PXD076207

PXD076207 is an original dataset announced via ProteomeXchange.

Title	road therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy
Description	Myosin inhibitor mavacamten is the first targeted treatment available for hypertrophic cardiomyopathy (HCM), a disease caused by hundreds of genetic variants that affect mainly sarcomeric myosin and its negative regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here, we have examined whether the reported limited efficacy of mavacamten in a fraction of HCM patients can result from dissimilar HCM pathomechanisms triggered by different genetic variants, a scenario particularly relevant for MYBPC3-associated HCM. To this aim, we have generated knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which, different from patients who carry truncations in the protein, develop progressive pathogenic myocardial remodeling in the absence of alterations of cMyBP-C levels and localization. Mechanistically, mutation R502W reduces the binding affinity of cMyBP-C for myosin, increases Ca2+ sensitivity and promotes the ON structural state of myosin heads without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced. Despite these differences, we demonstrate that mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient, knock-out hearts, correlating with its ability to normalize the levels of ON myosins in R502W sarcomeres. These beneficial effects are accompanied by improved tolerance to exercise in R502W animals. In human engineered heart tissues carrying R502W, we show that mavacamten opposes hypercontractility induced by the mutation. Hence, in combination our results indicate that myosin inhibition is effective to treat HCM caused by both truncating and missense variants in MYBPC3 regardless of the primary pathomechanisms they elicit.
HostingRepository	PRIDE
AnnounceDate	2026-06-02
AnnouncementXML	Submission_2026-06-02_03:30:24.812.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Enrique Calvo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2026-03-26 14:52:28	ID requested
⏵ 1	2026-06-02 03:30:25	announced

Dataset with its publication pending

submitter keyword: hypertrophic cardiomyopathy, myosin inhibition

Enrique Calvo
contact affiliation	CNIC
contact email	ecalvo@cnic.es
lab head
Enrique Calvo
contact affiliation	CNIC
contact email	ecalvo@cnic.es
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD076207
     1. Label: PRIDE project
     2. Name: road therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy