Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorTOEPFER, Christopher N.
dc.contributor.authorGARFINKEL, Amanda C.
dc.contributor.authorVENTURINI, Gabriela
dc.contributor.authorWAKIMOTO, Hiroko
dc.contributor.authorREPETTI, Giuliana
dc.contributor.authorALAMO, Lorenzo
dc.contributor.authorSHARMA, Arun
dc.contributor.authorAGARWAL, Radhika
dc.contributor.authorEWOLDT, Jourdan F.
dc.contributor.authorCLOONAN, Paige
dc.contributor.authorLETENDRE, Justin
dc.contributor.authorLUN, Mingyue
dc.contributor.authorOLIVOTTO, Iacopo
dc.contributor.authorCOLAN, Steve
dc.contributor.authorASHLEY, Euan
dc.contributor.authorJACOBY, Daniel
dc.contributor.authorMICHELS, Michelle
dc.contributor.authorREDWOOD, Charles S.
dc.contributor.authorWATKINS, Hugh C.
dc.contributor.authorDAY, Sharlene M.
dc.contributor.authorSTAPLES, James F.
dc.contributor.authorPADRON, Raul
dc.contributor.authorCHOPRA, Anant
dc.contributor.authorHO, Carolyn Y.
dc.contributor.authorCHEN, Christopher S.
dc.contributor.authorPEREIRA, Alexandre C.
dc.contributor.authorSEIDMAN, Jonathan G.
dc.contributor.authorSEIDMAN, Christine E.
dc.date.accessioned2020-06-01T15:01:34Z
dc.date.available2020-06-01T15:01:34Z
dc.date.issued2020
dc.description.abstractBackground: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. Methods: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. Results: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. Conclusions: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM.eng
dc.description.indexMEDLINEeng
dc.description.sponsorshipWellcome TrustWellcome Trust [206466/Z/17/Z]
dc.description.sponsorshipSarnoff Foundation
dc.description.sponsorshipEngineering Research Centers Program of the National Science FoundationNational Science Foundation (NSF) [EEC-1647837]
dc.description.sponsorshipMyoKardia Inc
dc.description.sponsorshipItalian Ministry of HealthMinistry of Health, Italy [RF-2013-02356787, NET-2011-02347173]
dc.description.sponsorshipFAS-Salute 2014
dc.description.sponsorshipRegione ToscanaRegione Toscana
dc.description.sponsorshipTaubman Medical Institute
dc.description.sponsorshipBritish Heart FoundationBritish Heart Foundation [RG/12/16/29939]
dc.description.sponsorshipBritish Heart Foundation Centre of Research Excellence (Oxford)
dc.description.sponsorshipFondation LeducqLeducq Foundation
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1P50HL112349, 1U01HL117006, HL11572784, U01HL098166, 5R01HL080494, 5R01HL084553]
dc.description.sponsorshipHoward Hughes Medical InstituteHoward Hughes Medical Institute
dc.description.sponsorshipSato o Paulo Research Foundation [2017/20593-7]
dc.description.sponsorshipAmerican Heart AssociationAmerican Heart Association
dc.identifier.citationCIRCULATION, v.141, n.10, p.828-842, 2020
dc.identifier.doi10.1161/CIRCULATIONAHA.119.042339
dc.identifier.eissn1524-4539
dc.identifier.issn0009-7322
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/36238
dc.language.isoeng
dc.publisherLIPPINCOTT WILLIAMS & WILKINSeng
dc.relation.ispartofCirculation
dc.rightsopenAccesseng
dc.rights.holderCopyright LIPPINCOTT WILLIAMS & WILKINSeng
dc.subjectcardiomyopathyeng
dc.subjecthypertrophiceng
dc.subjectcardiovascular physiological phenomenaeng
dc.subjectmyosinseng
dc.subjectsarcomereseng
dc.subject.otherbeta-cardiac myosineng
dc.subject.otherheart-failureeng
dc.subject.otherbindingeng
dc.subject.otherphosphorylationeng
dc.subject.othermutationseng
dc.subject.otherdiseaseeng
dc.subject.otheratpeng
dc.subject.othermechanismseng
dc.subject.othergenotypeeng
dc.subject.otheralterseng
dc.subject.wosCardiac & Cardiovascular Systemseng
dc.subject.wosPeripheral Vascular Diseaseeng
dc.titleMyosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathyeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryVenezuela
hcfmusp.affiliation.countryHolanda
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryItália
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisove
hcfmusp.affiliation.countryisoit
hcfmusp.affiliation.countryisonl
hcfmusp.affiliation.countryisoca
hcfmusp.author.externalTOEPFER, Christopher N.:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA; Univ Oxford, Radcliffe Dept Med, Cardiovasc Med, Oxford, England; Univ Oxford, Wellcome Ctr Human Genet, Oxford, England
hcfmusp.author.externalGARFINKEL, Amanda C.:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalWAKIMOTO, Hiroko:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalREPETTI, Giuliana:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalALAMO, Lorenzo:IVIC, Ctr Biol Estruct, Caracas, Venezuela
hcfmusp.author.externalSHARMA, Arun:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalAGARWAL, Radhika:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalEWOLDT, Jourdan F.:Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
hcfmusp.author.externalCLOONAN, Paige:Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
hcfmusp.author.externalLETENDRE, Justin:Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
hcfmusp.author.externalLUN, Mingyue:Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA
hcfmusp.author.externalOLIVOTTO, Iacopo:Careggi Univ Hosp, Cardiomyopathy Unit, Florence, Italy; Careggi Univ Hosp, Genet Unit, Florence, Italy
hcfmusp.author.externalCOLAN, Steve:Boston Childrens Hosp, Dept Cardiol, Boston, MA USA
hcfmusp.author.externalASHLEY, Euan:Stanford Univ, Ctr Inherited Cardiovasc Dis, Stanford, CA 94305 USA
hcfmusp.author.externalJACOBY, Daniel:Yale Sch Med, Dept Internal Med, Sect Cardiovasc Dis, New Haven, CT USA
hcfmusp.author.externalMICHELS, Michelle:Erasmus MC, Dept Cardiol, Thorax Ctr, Rotterdam, Netherlands
hcfmusp.author.externalREDWOOD, Charles S.:Univ Oxford, Radcliffe Dept Med, Cardiovasc Med, Oxford, England
hcfmusp.author.externalWATKINS, Hugh C.:Univ Oxford, Radcliffe Dept Med, Cardiovasc Med, Oxford, England; Univ Oxford, Wellcome Ctr Human Genet, Oxford, England
hcfmusp.author.externalDAY, Sharlene M.:Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
hcfmusp.author.externalSTAPLES, James F.:Univ Western Ontario, Dept Biol, London, ON, Canada
hcfmusp.author.externalPADRON, Raul:IVIC, Ctr Biol Estruct, Caracas, Venezuela; Univ Massachusetts, Dept Radiol, Sch Med, Div Cell Biol & Imaging, Worcester, MA USA
hcfmusp.author.externalCHOPRA, Anant:Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
hcfmusp.author.externalHO, Carolyn Y.:Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA
hcfmusp.author.externalCHEN, Christopher S.:Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA
hcfmusp.author.externalSEIDMAN, Jonathan G.:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA
hcfmusp.author.externalSEIDMAN, Christine E.:Harvard Med Sch, Dept Genet, NRB Room 256,77 Ave Louis Pasteur, Boston, MA 02115 USA; Brigham & Womens Hosp, Cardiovasc Div, 75 Francis St, Boston, MA 02115 USA; Howard Hughes Med Inst, Chevy Chase, MD USA
hcfmusp.citation.scopus165
hcfmusp.contributor.author-fmusphcGABRIELA VENTURINI DA SILVA
hcfmusp.contributor.author-fmusphcALEXANDRE DA COSTA PEREIRA
hcfmusp.description.beginpage828
hcfmusp.description.endpage842
hcfmusp.description.issue10
hcfmusp.description.volume141
hcfmusp.origemWOS
hcfmusp.origem.pubmed31983222
hcfmusp.origem.scopus2-s2.0-85081944953
hcfmusp.origem.wosWOS:000528596700012
hcfmusp.publisher.cityPHILADELPHIAeng
hcfmusp.publisher.countryUSAeng
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