://www.omim.org/entry/615671"},{"mim_id":"608099","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3; LGMDR3","url":"https://www.omim.org/entry/608099"},{"mim_id":"606009","title":"DOUBLE HOMEOBOX PROTEIN 4; DUX4","url":"https://www.omim.org/entry/606009"},{"mim_id":"605921","title":"STROMAL INTERACTION MOLECULE 1; STIM1","url":"https://www.omim.org/entry/605921"},{"mim_id":"604559","title":"PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB; PFHB1B","url":"https://www.omim.org/entry/604559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":68908.9},{"tissue":"tongue","ntpm":24326.4}],"url":"https://www.proteinatlas.org/search/CKM"},"hgnc":{"alias_symbol":[],"prev_symbol":["CKMM"]},"alphafold":{"accession":"P06732","domains":[{"cath_id":"1.10.135.10","chopping":"3-96","consensus_level":"high","plddt":95.9328,"start":3,"end":96},{"cath_id":"3.30.590.10","chopping":"111-368","consensus_level":"medium","plddt":94.9278,"start":111,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06732","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06732-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06732-F1-predicted_aligned_error_v6.png","plddt_mean":94.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CKM","jax_strain_url":"https://www.jax.org/strain/search?query=CKM"},"sequence":{"accession":"P06732","fasta_url":"https://rest.uniprot.org/uniprotkb/P06732.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06732/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06732"}},"corpus_meta":[{"pmid":"17478608","id":"PMC_17478608","title":"CK-MM and ACE genotypes and physiological prediction of the creatine kinase response to exercise.","date":"2007","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/17478608","citation_count":82,"is_preprint":false},{"pmid":"2309701","id":"PMC_2309701","title":"A long-range restriction map of the human chromosome 19q13 region: close physical linkage between CKMM and the ERCC1 and ERCC2 genes.","date":"1990","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2309701","citation_count":52,"is_preprint":false},{"pmid":"3174399","id":"PMC_3174399","title":"Creatine kinase isoenzyme profiles after exercise in the rat: sex-linked differences in leakage of CK-MM.","date":"1988","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/3174399","citation_count":51,"is_preprint":false},{"pmid":"3815799","id":"PMC_3815799","title":"Early diagnosis of acute myocardial infarction by rapid analysis of creatine kinase isoenzyme-3 (CK-MM) sub-types.","date":"1987","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3815799","citation_count":51,"is_preprint":false},{"pmid":"16037885","id":"PMC_16037885","title":"Is there an association between ACE and CKMM polymorphisms and cycling performance status during 3-week races?","date":"2005","source":"International journal of sports medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16037885","citation_count":50,"is_preprint":false},{"pmid":"2703233","id":"PMC_2703233","title":"Myotonic dystrophy is closely linked to the gene for muscle-type creatine kinase (CKMM).","date":"1989","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2703233","citation_count":49,"is_preprint":false},{"pmid":"21059062","id":"PMC_21059062","title":"Association of sequence variants in CKM (creatine kinase, muscle) and COX4I2 (cytochrome c oxidase, subunit 4, isoform 2) genes with racing performance in Thoroughbred horses.","date":"2010","source":"Equine veterinary journal. 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Comparison of five fixation methods and three immunohistochemical techniques.","date":"1985","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/3902962","citation_count":7,"is_preprint":false},{"pmid":"20157874","id":"PMC_20157874","title":"CK-MM gene polymorphism does not influence the blood CK activity levels after exhaustive eccentric exercise.","date":"2010","source":"International journal of sports medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20157874","citation_count":7,"is_preprint":false},{"pmid":"3613854","id":"PMC_3613854","title":"Accumulation of CK-MM is impaired in innervated and contracting cultured muscle fibers of Duchenne muscular dystrophy patients.","date":"1987","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/3613854","citation_count":7,"is_preprint":false},{"pmid":"28790154","id":"PMC_28790154","title":"CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia.","date":"2017","source":"Circulation. 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Acta Academiae Medicinae Sinicae","url":"https://pubmed.ncbi.nlm.nih.gov/1317271","citation_count":0,"is_preprint":false},{"pmid":"41204549","id":"PMC_41204549","title":"Red blood cell distribution width-to-albumin ratio is a risk factor for all-cause and cardiovascular mortality in patients with CKM stages 1 to 4: Evidence from the NHANES 2007 to 2016.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41204549","citation_count":0,"is_preprint":false},{"pmid":"41277678","id":"PMC_41277678","title":"Experiences of parents who receive a false-positive CK-MM screening for their newborn.","date":"2025","source":"Journal of genetic counseling","url":"https://pubmed.ncbi.nlm.nih.gov/41277678","citation_count":0,"is_preprint":false},{"pmid":"41913588","id":"PMC_41913588","title":"Social Isolation Trajectories Spanning Childhood to Adulthood and Mortality Risk in CKM Syndrome: Evidence From CHARLS.","date":"2026","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/41913588","citation_count":0,"is_preprint":false},{"pmid":"22505417","id":"PMC_22505417","title":"Crystallization and preliminary X-ray diffraction analysis of a novel wild-type blue fluorescent protein from Vibrio vulnificus CKM-1.","date":"2012","source":"Acta crystallographica. 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chronic insulin therapy restored both to normal levels.\",\n      \"method\": \"Northern blot quantitation with specific cDNA probes in streptozotocin-diabetic rat hearts; acute and chronic insulin administration\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative Northern blot with specific probes, multiple time points and treatment conditions, single lab\",\n      \"pmids\": [\"1887884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Sequencing of CKMM cDNA from a myotonic dystrophy (DM) patient revealed two novel polymorphisms but no translationally significant mutation, ruling out a coding-sequence defect in CKMM as a cause of DM.\",\n      \"method\": \"cDNA isolation and sequencing from skeletal muscle of a DM patient\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct cDNA sequencing, negative result rigorously established, single lab\",\n      \"pmids\": [\"2016086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Accumulation of CK-MM (muscle-specific creatine kinase isoenzyme) is specifically and preferentially impaired in innervated, contracting cultured muscle fibers from Duchenne muscular dystrophy (DMD) patients compared to controls, while accumulation of other muscle-specific isozymes (glycogen phosphorylase, phosphoglycerate mutase, lactate dehydrogenase) is not significantly impaired.\",\n      \"method\": \"Long-term innervated contracting muscle fiber cultures from DMD patients and controls; CK-MM and other isozyme activity assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparison across multiple DMD and control patients, multiple isozymes as internal specificity controls, single lab\",\n      \"pmids\": [\"3613854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Exercise-induced release into plasma is predominantly CK-MM (skeletal muscle isoform); in male rats CK-MM increased ~678% after treadmill running vs. ~114% in females, while CK-BB showed a small similar increase in both sexes (~35–41%), establishing sex-linked differences specifically in CK-MM leakage from skeletal muscle.\",\n      \"method\": \"Treadmill exercise in rats; plasma and tissue total CK activity and CK isoenzyme profile assays (including CK-MM and CK-BB); comparison between males and females\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct isoenzyme profiling in plasma and multiple muscle/tissue homogenates, sex-comparison with internal controls (CK-BB), single lab\",\n      \"pmids\": [\"3174399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"Following release from injured myocardium, the tissue isoform CK-MM3 is converted in the circulation to post-translational products MM2 and then MM1 (carboxy-terminal lysine cleavage by carboxypeptidase). The MM3/MM1 ratio peaks 2–6 hours after AMI onset, earlier than total CK or CK-MB, enabling early diagnosis; during successful reperfusion the MM3/MM1 ratio peaks earlier than without reperfusion.\",\n      \"method\": \"Serial blood sampling from AMI patients; anion-exchange liquid chromatography and high-voltage electrophoresis for CK-MM isoform quantitation; comparison of reperfused vs. non-reperfused patients\",\n      \"journal\": \"Clinics in laboratory medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clinical isoform kinetics with two orthogonal separation methods, multiple patient groups, single review/lab\",\n      \"pmids\": [\"2686906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"CK-MM isoform subtype analysis (MM3, MM2, MM1) provides earlier diagnosis of acute myocardial infarction (within first 3–9 h) than CK-MB; MM3 (tissue isoform) rises and peaks earlier than total CK or CK-MB after AMI. During successful thrombolytic reperfusion, the rate of rise of MM3 is more rapid and MM3/MM1 ratio peaks earlier than without reperfusion.\",\n      \"method\": \"Serial blood sampling at 3-h intervals in AMI and non-AMI patients; anion-exchange HPLC and modified high-voltage electrophoresis for CK-MM isoform subtypes; immunoprecipitation for CK-MB\",\n      \"journal\": \"Clinical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal quantitation methods, controlled patient cohorts with and without reperfusion, single lab\",\n      \"pmids\": [\"3815799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CK-MM autoantibodies are present in all human subjects tested (levels highly variable); they form immune complexes with CK-MM in plasma; the percentage of CK in immune complexes correlates with CK-MM autoantibody level at lower CK concentrations. Administration of CK-MM antibodies to mice reduced plasma CK activity following bolus CK injection by 11–32%, demonstrating that CK-MM autoantibodies modulate the rate of CK clearance from the circulation.\",\n      \"method\": \"ELISA for CK-MM autoantibodies in 25 human subjects; protein A-sepharose immune complex isolation; in vivo mouse bolus CK injection with and without CK-MM antibody administration\",\n      \"journal\": \"Muscle & nerve\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ELISA + immune complex pulldown + in vivo mouse experiment, three orthogonal approaches, single lab\",\n      \"pmids\": [\"16810680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A patient with acute myocardial infarction showed no elevation of serum CK activity; CK-MM protein was absent from serum and myocardial tissue. Molecular analysis of cDNA and genomic DNA from the patient's myocardium revealed depressed CK-MM mRNA and a point mutation at codon 54 (Exon 2: GAC [Asp] → GGC [Gly]) on the beta-sheet of CK-MM, associated with CK-MM protein deficiency.\",\n      \"method\": \"Immunoassay for CK-MM protein in serum and tissue; cDNA and genomic DNA isolation and sequencing from myocardial tissue; mRNA quantitation\",\n      \"journal\": \"Rinsho byori. The Japanese journal of clinical pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single case, cDNA sequencing + protein immunoassay, no functional validation of the point mutation\",\n      \"pmids\": [\"7884961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Monoclonal antibody-based immunoinhibition of CK-MM isoforms demonstrates that CK-MM3 (tissue isoform) is completely inhibited, MM2 is ~57% inhibited, and MM1 (serum isoform) is not inhibited. The tissue isoform is a metal-dependent enzyme (inhibited by EDTA and heat-labile). The MM3/MM1 ratio peaks ~2–6 h after AMI onset and a ratio >1.0 indicates pathological release from tissue.\",\n      \"method\": \"Immunoinhibition assay with monoclonal antibody; EDTA inhibition and heat lability tests; clinical serial sampling in AMI patients\",\n      \"journal\": \"Rinsho byori. The Japanese journal of clinical pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunoinhibition method, partial biochemical characterization (metal dependence), single lab/review\",\n      \"pmids\": [\"1762189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CKM inhibits proliferation, promotes apoptosis, and promotes differentiation of chicken primary myoblasts (CPMs). Overexpression and RNA interference experiments showed these effects, and transcriptome sequencing of CKM-disrupted CPMs identified differentially expressed genes in myogenesis pathways, indicating CKM participates in regulation of skeletal muscle development.\",\n      \"method\": \"qPCR expression profiling; overexpression and RNAi knockdown in primary myoblasts; proliferation, apoptosis, and differentiation assays; transcriptome sequencing (RNA-seq) of CKM-disrupted CPMs\",\n      \"journal\": \"Animals : an open access journal from MDPI\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain/loss-of-function in primary cells with phenotypic readouts, single lab, chicken model only\",\n      \"pmids\": [\"37508090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CKM Glu83Gly variant (rs11559024) is associated with ~18% lower baseline serum CK levels and ~24% lower CK variability/inducibility in carriers, indicating that this amino acid change affects constitutive CK protein levels or release from muscle; however, the variant is not associated with myalgia.\",\n      \"method\": \"Meta-analysis of longitudinal cohort (GoDARTS) and randomized clinical trial (JUPITER); genetic association with baseline CK, CK SD, and myalgia outcomes\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — genetic association study (no direct biochemical mechanism experiment), but replicated across two independent cohorts with specific phenotypic readout\",\n      \"pmids\": [\"28790154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CKM (muscle-type creatine kinase, CK-MM) is the muscle-specific isoenzyme that catalyzes reversible transfer of phosphate between creatine and ATP; it is released from injured skeletal and cardiac muscle as the MM homodimer, undergoes sequential carboxypeptidase-mediated post-translational cleavage in blood from the tissue isoform MM3 to MM2 to MM1, and its clearance is modulated by circulating CK-MM autoantibodies that form immune complexes; CK-MM mRNA expression is insulin-responsive and reduced in diabetic heart, while a Glu83Gly coding variant (rs11559024) lowers constitutive serum CK levels, and CKM loss-of-function in muscle cells inhibits proliferation and promotes differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CKM encodes the muscle-specific isoenzyme of creatine kinase (CK-MM), a muscle metabolic enzyme whose expression and release are tied to muscle integrity and energy metabolism [#0, #2]. Its mRNA is insulin-responsive: CK-M transcript levels fall markedly in diabetic rat heart and are restored toward normal by acute and chronic insulin administration [#0]. CK-MM is a metal-dependent enzyme that, upon release from injured skeletal or cardiac muscle, circulates as the tissue isoform MM3 and undergoes sequential carboxy-terminal lysine cleavage by carboxypeptidase to MM2 and then the serum isoform MM1, with the MM3/MM1 ratio rising earlier than total CK or CK-MB and providing early detection of acute myocardial infarction and reperfusion [#4, #5, #8]. Circulating CK-MM autoantibodies, present in all subjects tested, form immune complexes with CK-MM and modulate its clearance rate from plasma [#6]. Within muscle cells, CKM regulates skeletal muscle development, inhibiting proliferation and promoting apoptosis and differentiation of primary myoblasts [#9]. A CKM Glu83Gly coding variant (rs11559024) lowers baseline serum CK levels and CK inducibility, indicating that the amino acid sequence affects constitutive enzyme levels or release [#10]. Beyond these findings, the catalytic mechanism, structure, and protein partners of CK-MM have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Established that CK-MM accumulation is a specific defect in muscular dystrophy and that CK-MM subtype profiling can report on muscle pathology earlier than existing markers, motivating CK-MM as both a disease readout and a clinical tool.\",\n      \"evidence\": \"Innervated contracting DMD muscle fiber cultures with isozyme activity assays; serial AMI blood sampling with anion-exchange HPLC and electrophoresis for MM subtypes\",\n      \"pmids\": [\"3613854\", \"3815799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CK-MM accumulation is selectively impaired in DMD not defined\",\n        \"No molecular explanation for the basis of MM3/MM1 conversion kinetics\"\n      ]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Showed that exercise-induced plasma CK is predominantly the muscle MM isoform with sex-linked differences in leakage, linking serum CK levels directly to skeletal muscle release dynamics.\",\n      \"evidence\": \"Treadmill exercise in male and female rats with plasma and tissue CK isoenzyme profiling, CK-BB as internal control\",\n      \"pmids\": [\"3174399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of sex difference in CK-MM leakage not established\",\n        \"Does not address membrane mechanism of release from muscle\"\n      ]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defined the post-translational processing pathway of circulating CK-MM (MM3→MM2→MM1 via carboxypeptidase) and its kinetic value for early AMI and reperfusion diagnosis.\",\n      \"evidence\": \"Serial AMI patient sampling with anion-exchange chromatography and high-voltage electrophoresis, reperfused vs non-reperfused comparison\",\n      \"pmids\": [\"2686906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity and regulation of the responsible carboxypeptidase not pinned down here\",\n        \"Tissue vs circulating processing rates not separated mechanistically\"\n      ]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstrated CK-M mRNA is insulin-responsive, connecting CKM expression to metabolic/hormonal control in heart, and ruled out a CKM coding defect as a cause of myotonic dystrophy.\",\n      \"evidence\": \"Northern blot quantitation in streptozotocin-diabetic rat hearts with insulin treatment; cDNA sequencing from a DM patient; monoclonal antibody immunoinhibition with EDTA/heat lability tests\",\n      \"pmids\": [\"1887884\", \"2016086\", \"1762189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transcriptional mechanism of insulin responsiveness not defined\",\n        \"Metal-dependence of the tissue isoform only partially characterized\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Linked a CK-MM coding point mutation (codon 54 Asp→Gly) to CK-MM protein deficiency, providing first genetic evidence that CKM sequence variation controls enzyme presence.\",\n      \"evidence\": \"Single AMI patient case with serum/tissue CK-MM immunoassay and cDNA/genomic DNA sequencing\",\n      \"pmids\": [\"7884961\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single case with no functional validation of the point mutation\",\n        \"Causal link between mutation and protein deficiency not established by reconstitution\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified CK-MM autoantibodies as a universal modulator of CK-MM clearance, explaining inter-individual variability in circulating CK levels independent of muscle release.\",\n      \"evidence\": \"ELISA in 25 subjects, protein A-sepharose immune complex isolation, and in vivo mouse bolus CK injection with antibody administration\",\n      \"pmids\": [\"16810680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of antibody-mediated clearance (Fc receptor, organ site) not defined\",\n        \"Physiological/pathological relevance of autoantibody levels not established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed a common CKM coding variant (Glu83Gly) lowers baseline serum CK and its inducibility, tying genotype to constitutive enzyme level/release without a myalgia phenotype.\",\n      \"evidence\": \"Meta-analysis of GoDARTS cohort and JUPITER trial for genetic association with baseline CK, CK SD, and myalgia\",\n      \"pmids\": [\"28790154\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Genetic association without a direct biochemical mechanism experiment\",\n        \"Whether the variant alters enzyme stability, activity, or release is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided functional evidence that CKM regulates myogenic cell fate, inhibiting proliferation and promoting differentiation, extending its role beyond a passive metabolic enzyme.\",\n      \"evidence\": \"Overexpression and RNAi in chicken primary myoblasts with proliferation/apoptosis/differentiation assays and transcriptome sequencing\",\n      \"pmids\": [\"37508090\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Chicken model only, not confirmed in mammalian muscle\",\n        \"Molecular pathway linking CKM to myogenic gene expression not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic mechanism, three-dimensional structure, direct protein partners, and the molecular basis by which CKM influences myoblast differentiation remain uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CK-MM in the timeline\",\n        \"No identified direct physical partners\",\n        \"Mechanism connecting enzyme function to muscle development unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}