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Showing CSRP3 — MLP is a alias.

CSRP3

Cysteine and glycine-rich protein 3 · UniProt P50461

Length
194 aa
Mass
21.0 kDa
Annotated
2026-06-09
20 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CSRP3 (MLP) is a muscle-specific LIM-domain protein that acts as a structural and regulatory hub in cardiac and skeletal muscle, coordinating autophagy, myogenic differentiation, metabolic remodeling, and hypertrophic responses (PMID:27551448, PMID:35652451, PMID:41812695). In cardiomyocytes it is predominantly cytosolic rather than tightly anchored to sarcomeric structures, and at least one HCM-associated mutant form is destabilized in patient hearts (PMID:18505755). CSRP3 directly binds LC3 to promote autophagosome formation and sustain autophagic flux; its loss impairs autophagy, blocks myoblast differentiation, and sensitizes cells to apoptosis (PMID:27551448, PMID:31979369). During differentiation CSRP3 translocates to the nucleus and engages the myogenic transcription factors MyoD and MyoG to drive muscle development and injury repair (PMID:35652451), and it supports satellite cell differentiation by restraining TGF-β/Smad3 signaling (PMID:30930226). In skeletal muscle CSRP3 binds D-lactate dehydrogenase (LDHD) through a defined 33-amino-acid region to promote D-lactate metabolism, mitochondrial biogenesis, oxidative phosphorylation, and a shift toward oxidative myofibers, with in vivo knockdown compromising exercise performance (PMID:41812695). In the heart CSRP3 mediates hypertrophic responses, as silencing reverses and overexpression induces cardiomyocyte hypertrophy (PMID:30703746). Its expression is mechanically regulated, declining when mechanical loading is withdrawn (PMID:22282489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    Established that MLP is mainly cytosolic in cardiomyocytes rather than a rigidly sarcomere-anchored protein, and linked disease mutations to protein destabilization, reframing how its function and pathogenicity should be interpreted.

    Evidence Monoclonal antibody immunolocalization plus in vitro and in vivo mutant stability assays in cardiomyocytes

    PMID:18505755

    Open questions at the time
    • Does not define the cytosolic binding partners that retain MLP
    • Mechanistic basis of mutant destabilization not resolved at structural level
  2. 2012 Low

    Identified CSRP3 as a mechano-sensitive gene by showing its expression tracks mechanical loading, connecting it to load-dependent muscle adaptation.

    Evidence Microarray of polyribosomal fraction with RT-PCR and protein validation in rat wheel-lock model

    PMID:22282489

    Open questions at the time
    • Expression correlation only, no molecular mechanism of mechanotransduction
    • Does not show CSRP3 is causal in the adaptive response
  3. 2015 Medium

    Defined a direct CSRP3–LC3 interaction required for autophagosome formation and linked autophagy competence to myoblast differentiation and survival, placing CSRP3 in the autophagy machinery.

    Evidence Reciprocal co-IP, PLA, siRNA/overexpression with LC3-II, protein degradation, differentiation, and caspase/PARP readouts in C2C12 cells

    PMID:27551448

    Open questions at the time
    • LC3 binding interface on CSRP3 not mapped
    • Whether autophagy defect is the proximate cause of impaired differentiation not separated from other roles
  4. 2019 Medium

    Showed CSRP3 supports satellite cell differentiation by restraining the TGF-β/Smad3 axis, providing a signaling mechanism for its pro-differentiation effect.

    Evidence siRNA knockdown in primary chicken satellite cells with qPCR/western for TGF-β/Smad3 and myotube formation assay

    PMID:30930226

    Open questions at the time
    • No demonstrated direct interaction linking CSRP3 to TGF-β/Smad3 components
    • Whether Smad3 modulation is direct or downstream of autophagy/transcriptional roles unknown
  5. 2019 Medium

    Demonstrated CSRP3 is a causal mediator of cardiomyocyte hypertrophy, with loss reversing and gain inducing the hypertrophic phenotype.

    Evidence siRNA silencing and overexpression in neonatal rat ventricular cardiomyocytes under phenylephrine-induced hypertrophy

    PMID:30703746

    Open questions at the time
    • Downstream effectors of CSRP3-driven hypertrophy not identified
    • Relationship to its autophagy and metabolic roles not integrated
  6. 2020 Medium

    Replicated the CSRP3–LC3 autophagy mechanism in an independent species and showed autophagy activation rescues the apoptotic phenotype, strengthening the autophagy-promoting role.

    Evidence Co-IP, siRNA knockdown, autophagy/apoptosis markers, and autophagy activator rescue in chicken primary myoblasts

    PMID:31979369

    Open questions at the time
    • Binding region still unmapped
    • Does not address the cardiac context
  7. 2022 Medium

    Revealed a nuclear, transcriptional arm of CSRP3 function: stimulus-induced nuclear translocation and interaction with MyoD and MyoG to drive myogenesis and injury repair.

    Evidence Nuclear fractionation/imaging, co-IP with MyoD and MyoG, C2C12 differentiation, and mouse muscle injury model

    PMID:35652451

    Open questions at the time
    • Mechanism triggering nuclear translocation beyond vitamin C stimulus unclear
    • Whether CSRP3 directly modulates MyoD/MyoG target transcription not shown
  8. 2022 Low

    Provided a structural rationale for pathogenicity by showing the HCM/DCM L44P mutation destabilizes the LIM domain via disrupted hydrophobic packing, while a neutral substitution does not.

    Evidence In silico virtual mutagenesis and molecular dynamics simulations of the LIM domain

    PMID:35241752

    Open questions at the time
    • Purely computational with no experimental validation of predicted destabilization
    • Does not connect destabilization to a specific functional loss
  9. 2026 Medium

    Connected CSRP3 to skeletal muscle energy metabolism by mapping a 33-aa LDHD-binding region that drives D-lactate metabolism, mitochondrial biogenesis, oxidative fiber remodeling, and exercise capacity.

    Evidence Co-IP with domain mapping, AAV-mediated knockdown in mice, mitochondrial function and myofiber-type assays, exercise testing

    PMID:41812695

    Open questions at the time
    • How LDHD binding mechanistically alters mitochondrial biogenesis is not resolved
    • Integration with autophagic and transcriptional roles unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CSRP3 coordinates its distinct cytosolic (autophagy, metabolism), nuclear (myogenic transcription), and hypertrophy-modulating activities into a unified mechanosensing program remains unresolved.
  • No structure of CSRP3 bound to LC3, LDHD, or MyoD/MyoG
  • Signals partitioning CSRP3 between cytosol and nucleus not defined
  • Causal link between LIM-domain destabilization and specific functional losses not experimentally established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-9612973 Autophagy 2 R-HSA-1430728 Metabolism 1
Partners
LC3LDHDMYODMYOG

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 MLP (encoded by CSRP3) is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures, as demonstrated using a newly designed monoclonal antibody. At least one HCM-associated mutant form of MLP appears destabilized in the heart of HCM patients, based on in vitro and in vivo functional analyses. Monoclonal antibody immunolocalization, in vitro and in vivo functional analyses of mutant protein stability Human molecular genetics Medium 18505755
2015 MLP/CSRP3 interacts with LC3 (as shown by co-immunoprecipitation and proximity ligation assay) and is required for correct autophagosome formation and autophagic flux in C2C12 mouse myoblasts. MLP silencing decreases LC3-II staining, impairs degradation of long-lived proteins, impairs myoblast differentiation (reduced MyoD1, MyoG1, myosin heavy chain expression), and increases susceptibility to apoptosis (increased caspase-3 and PARP cleavage). Co-immunoprecipitation, proximity ligation assay (PLA), siRNA silencing and overexpression in C2C12 cells, LC3-II immunostaining, long-lived protein degradation assay, ultrastructural analysis, caspase/PARP cleavage assay Cell death discovery Medium 27551448
2019 Knockdown of CSRP3 in chicken satellite cells inhibits their differentiation into myotubes without affecting proliferation. The mechanism involves upregulation of TGF-β and Smad3 mRNA and protein, and increased phosphorylation of Smad3 during differentiation. siRNA knockdown in primary chicken satellite cells, qPCR and western blot for TGF-β/Smad3 pathway components, differentiation assay (myotube formation at 24/48/72 h) Gene Medium 30930226
2020 CSRP3 interacts with LC3 protein to promote autophagosome formation during autophagy in chicken primary myoblasts. CSRP3 silencing impairs autophagy (reduced ATG5, ATG7 mRNA, and LC3-II and Beclin-1 protein levels), increases apoptosis (elevated caspase-3 and caspase-9 cleavage), and these effects are alleviated by autophagy activation. siRNA knockdown in chicken primary myoblasts, co-immunoprecipitation (CSRP3–LC3 interaction), western blot and qPCR for autophagy markers, caspase cleavage assay, autophagy activator rescue experiment International journal of molecular sciences Medium 31979369
2022 CSRP3 promotes myoblast differentiation by undergoing nuclear translocation in response to vitamin C, after which it interacts with the myogenic transcription factors MyoD and MyoG to promote muscle development and muscle injury repair in mice. Cell and molecular biology, proteomics, nuclear fractionation/localization imaging, co-immunoprecipitation of CSRP3 with MyoD and MyoG, C2C12 differentiation assay, mouse muscle injury model Journal of agricultural and food chemistry Medium 35652451
2019 CSRP3 is a target of the polyphenol metabolite 4-methylcatechol sulfate in cardiomyocytes. siRNA silencing of CSRP3 reverses phenylephrine-induced cardiomyocyte hypertrophy, and CSRP3 overexpression induces hypertrophy, establishing CSRP3 as a mediator of cardiomyocyte hypertrophic responses. siRNA silencing and overexpression in neonatal rat ventricular cardiomyocytes, phenylephrine-induced hypertrophy model, proteomics identification, 4-methylcatechol sulfate treatment The Journal of nutritional biochemistry Medium 30703746
2022 Computational virtual mutagenesis and molecular dynamics simulations show that the HCM/DCM-associated L44P mutation in the LIM domain of CSRP3 destabilizes the domain by altering secondary structure and disrupting a hydrophobic interaction with Phenylalanine 35, whereas the neutral L44M substitution does not have this effect. In silico mutational landscape mapping, molecular dynamics (MD) simulations, sequence and structural analysis of LIM domains Scientific reports Low 35241752
2026 CSRP3 binds to D-lactate dehydrogenase (LDHD) via a specific 33-amino acid region, promoting D-lactate metabolism in skeletal muscle. This interaction regulates mitochondrial morphology, biogenesis, oxidative phosphorylation efficiency, and TCA cycle activity, driving skeletal muscle mitochondrial metabolic rewiring and fiber type remodeling toward oxidative (aerobic) myofibers. AAV-mediated CSRP3 knockdown perturbs mitochondrial energy metabolism, reduces oxidative fiber proportion, and compromises exercise performance. Co-immunoprecipitation (CSRP3–LDHD), domain mapping (33-aa region), AAV-mediated knockdown in live mice, mitochondrial function assays, myofiber type analysis, exercise performance testing Metabolism: clinical and experimental Medium 41812695
2012 Csrp3 mRNA and protein levels decline in rat skeletal muscle following removal of voluntary running (wheel-lock model), identifying CSRP3 as a mechano-sensitive gene whose expression is regulated by mechanical loading in skeletal muscle. Affymetrix microarray of polyribosomal fraction, RT-PCR verification, whole-tissue mRNA and protein quantification across multiple time points after wheel-lock Journal of applied physiology Low 22282489

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clinical and translational science 159 19412328
2008 Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Human molecular genetics 138 18505755
2019 Knockdown of CSRP3 inhibits differentiation of chicken satellite cells by promoting TGF-β/Smad3 signaling. Gene 37 30930226
2015 Muscle LIM protein/CSRP3: a mechanosensor with a role in autophagy. Cell death discovery 34 27551448
2009 Porcine CSRP3: polymorphism and association analyses with meat quality traits and comparative analyses with CSRP1 and CSRP2. Molecular biology reports 34 19634002
2020 The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy. International journal of molecular sciences 32 31979369
2019 CSRP3 mediates polyphenols-induced cardioprotection in hypertension. The Journal of nutritional biochemistry 18 30703746
2022 Vitamin C Promotes Muscle Development Mediated by the Interaction of CSRP3 with MyoD and MyoG. Journal of agricultural and food chemistry 17 35652451
2018 First identification of homozygous truncating CSRP3 variants in two unrelated cases with hypertrophic cardiomyopathy. Gene 17 30012424
2013 Expression, SNV identification, linkage disequilibrium, and combined genotype association analysis of the muscle-specific gene CSRP3 in Chinese cattle. Gene 17 24279998
2021 CSRP3, p.Arg122*, is responsible for hypertrophic cardiomyopathy in a Chinese family. The journal of gene medicine 15 34558151
2012 Early depression of Ankrd2 and Csrp3 mRNAs in the polyribosomal and whole tissue fractions in skeletal muscle with decreased voluntary running. Journal of applied physiology (Bethesda, Md. : 1985) 14 22282489
2022 LIM domain-wide comprehensive virtual mutagenesis provides structural rationale for cardiomyopathy mutations in CSRP3. Scientific reports 12 35241752
2020 Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy. Polish archives of internal medicine 12 31919335
2021 Effect of growth selection of broilers on breast muscle satellite cell function: Response of satellite cells to NOV, COMP, MYBP-C1, and CSRP3. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 6 33548540
2020 CRISPR/Cas9 mediated establishment of a human CSRP3 compound heterozygous knockout hESC line to model cardiomyopathy and heart failure. Stem cell research 5 33176267
2023 Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy. Molecular biology reports 4 36877346
2016 Molecular cloning, characterization and tissue specificity of the expression of the ovine CSRP2 and CSRP3 genes from Small-tail Han sheep (Ovis aries). Gene 4 26779824
2020 Discriminating aspects of global metabolism of neonatal cardiomyocytes from wild type and KO-CSRP3 rats using proton magnetic resonance spectroscopy of culture media samples. In vitro cellular & developmental biology. Animal 2 32914385
2026 CSRP3 promotes skeletal muscle remodeling toward aerobic metabolism and enhances exercise endurance through increasing LDHD activity. Metabolism: clinical and experimental 0 41812695

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