Affinage

MYOT

Myotilin · UniProt Q9UBF9

Length
498 aa
Mass
55.4 kDa
Annotated
2026-06-10
22 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Myotilin is a Z-disc protein of skeletal muscle that directly binds and cross-links F-actin and protects filaments from depolymerization, thereby organizing the contractile sarcomeric apparatus (PMID:12499399). Its actin-bundling activity depends on homodimerization mediated by the C-terminal half of the protein, while the N-terminal region directs the actin engagement and is required for proper sarcomeric architecture (PMID:12499399, PMID:37553249). Pathogenic missense mutations disrupt these activities: a mutation in the second Ig-like domain impairs homodimerization and weakens binding to alpha-actinin (PMID:19458539), and disease-associated mutants drive progressive myofibrillar pathology with Z-disc streaming and plaque-like protein aggregates that reduce contractile force (PMID:16801328, PMID:37511242). Aggregate burden scales with total myotilin protein level and is causally linked to muscle weakness, since increasing wild-type myotilin worsens aggregation (PMID:18335471) while silencing mutant myotilin reduces aggregates and restores force (PMID:24781192). These aggregates are cleared by the BAG3-mediated autophagy-lysosome pathway, and boosting BAG3 normalizes autophagy and reduces aggregate load in disease models (PMID:42137292). Mutant myotilin underlies dominant myofibrillar/limb-girdle muscular dystrophy phenotypes, as demonstrated by transgenic and patient-derived models (PMID:16801328, PMID:19458539).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2003 High

    Established the core biochemical function of myotilin: whether it acts on the actin cytoskeleton was unknown, and reconstitution showed it directly binds, cross-links, and stabilizes F-actin in a dimerization-dependent manner.

    Evidence In vitro F-actin binding/cross-linking and Latrunculin A disassembly assays with domain-deletion mutagenesis and cellular overexpression

    PMID:12499399

    Open questions at the time
    • Did not define the precise actin-binding residues within the N-terminus
    • Endogenous stoichiometry with alpha-actinin and filamin C at the native Z-disc not resolved
  2. 2003 Medium

    Asked whether myotilin participates in human muscle pathology beyond its dystrophy associations; immunostaining placed it as a structural constituent of nemaline rods and central core lesions.

    Evidence Immunohistochemistry and Western blot of nemaline myopathy and central core disease biopsies

    PMID:12899871

    Open questions at the time
    • Identity of the ~75 kDa modified species not determined
    • Whether myotilin accumulation is causal or secondary to rod/core formation unresolved
  3. 2006 High

    Tested whether a disease mutation is sufficient to cause myopathy in vivo; transgenic mutant myotilin reproduced progressive myofibrillar aggregate pathology with measurable loss of contractile force.

    Evidence Three transgenic mouse lines expressing T57I myotilin with histology, immunolocalization, and isometric force physiology

    PMID:16801328

    Open questions at the time
    • Molecular mechanism linking aggregates to force loss not dissected
    • Did not establish whether aggregates are toxic per se or sequester essential partners
  4. 2008 Medium

    Addressed whether myotilin abundance modulates disease; genetic epistasis showed that adding wild-type protein accelerates and worsens aggregation, implicating total protein dosage in pathology.

    Evidence Double-transgenic cross of wild-type and T57I mice with histological aggregation analysis

    PMID:18335471

    Open questions at the time
    • Did not separate gene dosage from mutant-specific seeding effects
    • No functional force readout in the double-transgenic
  5. 2009 Medium

    Defined the molecular consequence of an Ig-domain mutation; it impairs homodimerization and reduces alpha-actinin interaction, connecting loss of normal binding activities to disease.

    Evidence Yeast two-hybrid and reciprocal immunoprecipitation of patient muscle with monomer/dimer quantification

    PMID:19458539

    Open questions at the time
    • Did not link the dimerization defect directly to aggregate seeding in vivo
    • Effect on actin-bundling activity not measured
  6. 2014 Medium

    Tested causality between aggregate burden and dysfunction; silencing mutant myotilin reduced aggregates and improved force, establishing aggregates as a driver of contractile failure and a therapeutic target.

    Evidence AAV6-delivered miMYOT RNAi in TgT57I mice with mRNA/protein knockdown, aggregate quantification, and force measurement

    PMID:24781192

    Open questions at the time
    • Long-term durability of knockdown not assessed
    • Whether residual soluble mutant retains dominant effects unresolved
  7. 2023 Medium

    Extended causality to additional mutations and a vertebrate model and assigned a structural role to the N-terminus; mutant MYOT in zebrafish caused sarcomeric disorganization, I-band widening, aggregates, and motor impairment.

    Evidence Zebrafish embryo injection of mutant human MYOT RNA/plasmid (p.Ser95Ile; Tyr4-His9 deletion) with microscopy, motor assays, and molecular modeling

    PMID:37511242 PMID:37553249

    Open questions at the time
    • Modeling of N-terminal interactions not experimentally validated
    • Single-lab zebrafish readouts not yet confirmed in mammalian models
  8. 2023 Low

    Probed whether myotilin influences proteostasis machinery; knockdown reduced autophagy markers and flux, suggesting a role in supporting autophagy in skeletal muscle cells.

    Evidence siRNA knockdown of MYOT in human skeletal muscle cells with autophagy marker Western blots, LC3B reporter imaging, and MDC staining

    PMID:36776921

    Open questions at the time
    • No rescue experiment to confirm specificity; correlative only
    • Direction of causality between myotilin and autophagy not established
    • Mechanism connecting myotilin to ATG5/ATG7 expression unknown
  9. 2026 Medium

    Identified the clearance route for myotilin aggregates; boosting BAG3 reduced aggregate burden and normalized autophagy, placing aggregate disposal in the BAG3-mediated autophagy-lysosome pathway under proteasome overload.

    Evidence Systemic AAV-hBAG3 in TgT57I mice with rotarod, treadmill, grip, and tetanic force measures, aggregate histology, and autophagy Western blots

    PMID:42137292

    Open questions at the time
    • Direct physical handoff of myotilin to BAG3 not demonstrated
    • Relative contributions of proteasomal vs. autophagic clearance not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the homodimerization/alpha-actinin-binding defects mechanistically initiate aggregate seeding, and whether myotilin's reported role in supporting autophagy is direct, remain unresolved.
  • No structural model of mutant-driven oligomerization validated experimentally
  • Direct molecular link between myotilin and the autophagy machinery undefined
  • Native quaternary organization of myotilin with alpha-actinin and filamin C at the Z-disc not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-397014 Muscle contraction 2 R-HSA-9612973 Autophagy 1
Partners
ACTA1ACTN2BAG3
Complex memberships
Z-disc

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Myotilin directly binds F-actin, cross-links actin filaments alone or in concert with alpha-actinin, and prevents filament disassembly induced by Latrunculin A. Myotilin forms dimers via its carboxy-terminal half, which is necessary for actin-bundling activity. Overexpression of full-length myotilin (but not the carboxy-terminal half alone) induces thick actin cables in non-muscle cells, and expression of truncated myotilin fragments (but not wild-type) in differentiating myocytes causes myofibril disarray. In vitro F-actin binding and cross-linking assays, Latrunculin A filament disassembly assay, overexpression in non-muscle cells and differentiating myocytes, domain-deletion mutagenesis Human molecular genetics High 12499399
2003 Myotilin is a core structural component of nemaline rods and central core lesions, as shown by prominent myotilin immunostaining in all examined cases of nemaline myopathy and central core disease. An upregulated ~75 kDa myotilin immunoreactive band was detected in nemaline myopathy muscle, suggesting post-translational modification of myotilin in disease. Immunohistochemistry of patient muscle biopsies, Western blot analysis Neuromuscular disorders : NMD Medium 12899871
2006 Transgenic mice expressing mutant myotilin (T57I) develop progressive myofibrillar pathology including Z-disc streaming, vacuolization, and plaque-like aggregates. Mutant myotilin localizes to the Z-disc and populates aggregates along with other Z-disc proteins. EDL muscles of transgenic mice show significantly reduced maximum specific isometric force, establishing that myotilin mutations promote aggregate-dependent contractile dysfunction. Transgenic mouse model with human skeletal actin promoter-driven T57I myotilin; histology, immunolocalization, whole-muscle physiological force measurements Human molecular genetics High 16801328
2009 A mutation in the second Ig-like domain of myotilin (Exon 9) impairs myotilin homodimerization and reduces interaction between myotilin and alpha-actinin. The myotilin monomer was increased and the homodimeric band decreased in patient muscle. Functional analysis confirmed the homodimerization defect and altered alpha-actinin binding. Yeast two-hybrid system for interaction assays, immunoprecipitation of patient and control muscle lysates, immunoblot quantification of monomer vs. dimer bands Journal of neuropathology and experimental neurology Medium 19458539
2008 Overexpression of wild-type myotilin in the LGMD1A (T57I) mouse model enhanced muscle degeneration, increased myofibrillar aggregation, and caused earlier onset of aggregation compared to single-transgenic mutant mice, indicating that total myotilin protein level contributes to aggregate-dependent pathology. Genetic cross of wild-type and mutant (T57I) transgenic mice; histological analysis of myofibrillar aggregation Muscle & nerve Medium 18335471
2014 AAV6-delivered microRNA targeting mutant myotilin (miMYOT) significantly reduced mutant myotilin mRNA and soluble protein, decreased intramuscular protein aggregate deposition, increased muscle weight, and improved specific force in the gastrocnemius of LGMD1A (TgT57I) mice, demonstrating that myotilin aggregate burden is causally linked to contractile dysfunction. AAV6-mediated RNAi gene silencing in vivo; qRT-PCR and Western blot for mRNA/protein knockdown; histological aggregate quantification; muscle force measurements Molecular therapy. Nucleic acids Medium 24781192
2023 Injection of mutated human MYOT RNA (p.Ser95Ile) or plasmid carrying mutated MYOT cDNA into zebrafish embryos caused myopathic phenotype including sarcomeric disorganization, widening of the I-band, protein aggregate formation, and severe motor impairment, demonstrating that pathogenic myotilin mutations are sufficient to cause structural and functional skeletal muscle defects in vivo. Zebrafish embryo injection of wildtype vs. mutant human MYOT RNA/plasmid; muscle structure assessment by electron and fluorescence microscopy; motor behavior assay International journal of molecular sciences Medium 37511242
2023 A heterozygous in-frame deletion of residues Tyr4–His9 in myotilin caused early-adult onset distal myopathy with sarcomeric disorganization and I-band widening in zebrafish, and molecular modeling indicated these residues participate in local interactions within the N-terminal domain, supporting a structural role for the myotilin N-terminus in sarcomeric organization. Zebrafish embryo injection of mutated human MYOT RNA/plasmid; structural assessment of muscle by microscopy; molecular modeling of full-length myotilin protein Clinical genetics Medium 37553249
2023 Knockdown of MYOT in human skeletal muscle cells (HSkMCs) by siRNA decreased expression of p62 and LC3B-II, inhibited autophagic flux (assessed by mCherry-GFP-LC3B and MDC staining), and downregulated ATG7 and ATG5, indicating that myotilin is required for normal autophagy in human skeletal muscle cells. siRNA knockdown of MYOT in HSkMCs; Western blot for autophagy markers (p62, LC3B-II, ATG7, ATG5); immunofluorescence with Ad-mCherry-GFP-LC3B; MDC staining; pharmacological autophagy induction/inhibition Disease markers Low 36776921
2026 In LGMD1A (TgT57I) mice, AAV-mediated overexpression of BAG3 reduced myotilin aggregate burden, normalized autophagy levels, and restored the endogenous Bag1/Bag3 ratio, establishing that myotilin aggregates are cleared via the BAG3-mediated autophagy-lysosome pathway when the ubiquitin-proteasome system is overloaded. Systemic AAV delivery of hBAG3 in TgT57I mice; rotarod, treadmill, grip strength, and tetanic force measurements; histological aggregate quantification; Western blot for autophagy markers Molecular therapy. Advances Medium 42137292

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Human molecular genetics 126 12499399
2002 myotilin Mutation found in second pedigree with LGMD1A. American journal of human genetics 64 12428213
2006 Transgenic mice expressing the myotilin T57I mutation unite the pathology associated with LGMD1A and MFM. Human molecular genetics 36 16801328
2003 Beyond LGMD1A: myotilin is a component of central core lesions and nemaline rods. Neuromuscular disorders : NMD 32 12899871
1994 Development of a microsatellite genetic map spanning 5q31-q33 and subsequent placement of the LGMD1A locus between D5S178 and IL9. Neuromuscular disorders : NMD 28 7881291
2011 A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A). Journal of neurology 21 21336781
2009 Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient. Journal of neuropathology and experimental neurology 18 19458539
1999 TTID: A novel gene at 5q31 encoding a protein with titin-like features. Genomics 17 10486214
1998 Use of a CEPH meiotic breakpoint panel to refine the locus of limb-girdle muscular dystrophy type 1A (LGMD1A) to a 2-Mb interval on 5q31. Genomics 17 9828127
2014 RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. Molecular therapy. Nucleic acids 14 24781192
2017 MicroRNA-17-3p promotes keratinocyte cells growth and metastasis via targeting MYOT and regulating Notch1/NF-κB pathways. Die Pharmazie 13 29441982
1999 A radiation hybrid breakpoint map of the acute myeloid leukemia (AML) and limb-girdle muscular dystrophy 1A (LGMD1A) regions of chromosome 5q31 localizing 122 expressed sequences. Genomics 13 10191080
2008 Myotilin overexpression enhances myopathology in the LGMD1A mouse model. Muscle & nerve 10 18335471
2023 A novel in-frame deletion in MYOT causes an early adult onset distal myopathy. Clinical genetics 5 37553249
2023 Human Mutated MYOT and CRYAB Genes Cause a Myopathic Phenotype in Zebrafish. International journal of molecular sciences 4 37511242
2023 Silencing MYOT Expression May Inhibit Autophagy in Human Skeletal Muscle Cells. Disease markers 3 36776921
2020 Multisystem Myotilinopathy, including Myopathy and Left Ventricular Noncompaction, due to the MYOT Variant c.179C>T. Case reports in cardiology 2 32509353
2012 Molecular characterization, expression analysis and association study with meat quality traits of porcine TTID gene. Molecular biology reports 2 23096086
2024 Exploration of the genetic influence of MYOT and MB genes on the plumage coloration of Muscovy ducks. Open life sciences 1 38585635
2026 Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A. Molecular therapy. Advances 0 42137292
2026 MYOT-related myofibrillar myopathy presenting with normal creatine kinase and electromyography: importance of early genetic testing. BMJ case reports 0 42191229
2014 Transcriptional analysis of the porcine TTID gene and association of different TTID genotypes with carcass traits. Genetics and molecular research : GMR 0 24634176

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