TY - JOUR
T1 - N-acetylneuraminate pyruvate lyase controls sialylation of muscle glycoproteins essential for muscle regeneration and function
AU - da Silva, Afitz
AU - Dort, Junio
AU - Orfi, Zakaria
AU - Pan, Xuefang
AU - Huang, Sjanie
AU - Kho, Ikhui
AU - Heckel, Emilie
AU - Muscarnera, Giacomo
AU - van Vliet, Patrick Piet
AU - Sturiale, Luisa
AU - Messina, Angela
AU - Romeo, Donata Agata
AU - van Karnebeek, Clara D. M.
AU - Wen, Xiao-Yan
AU - Hinek, Aleksander
AU - Molina, Thomas
AU - Andelfinger, Gregor
AU - Ellezam, Benjamin
AU - Yamanaka, Yojiro
AU - Olivos, Hernando J.
AU - Morales, Carlos R.
AU - Joyal, Jean-S. bastien
AU - Lefeber, Dirk J.
AU - Garozzo, Domenico
AU - Dumont, Nicolas A.
AU - Pshezhetsky, Alexey V.
N1 - Funding Information: Acknowledgments:W ethankV .BunikandA.CaillonforhelpfuladviceandM.Ashmarinafor critical reading of the manuscript. W e also thank R. Veizaj and F . Zijlstr a for technical support. Funding:ThisstudywaspartiallyfundedbyGlycoNetcollaborativeteamgrants(CD-2toA.V .P . andID-01toA.V .P .), CanadianRareDiseaseModelsandMechanismsNetwork(RDMM)(grant 150905-001-001toA.V .P .), andtheCanadianInstitutesofHealthResearch(grantPJT-148863to A.V .P .). N.A.D.issupportedbyanFRQS(FondsdeRechercheduQuébec—Santé)Junior-2award and by research grants from Canadian Institutes of Health Research (grant PJT-156408) and NaturalSciencesandEngineeringResearchCouncil(RGPIN/05979-2018).J.-S.J.wassupported bytheCanadianInstituteofHealthResearch(CIHR;390615and479607),theNationalSciences andEngineeringResearchCouncilofCanada(NSERC;06743),andFRQSJunior-2(284059). Authorcontributions:Conductedexperimentsandacquireddata:A.D.S.,J.D.,L.S.,A.M.,Z.O., I.K.,X.P ., E.H.,G.M.,P .P .v.V ., S.H.,H.J.O.,D.A.R.,andT .M. Analyzeddata:A.D.S.,E.H.,A.H.,D.J.L.,J.-S.J., Y .Y ., D.A.R., D.G., N.A.D., and A.V .P . Pro vided reagents: J.-S.J. Wr ote the manuscript (first draft):A.D.S.,L.S.,andA.V .P .Wr ote andeditedthemanuscript:A.V .P ., A.D.S.,N.A.D.,D.G.,L.S., C.D.M.v.K.,D.J.L.,J.-S.J.,Y .Y ., G.A.,andC.R.M.Allauthorsreadandapprovedthefinalmanuscript. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:Alldataneededtoevaluatetheconclusionsinthepaperarepresentin thepaperand/ortheSupplementaryMaterials. Publisher Copyright: © 2023 The Authors.
PY - 2023/6/30
Y1 - 2023/6/30
N2 - Deleterious variants in N-acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: NplR63C, carrying the human p.Arg63Cys variant, and Npldel116 with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of N-acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in NplR63C mice, suggesting a potential treatment for human patients.
AB - Deleterious variants in N-acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: NplR63C, carrying the human p.Arg63Cys variant, and Npldel116 with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of N-acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in NplR63C mice, suggesting a potential treatment for human patients.
UR - http://www.scopus.com/inward/record.url?scp=85164231894&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.ade6308
DO - https://doi.org/10.1126/sciadv.ade6308
M3 - Article
C2 - 37390204
SN - 2375-2548
VL - 9
SP - eade6308
JO - Science advances
JF - Science advances
IS - 26
M1 - eade6308
ER -