310 Stainless steel capillary coil tubing chemical component, Karolo ea Dystrophin glycoprotein complexes ho mechanotransduction ea lisele tsa mesifa.

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Dystrophin ke protheine e ka sehloohong ea dystrophin-glycoprotein complex (DGC) ka har'a mesifa ea masapo le cardiomyocyte.Dystrophin e tlama actin cytoskeleton ho matrix a extracellular (ECM).Ho phatloha ha kamano pakeng tsa matrix a extracellular le cytoskeleton ea intracellular ho ka ba le liphello tse senyang bakeng sa homeostasis ea lisele tsa mesifa ea masapo, e leng se lebisang ho palo ea mesifa ea mesifa.Ntle le moo, tahlehelo ea li-DGC tse sebetsang e lebisa ho nts'etsopele ea lefu la pelo le lefu la pele ho nako.Dystrophin e sebetsa e le selemo sa molek'hule 'me DHA e phetha karolo ea bohlokoa ho boloka botšepehi ba sarcolemma.Ho feta moo, bopaki bo ntse bo bokellana bo hokahanyang DGC le lipontšo tsa mochini, leha karolo ena e ntse e sa utloisisoe hantle.Sengoliloeng sena sa tlhahlobo se ikemiselitse ho fana ka pono ea sejoale-joale ea li-DGC le karolo ea tsona ho mechanotransduction.Re qala ho buisana ka kamano e rarahaneng pakeng tsa mechine ea lisele tsa mesifa le ts'ebetso, ebe re hlahloba lipatlisiso tsa morao-rao mabapi le karolo ea motsoako oa dystrophin glycoprotein ho mechanotransduction le ho boloka botšepehi ba biomechanical integrity.Qetellong, re hlahloba lingoliloeng tsa morao-rao ho utloisisa hore na pontšo ea DGC e kopana joang le litsela tsa mechanosignaling ho totobatsa lintlha tse ka 'nang tsa e-ba teng nakong e tlang, ka ho lebisa tlhokomelo e khethehileng ho lefu la pelo.
Lisele li buisana kamehla le microenvironment ea tsona, 'me puisano ea litsela tse peli pakeng tsa tsona e hlokahala bakeng sa tlhaloso le ho kopanngoa ha tlhahisoleseding ea biomechanical.Biomechanics e laola liketsahalo tsa bohlokoa tse latelang (mohlala, cytoskeletal rearrangements) ka ho laola phenotype ea cellular ka kakaretso sebakeng le nako.Bohareng ba ts'ebetso ena ho cardiomyocytes ke sebaka se theko e boima, sebaka seo sarcolemma e hokahanang le sarcomere e entsoeng ka metsoako ea integrin-talin-vinculin le dystrophin-glycoprotein (DGC).E khomaretsoe ho cytoskeleton ea intracellular, li-discrete focal adhesions (FAs) li phatlalatsa ho fokotseha ha liphetoho tsa cellular tsa biomechanical le biochemical tse laolang phapang, ho ata, organogenesis, ho falla, tsoelo-pele ea mafu, le tse ling.Phetoho ea matla a biomechanical ho biochemical le / kapa (epi) liphetoho tsa liphatsa tsa lefutso li tsejoa e le mechanotransduction1.
The integrin transmembrane receptor 2 e 'nile ea tsejoa ka nako e telele hore e tiisa matrix a extracellular liseleng le ho hokahanya lipontšo tsa ka hare le tsa ka ntle.Ka ho tsamaisana le li-integrin, li-DGC li tlamella ECM ho cytoskeleton, ho theha sehokelo sa bohlokoa lipakeng tsa kantle le kahare ho sele3.Dystrophin ea bolelele bo felletseng (Dp427) e hlahisoa haholo ke mesifa ea pelo le ea marapo, empa e boetse e bonoa ka har'a lisele tsa methapo ea methapo e bohareng, ho kenyelletsa le retina le Purkinje tissue4.Liphetoho tsa li-interins le DGC ho nahanoa hore ke lisosa tsa ho senyeha ha mesifa le tsoelo-pele e tsoelang pele ea pelo (DCM) (Letlapa 1) 5,6.Haholo-holo, liphetoho tsa DMD tse kenyang liprotheine tse bohareng tsa dystrophin DGC li baka Duchenne muscular dystrophy (DMD)7.DGC e entsoe ka li-subcomplexes tse 'maloa tse kenyeletsang α- le β-dystroglycan (α/β-DG), sarcoglycan-sarcospan, syntrophin, le dystrophin8.
Dystrophin ke protheine ea cytoskeletal e kentsoeng ke DMD (Xp21.1-Xp22) e bapalang karolo ea mantlha ho bolokeng DGC.DGC e boloka botšepehi ba sarcolemma, lera la plasma la mesifa e tsitsitsoeng.Dystrophin e tsoela pele ho fokotsa tšenyo e bakiloeng ke ho honyela ka ho sebetsa joalo ka seliba sa molek'hule le scaffold ea molek'hule9,10.Dystrophin ea bolelele bo felletseng e na le boima ba molek'hule ea 427 kDa, leha ho le joalo, ka lebaka la bahlahisi ba bangata ba kahare ho DMD, ho na le li-isoform tse 'maloa tse hlahang ka tlhaho, ho kenyelletsa le Dp7111.
Liprotheine tsa lisebelisoa li 'nile tsa bontšoa hore li fumaneha sebakeng sa dystrophin, ho kenyelletsa le mechanotransducers ea' nete e kang neuronal nitric oxide synthase (nNOS), protheine e amanang le Ee (YAP), le caveolin-3, kahoo e emela likarolo tsa bohlokoa tsa pontšo ea lisele.Lik'hemik'hale 12, 13, 14. Ntle le ho khomarela, mochine oa selefouno o amanang le ho sebelisana pakeng tsa lisele le matrix, tse entsoeng ke li-integrins le lipakane tsa tsona tse tlaase, lihlopha tsena tse peli li emela sebopeho pakeng tsa "ka hare" le "ka ntle" ea sele. .Ho sireletsa likhomaretsi tsena tse tsepamisitsoeng ho tloha timetsong e sa tloaelehang ho bohlokoa boitšoarong ba lisele le ho phela.Ho phaella moo, ts'ehetso ea data ea hore dystrophin ke modulator ea mechanosensitive ion channels, ho kenyelletsa le mechine e otlolohileng, haholo-holo L-mofuta oa Ca2 + le liteishene tsa TRPC 15.
Le hoja dystrophin e le ea bohlokoa bakeng sa mosebetsi oa homeostatic oa lisele tsa mesifa tse striated, mekhoa e nepahetseng ea ts'ehetso ha e hlake haholo, haholo-holo karolo ea dystrophin le bokhoni ba eona ba ho sebetsa e le mochine oa mochine le mosireletsi oa mechine.Ka lebaka la tahlehelo ea dystrophin, ho hlahile lipotso tse 'maloa tse sa arajoang, tse kenyeletsang: ke liprotheine tsa mechanosensitive tse kang YAP le AMPK tse khelohileng ho sarcolemma;Na ho na le crosstalk le li-interins, maemo a ka lebisang ho mechanotransduction e sa tloaelehang?Likarolo tsena kaofela li ka kenya letsoho ho matla a DCM phenotype a bonoang ho bakuli ba nang le DMD.
Ho phaella moo, mokhatlo oa liphetoho ho li-biomechanics tsa cellular le phenotype ea DMD ka kakaretso e na le liphello tsa bohlokoa tsa kliniki.DMD ke X-linked muscular dystrophy e amang 1: 3500-5000 banna, e khetholloang ke tahlehelo ea pele ea ho tsamaea (<5 lilemo) le DCM e tsoelang pele e nang le ts'oaetso e mpe haholo ho feta DCM ea li-etiology tse ling16,17,18.
Li-biomechanics tsa tahlehelo ea dystrophin ha li e-s'o hlalosoe ka botlalo, 'me mona re hlahloba bopaki bo tšehetsang maikutlo a hore dystrophin e hlile e bapala karolo ea mechanoprotective, ke hore ho boloka botšepehi ba sarcolemma,' me ke habohlokoa ho mechanotransduction.Ho phaella moo, re ile ra hlahloba bopaki bo bontšang hore crosstalk ea bohlokoa e na le li-integrin, haholo-holo e tlamang laminin α7β1D liseleng tsa mesifa e tsitsitseng.
Ho kenya le ho hlakolwa ho ikarabella bakeng sa palo e kgolo ya diphetoho ho DMD, mme 72% ya diphetoho di bakwa ke diphetoho tse jwalo19.Ka kakaretso, DMD e hlahisa bongoaneng (≤5 lilemo) ka hypotension, pontšo e ntle ea Gower, tsoelo-pele e liehang ea liphetoho tse amanang le lilemo, ho holofala kelellong, le ho fokola ha mesifa ea masapo.Khatello ea ho hema e 'nile ea e-ba sesosa se ka sehloohong sa lefu ho bakuli ba DMD, empa tlhokomelo e ntlafetseng ea tšehetso (corticosteroids, khatello e tsoelang pele e ntle ea moea) e ekelitse nako ea bophelo ho bakuli bana,' me lilemo tse bohareng tsa bakuli ba DMD ba hlahileng ka mor'a 1990 ke lilemo tse 28.1 20,21 ..Leha ho le joalo, ha ho pholoha ha mokuli ho ntse ho eketseha, tlhaloso ea DCM e tsoelang pele e mpe haholo ha e bapisoa le tse ling tsa cardiomyopathies16, e lebisang ho hloleha ha pelo ea ho qetela, eo hona joale e leng sesosa se ka sehloohong sa lefu, se etsang hoo e ka bang 50% ea lefu la DMD17,18.
DCM e tsoelang pele e khetholloa ka ho eketseha ha ventricular dilatation le ho lumellana, ho fokotseha ha ventricular, ho eketseha ha fibrofatty infiltration, ho fokotseha ha mosebetsi oa systolic, le ho eketseha ha maqhubu a arrhythmias.Tekanyo ea DCM ho bakuli ba nang le DMD e batla e fumaneha hohle lilemong tsa bocha (90% ho ea ho lilemo tse 18), empa e teng ho hoo e ka bang 59% ea bakuli ka lilemo tse 10 tsa lilemo tse8,22.Ho sebetsana le taba ena ho bohlokoa kaha karoloana ea ejection ea ventricular e ka letsohong le letšehali e ntse e theoha butle-butle ka sekhahla sa 1.6% ka selemo23.
Cardiac arrhythmias e tloaelehile ho bakuli ba DMD, haholo-holo sinus tachycardia le ventricular tachycardia, 'me ke sesosa sa lefu la tšohanyetso la pelo22.Arrhythmias ke phello ea ho kenella ha fibrofatty, haholo-holo ho subbasal left ventricle, e senyang potoloho ea ho khutla hammoho le [Ca2+] i sebetsa ho se sebetse le ho se sebetse ha mocha oa ion24,25.Ho ela hloko tlhahiso ea pelo ea kliniki ho bohlokoa, kaha mekhoa ea pele ea phekolo e ka 'na ea liehisa ho qala ha DCM e matla.
Bohlokoa ba ho phekola ho se sebetse ha pelo le ho fokola ha mesifa ea masapo ho bontšoa thutong e thahasellisang e sebelisitseng mohlala oa mouse oa DMD o bitsoang mdx26 ho ithuta liphello tsa ho ntlafatsa mesifa ea masapo ntle le ho sebetsana le mathata a ka sehloohong a pelo a teng ho DMD.Mona, bangoli ba bontšitse keketseho e makatsang ea 5 ea ho se sebetse ha pelo ka mor'a ho ntlafatsoa ha mesifa ea masapo, 'me litoeba li bile le phokotso e kholo ea karolo ea ejection26.Ts'ebetso e ntlafetseng ea mesifa ea masapo e lumella boikoetliso bo phahameng ba 'mele ho beha khatello e eketsehileng ho myocardium, e leng ho etsang hore e be bonolo haholoanyane ho se sebetse ka kakaretso.Sena se totobatsa bohlokoa ba ho phekola bakuli ba DMD ka kakaretso le ho lemosa khahlanong le phekolo ea mesifa ea masapo feela.
Li-DGC li etsa mesebetsi e 'maloa e eketsehileng, e leng, ho fana ka botsitso ba sebopeho sa sarcolemma, ho fetoha scaffold ea molek'hule e sebetsang e le sehokelo sa pontšo, ho laola mechanosensitive ion channels, motheo oa costal mechanotransduction, le ho kenya letsoho phetisong ea matla a morao-rao sebakeng sa likhopo (setšoantšo sa 1b)..Dystrophin e phetha karolo ea bohlokoa ho bokhoni bona, 'me ka lebaka la boteng ba bahlahisi ba bangata ba ka hare, ho na le li-isoform tse ngata tse fapaneng, e' ngoe le e 'ngoe e bapala karolo e fapaneng meleng e fapaneng.Polelo e fapaneng ea lisele tsa dystrophin isoform e ts'ehetsa mohopolo oa hore isoform ka 'ngoe e bapala karolo e fapaneng.Mohlala, lisele tsa pelo li hlahisa bolelele bo felletseng (Dp427m) hammoho le Dp71m e khuts'oane ea isoform ea dystrophin, athe lisele tsa skeletal li hlahisa feela ea pele ho tse peli.Ho shebella karolo ea mofuta o mong le o mong ho ka senola eseng feela ts'ebetso ea eona ea 'mele, empa hape le pathogenesis ea dystrophy ea mesifa.
Setšoantšo sa schematic sa dystrophin ea bolelele bo felletseng (Dp427m) le e nyane, e khutsufalitsoeng ea Dp71 isoform.Dystrophin e na le makhetlo a 24 a pheta-phetoang a arohaneng ka li-loops tse 'nè, hammoho le sebaka se tlamang sa actin (ABD), sebaka sa cysteine-rich (CR), le C-terminus (CT).Balekane ba bohlokoa ba tlamang ba 'nile ba fumanoa, ho akarelletsa le microtubules (MTs) le sarcolemma.Ho na le li-isoform tse ngata tsa Dp71, Dp71m e bua ka mesifa ea mesifa, 'me Dp71b e bua ka isoform ea methapo ea kutlo.Haholo-holo, Dp71f e bua ka cytoplasmic isoform ea neurons.b Dystrophin-glycoprotein complex (DHA) e fumaneha ka har'a sarcolemma ka kakaretso.Matla a biomechanical a fetoha pakeng tsa ECM le F-actin.Ela hloko puisano e ka bang teng lipakeng tsa DGCs le integrin adhesion, Dp71 e ka bapala karolo ho tsepamisoang maikutlo.E entsoe ka Biorender.com.
DMD ke lefu le atileng ka ho fetesisa la mesifa 'me le bakoa ke liphetoho tsa DMD.Leha ho le joalo, ho ananela ka botlalo kutloisiso ea rona ea hona joale ea karolo ea anti-dystrophin, ke habohlokoa ho e beha boemong ba DGC ka kakaretso.Kahoo, likarolo tse ling tsa protheine li tla hlalosoa ka bokhutšoanyane.Sebopeho sa protheine ea DGC se qalile ho ithutoa ho elella bofelong ba lilemo tsa bo-1980, ka tlhokomelo e khethehileng ho dystrophin.Koenig27,28, Hoffman29 le Ervasti30 ba fumane tšibollo ea bohlokoa ka ho tsebahatsa dystrophin, protheine ea 427 kDa ka har'a mesifa e tsitsitseng31.
Ka mor'a moo, li-subcomplexes tse ling li ile tsa bontšoa li amahanngoa le dystrophin, ho akarelletsa le sarcoglycan, transsyn, dystrophin subcomplex, dysbrevin, le syntrophins8, tseo hammoho li etsang mohlala oa hona joale oa DGC.Karolo ena e tla qala ho phatlalatsa bopaki ba karolo ea DGC ponong ea mechanosensory ha e ntse e hlahloba likarolo tsa motho ka mong ka botlalo.
Dystrophin isoform ea bolelele bo felletseng e teng ka har'a mesifa ea mesifa ke Dp427m (mohlala "m" bakeng sa mesifa ho e khetholla ho boko) mme ke protheine e kholo e bōpehileng joaloka molamu e nang le likarolo tse 'nè tse sebetsang tlas'a cardiomyocyte sarcolemma, haholo-holo sebakeng sa costal. 29, 32. Dp427m, e kenyellelitsoeng ke mofuta oa DMD ho Xp21.1, e na le li-exons tse 79 tse hlahisoang ho 2.2 megabases kahoo ke gene e kholo ka ho fetisisa ho genome8 ea rona.
Bahlahisi ba 'maloa ba ka hare ho DMD ba hlahisa li-isoform tsa dystrophin tse ngata tse fokolang, tse ling tsa tsona e le lisele tse khethehileng.Ha e bapisoa le Dp427m, Dp71m e fokotsehile haholo 'me ha e na sebaka sa ho pheta-pheta sa spectrin kapa sebaka sa N-terminal ABD.Leha ho le joalo, Dp71m e boloka sebopeho se tlamang sa C-terminal.Ka cardiomyocytes, karolo ea Dp71m ha e hlake, empa e bontšitsoe hore e fumaneha sebakeng sa T tubules, e fana ka maikutlo a hore e ka thusa ho laola khokahanyo ea excitation-contraction 33,34,35.Ho ea ka tsebo ea rona, ho sibolloa ha morao tjena ha Dp71m ka lisele tsa pelo ho fumane tlhokomelo e fokolang, empa liphuputso tse ling li fana ka maikutlo a hore li amahanngoa le mechine ea ion e otlolohileng, 'me Masubuchi a fana ka tlhahiso ea hore e ka bapala karolo ea taolo ea nNOS33., 36. Ka ho etsa joalo, Dp71 e fumane tlhokomelo e kholo ho neurophysiology le lipatlisiso tsa platelet, libaka tse ka fanang ka temohisiso mabapi le karolo ea cardiomyocytes37,38,39.
Lithishung tsa methapo, Dp71b isoform e hlahisoa haholo, ho tlalehiloe li-isoform tse 14.Ho tlosoa ha Dp71b, molaoli oa bohlokoa oa li-aquaporin 4 le li-channel potassium tsa Kir4.1 tsamaisong ea methapo e bohareng, ho bontšitsoe ho fetola phepelo ea mali-boko ba boko40.Ho latela karolo ea Dp71b taolong ea mocha oa ion, Dp71m e kanna ea bapala karolo e ts'oanang ho li-cardiomyocyte.
Ho ba teng ha DGC ho ganglia e theko e boima hang-hang ho bontša karolo ea mechanotransduction, 'me ka sebele e bontšitsoe hore e kopane le li-complexes tsa integrin-talin-vinculin 41.Ho feta moo, ha ho nahanoa hore karolo ea litšenyehelo e lebisitsoe tlhokomelo bakeng sa mechanotransduction ea transverse, sebaka sa Dp427m mona se totobatsa karolo ea sona ea ho sireletsa lisele ho tsoa tšenyo e bakoang ke ho fokotseha.Ho feta moo, Dp427m e sebelisana le actin le microtubule cytoskeleton, kahoo e phethela kamano pakeng tsa tikoloho ea intracellular le matrix ea extracellular.
N-terminus e nang le actin-binding domain 1 (ABD1) e na le libaka tse peli tsa calmodulin homology (CH) tse hlokehang bakeng sa ho sebelisana le F-actin le ho tiisa γ-actin isoform ho sarcolemma42,43.Dystrophin e ka kenya letsoho ho li-viscoelasticity ka kakaretso tsa cardiomyocyte ka ho khomarela cytoskeleton ea subsarcolemmal, 'me sebaka sa eona sebakeng sa ganglia se theko e boima se tšehetsa ho kenya letsoho ho mechanotransduction hammoho le mechanoprotection44,45.
Sebaka se bohareng se na le liprotheine tse 24 tse pheta-phetoang tse kang li-spectrin, tseo e 'ngoe le e 'ngoe ea tsona e ka bang masala a 100 a amino acid ka bolelele.Ho pheta-pheta ha li-spectrin ho kopantsoe le libaka tse 'nè tsa li-hinge, ho fana ka phetoho ea protheine le tekanyo e phahameng ea ho atolosa.Dystrophin spectrin pheta-pheta e ka hlaha ka har'a mefuta e mengata ea matla (15-30 pN) e tlohang ho 21 nm ho ea ho 84 nm, matla a ka finyelloang bakeng sa thibelo ea myosin 46.Likarolo tsena tsa "spectrin repeater domain" li lumella dysstrophin hore e sebetse e le molecular shock absorber.
Molamu o bohareng oa Dp427m o netefatsa hore o na le sebaka sa sarcolemma, haholo-holo, ka ho sebelisana ha hydrophobic le electrostatic le phosphatidylserine 47,48.Hoa thahasellisa hore mokokotlo o bohareng oa dystrophin o sebelisana ka tsela e fapaneng le sarcolemma phospholipids meleng ea masapo le pelo, mohlomong ho bonahatsa mekhoa e fapaneng ea selemo.e mahlonoko, ha mesifa ea marapo e boetse e amahanngoa le R10-R1249.
Ho tlama ho γ-actin cytoskeleton ho hloka hore ABD2 spectrin e phete sebaka sa 11-17, e nang le masalla a motheo a amino acid 'me e fapane le sebaka sa F-actin-binding CH.Li-microtubules li sebelisana ka ho toba le sebaka sa mantlha sa dystrophin, tšebelisano ena e hloka masala a spectrin a pheta 4-15 le 20-23, 'me ho ba teng ha ankyrin B ho hlokahala ho thibela ho thehoa ha li-microtubules sebakeng sena.Li-tubes ha li eo 50,51,52.Phapang pakeng tsa li-microtubules le dystrophin e bontšitsoe ho mpefatsa lefu la DMD ka ho eketsa mefuta ea oksijene e sebetsang (X-ROS).
Sebaka sa CR ka ankyrin B ke ankora e 'ngoe bakeng sa sarcolemmal phospholipids52.Ankyrin-B le ankyrin-G lia hlokahala bakeng sa ho fumaneha ha likhopo tsa dystrophin/DGC, 'me ho ba sieo ha tsona ho fella ka mokhoa o fapaneng oa sarcolemmal oa DGC52.
Sebaka sa CR se na le sebaka se tlamang sa WW se sebetsanang ka ho toba le PPxY e tlamang motif ea β-DG.Ka ho ikamahanya le motsoako oa dystrophin-glycan, dystrophin e phethela sehokelo lipakeng tsa kahare le kantle ho sele54.Khokahano ena e bohlokoa haholo bakeng sa mesifa e tsitsitsoeng, joalo ka ha ho pakoa ke taba ea hore tšitiso ea khokahano lipakeng tsa ECM le bokahare ba sele e lebisa ho lefu le fokotsang mesifa.
Qetellong, sebaka sa CT ke sebaka se sirelelitsoeng haholo se etsang helix e kopantsoeng 'me e bohlokoa bakeng sa ho tlama α-dystrobrevin le α1-,β1-syntrophins55,56.α-dystrobrevin e tlama sebakeng sa CT sa dystrophin 'me e fana ka khanyetso e eketsehileng ho dystrophin ho sarcolemma57.
Nakong ea nts'etsopele ea embryonic le fetal, Utrophin e hlahisoa haholo ka har'a lisele tse fapaneng, ho kenyeletsoa lisele tsa endothelial, lisele tsa methapo, le mesifa ea mesifa58.Utrophin e hlahisoa ke UTRN e fumanehang ho chromosome 6q mme ke dystrophin autolog e nang le 80% ea protheine homology.Nakong ea nts'etsopele, utrophin e fumaneha sebakeng sa sarcolemma empa e hatelloa ka mokhoa o hlakileng ka har'a mesifa ea mesifa ea postnatal striated, moo e nkeloang sebaka ke dystrophin.Ka mor'a ho tsoaloa, sebaka sa utrophin se lekanyelitsoe ho li-tendon le li-neuromuscular junctions tsa mesifa ea masapo58,59.
Balekane ba tlamang ba Utrophin ba tšoana ka bophara le ba dystrophin, leha ho se ho hlalositsoe liphapang tse ling tsa bohlokoa.Ka mohlala, dystrophin e sebelisana le β-DG ka sebaka sa eona sa WW, e tsitsitseng ke sebaka sa ZZ (e bitsoang ka bokhoni ba eona ba ho tlama li-ion tse peli tsa zinki) ka har'a sebaka sa eona sa CT, moo masala a cysteic acid 3307-3354 a bohlokoa ka ho khetheha bakeng sa tšebelisano ena60 ., 61. Utrophin e boetse e tlama ho β-DG ka sebaka sa WW / ZZ, empa masala a nepahetseng a tšehetsang tšebelisano ena a fapane le masala a dystrophin (3307-3345 ka dystrophin le 3064-3102 ka utrophin) 60,61.Habohlokoa, tlamo ea utrophin ho β-DG e ne e batla e le tlase ka makhetlo a 2 ha e bapisoa le dystrophin 61. Dystrophin e tlalehiloe hore e tlama F-actin ka spectrin e pheta 11-17, ha libaka tse tšoanang tsa utrophin li ke ke tsa tlama F-actin, esita le likhahla tse phahameng, empa li ka sebelisana ka li-domain tsa tsona tsa CH.Ketso 62,63,64.Qetellong, ho fapana le dystrophin, utrophin e ke ke ea tlama ho microtubules51.
Ka biomechanical, ho pheta-pheta ha utrophin spectrin ho na le mokhoa o ikhethileng o hlahang ha o bapisoa le dystrophin65.Utrophin-spectrin e pheta-pheta ho romelloa ho matla a phahameng, a tšoanang le titin empa eseng dysstrophin65.Sena se lumellana le sebaka sa eona sa sebaka le karolo ea ho fetisoa ha matla a tsitsitseng a tsitsitseng lihlopheng tsa tendon, empa ho ka 'na ha etsa hore utrophin e se ke ea tšoaneleha ho sebetsa e le selemo sa molek'hule ka matla a buffering a bakoang ke ho thibela 65.Ha li kopane, lintlha tsena li fana ka maikutlo a hore bokhoni ba mechanotransduction le mechanobuffering bo ka fetoloa ka ho ba teng ha utrophin overexpression, haholo-holo ho fanoa ka balekane / mekhoa e fapaneng e tlamang, leha ho le joalo sena se hloka boithuto bo eketsehileng ba liteko.
Ho latela pono e sebetsang, taba ea hore utrophin ho lumeloa hore e na le liphello tse tšoanang ho dystrophin e etsa hore e be sepheo sa phekolo ea DMD66,67.Ha e le hantle, bakuli ba bang ba DMD ba 'nile ba bontšoa ho overexpress utrophin, mohlomong e le mokhoa oa ho lefella,' me phenotype e tsosolositsoe ka katleho ka mokhoa oa mouse ka utrophin overexpression 68.Le hoja upregulation ea utrophin e ka 'na ea e-ba leano la phekolo, ho nahanisisa ka phapang e tloaelehileng le e sebetsang pakeng tsa utrophin le dystrophin le thuso ea ho susumetsa maikutlo ana a feteletseng ka sebaka se nepahetseng sa sebaka sa sarcolemma ho etsa hore leano la nako e telele la utrophin le ntse le sa hlaka.Ka ho hlakileng, bajari ba basali ba bonts'a mokhoa oa mosaic oa polelo ea utrophin, 'me karolelano pakeng tsa dystrophin le utrophin e ka susumetsa tekanyo ea lefu la pelo ho bakuli bana, 69 le hoja mehlala ea murine ea bajari e bontšitse..
The subcomplex ea dystroglycan e na le liprotheine tse peli, α- le β-dystroglycan (α-, β-DG), ka bobeli li ngotsoe ho tloha ho liphatsa tsa lefutso tsa DAG1 'me ka mor'a ho fetolela ka mor'a phetolelo li phunyeletsoa ho liprotheine tse peli tsa likarolo tse 71.α-DG e na le glycosylated haholo karolong ea extracellular ea DGCs 'me e sebelisana ka ho toba le masala a proline ka laminin α2 hammoho le agrin72 le picaculin73 le sebaka sa CT/CR sa dystrophin73,74,75,76.O-linked glycosylation, haholo-holo masala a serine, a hlokahala bakeng sa ho sebelisana ha eona le ECM.Tsela ea glycosylation e kenyelletsa li-enzyme tse ngata tseo liphetoho tsa tsona li lebisang ho dystrophy ea mesifa (sheba le Lethathamo la 1).Tsena li kenyelletsa O-mannosyltransferase POMT2, protheine e amanang le fucutin le fucutin (FKRP), li-phosphotransferase tse peli tsa ribitol tse eketsang tandem ribitol phosphates ho core glycan, le protheine ea LARGE1 e eketsang xylose le glucose.Linear uronic acid polysaccharide, e tsejoang hape e le matrix glycan qetellong ea glycan77.FKRP e boetse e ameha ho nts'etsopele le tlhokomelo ea ECM, 'me liphetoho ho eona li lebisa ho fokotseha ha polelo ea laminin α2 le α-DG77,78,79.Ho feta moo, FKRP e ka boela ea tsamaisa sebopeho sa basal lamina le matrix a extracellular ea pelo ka glycosylated fibronectin 80.
β-DG e na le PPxY e tlamang motif e behang YAP12 sebakeng sa heno ka kotloloho.Ena ke phumano e khahlisang kaha e fana ka maikutlo a hore DGC e laola potoloho ea lisele tsa cardiomyocyte.α-DH ka neonatal cardiomyocytes e sebelisana le agrin, e khothalletsang ho tsosolosoa ha pelo le DGC76 lysis ka lebaka la ho hōla ha lisele.Ha li-cardiomyocyte li ntse li hola, polelo ea aggrin e fokotseha molemong oa laminin, eo ho nahanoang hore e kenya letsoho ho ts'oaroe ha seleng76.Morikawa12 e bonts'itse hore ho putlama habeli ha dystrophin le salvador, molaoli o mobe oa YAP, ho lebisa ho hyperproliferation ea cardiomyocyte ho rumen e bakang infarct.Sena se ile sa lebisa mohopolong o khahlisang oa hore ho qhekella ha YAP ho ka ba molemo ho thibela tahlehelo ea lisele ka mor'a lefu la myocardial infarction.Ka hona, DGC lysis e hlahisitsoeng ke agrin e ka emela axis e lumellang hore YAP e sebetse 'me e le tsela e ka' nang ea e-ba teng bakeng sa tsosoloso ea pelo.
Ka mechine, α- le β-DG e hlokeha ho boloka ho sebelisana pakeng tsa sarcolemma le basal layer 81.Ka bobeli α-DG le α7 integrins li kenya letsoho ho qobella tlhahiso ka har'a ganglion e theko e boima, 'me tahlehelo ea α-DG e baka karohano ea sarcolemma ho tloha ho basal lamina, e siea mesifa ea masapo e kotsing ea ho senyeha ho bakoang ke ho thibela.Joalokaha ho hlalositsoe pejana, motsoako oa dystroglycan o laola phetoho ea kakaretso ea li-DGC, moo ho tlamang ho kopanya ligand laminin ho fella ka tyrosine phosphorylation ea PPPY-binding motif ea β-DG892.Tyrosine phosphorylation mona e khothalletsa dystrophin disassembly, e fetolang setsi sa DGC.Physiologically, ts'ebetso ena e laoloa haholo, e leng sieo ho dystrophy ea mesifa82, le hoja mekhoa ea motheo e laolang ts'ebetso ena e sa utloisisoe ka botlalo.
Cyclic stretch e bontšitsoe ho kenya tšebetsong litsela tsa ERK1/2 le AMPK ka har'a motsoako oa dystrophin le protheine e amanang le plectin83.Hammoho, plectin le dystroglycan ha li hlokehe feela ho sebetsa e le scaffold, empa hape le ho kenya letsoho ho mechanotransduction, 'me ho kokota ha plectin ho lebisa ho fokotseha ha mosebetsi oa ERK1/2 le AMPK83.Plectin e boetse e tlama ho cytoskeletal intermediate filament desmin, 'me desmin overexpression e bontšitsoe ho ntlafatsa phenotype ea lefu ka mdx:desmin le mdx litoeba, DMD84 double knockout mouse model.Ka ho sebelisana le β-DG, plectin ka tsela e sa tobang e tlama DGC ho karolo ena ea cytoskeleton.Ntle le moo, dystroglycan e sebelisana le protheine e tlamang ea kholo ea receptor 2 (Grb2), e tsejoang e le karolo ea cytoskeletal rearrangements85.Tšebeliso ea Ras ka integrin e bonts'itsoe hore e kena lipakeng ka Grb2, e ka fanang ka tsela e ka bang teng ea ho kopana lipakeng tsa li-integrin le DGC86.
Liphetoho tsa liphatsa tsa lefutso tse amehang ho α-DH glycosylation li lebisa ho seo ho thoeng ke mesifa ea mesifa.Dystroglycanopathies e bontša ho fapana ha kliniki empa haholo-holo e bakoa ke tšitiso ea tšebelisano pakeng tsa α-DG le laminin α277.Dystrophiglicanoses e bakoang ke liphetoho tsa mantlha ho DAG1 hangata ha e fumanehe haholo, mohlomong hobane e le embryonic lethal87, ka hona e tiisa tlhoko ea khokahano ea cellular le ECM.Sena se bolela hore mafu a mangata a dystrophic glycan a bakoa ke liphetoho tsa bobeli tsa protheine tse amanang le glycosylation.Ka mohlala, liphetoho tse teng ho POMT1 li baka lefu le matla haholo la Walker-Warburg, le khetholloang ke anencephaly le nako ea bophelo e khutsufalitsoeng haholo (ka tlase ho lilemo tse 3)88.Leha ho le joalo, liphetoho tsa FKRP hangata li iponahatsa e le leoto-girdle muscular dystrophy (LGMD), eo hangata (empa eseng kamehla) e batlang e le bobebe.Leha ho le joalo, liphetoho ho FKRP li bonts'itsoe e le sesosa se sa tloaelehang sa WWS89.Liphetoho tse ngata li khethiloe ho FKRP, eo phetoho ea mothehi (c.826> A) hangata e bakang LGMD2I90.
LGMD2I ke lefu la ho fokola ha mesifa le batlang le le bobebe leo pathogenesis ea lona e itšetlehileng ka ho senyeha ha kamano pakeng tsa matrix a extracellular le cytoskeleton ea intracellular.Ha ho hlake haholo kamano pakeng tsa genotype le phenotype ho bakuli ba nang le liphetoho liphatseng tsena tsa lefutso, 'me ka sebele khopolo ena e sebetsa ho liprotheine tse ling tsa DSC.Ke hobane'ng ha bakuli ba bang ba nang le liphetoho tsa FKRP ba bontša lefu la phenotype le lumellanang le WWS ha ba bang ba na le LGMD2I?Karabo ea potso ena e ka ba ho i) ke mohato ofe oa tsela ea glycosylation e anngoeng ke phetoho, kapa ii) tekanyo ea hypoglycosylation mohatong ofe kapa ofe.Hypoglycosylation ea α-DG e ntse e ka lumella tekanyo e itseng ea ho sebelisana le ECM e hlahisang phenotype e bonolo ka kakaretso, ha ho arohana le lera le ka tlaase ho eketsa matla a lefu lena la phenotype.Bakuli ba nang le LGMD2I ba boetse ba hlahisa DCM, le hoja sena se ngotsoe ka tlaase ho DMD, se susumetsang ho potlakela ho utloisisa liphetoho tsena ho latela moelelo oa cardiomyocyte.
Sarcospan-sarcoglycan subcomplex e khothalletsa ho thehoa ha DHA le ho sebelisana ka ho toba le β-DH.Ho na le li-sarcoglycans tse 'nè tse sa tloaelehang ka har'a lisele tsa pelo: α, β, γ, le δ91.Haufinyane tjena ho hlalositsoe hore phetoho e fosahetseng ea c.218C>T ho exon 3 ea lefutso la SGCA le ho hlakolwa ha heterozygous ka karolo ho exons 7–8 ho baka LGMD2D92.Leha ho le joalo, tabeng ena, bangoli ha baa ka ba hlahloba phenotype ea pelo.
Lihlopha tse ling li fumane hore SGCD ka mefuta ea porcine93 le mouse94 e fella ka ho fokotseha ha polelo ea protheine ka har'a sarcoglycan subcomplex, e senyang sebopeho se akaretsang sa DGC le ho lebisa ho DCM.Ho phaella moo, 19% ea bakuli bohle ba nang le liphetoho tsa SGCA, SGCB, kapa SGCG ba tlalehiloe hore ba na le lefu la pelo le atolositsoeng, 'me karolo ea 25 lekholong ea bakuli bohle e boetse e hloka tšehetso ea phefumoloho95.
Liphetoho tse feto-fetohang ho sarcoglycan (SG) δ li baka phokotso kapa ho ba sieo ka ho feletseng ha li-sarcoglycan complexes kahoo DGC liphatseng tsa pelo 'me e ikarabella bakeng sa LGMD le DCM96 e amanang le eona.Hoa thahasellisa hore liphetoho tse matla-tse mpe ho SG-δ li tobile ho tsamaiso ea pelo le methapo ea pelo 'me ke sesosa sa malapa a nang le lefu la pelo97.SG-δ R97Q le R71T liphetoho tse ka sehloohong-tse mpe li bontšitsoe hore li hlahisoe ka mokhoa o tsitsitseng ho cardiomyocyte ea rat ntle le ho senyeha ho hoholo ha kakaretso ea DGC98.Leha ho le joalo, lisele tsa pelo tse jereng liphetoho tsena li ka hlaseloa habonolo ke tšenyo ea sarcolemma, permeability, le ho se sebetse ha mechine tlas'a khatello ea mochine, e lumellanang le phenotype ea DCM98.
Sarcospan (SSPN) ke tetraspanin ea 25 kDa e sebakeng sa sarcoglycan subcomplex 'me ho lumeloa hore e sebetsa e le protheine scaffold99,100.Joaloka protheine scaffold, SSPN e tsitsisa sebaka sa sebaka le glycosylation ea α-DG99,101.Ho fetisoa ho feteletseng ha SSPN ka mehlala ea mouse ho fumanoe ho eketsa ho tlama pakeng tsa mesifa le laminin 102.Ho phaella moo, SSPN e bontšitsoe ho sebelisana le li-integrin, e fana ka maikutlo a tekanyo ea crosstalk pakeng tsa likhopo tse peli tsa likhopo, DGC, le mohaho oa integrin-talin-vinculin glycoprotein100,101,102.Ho kokota ha SSPN ho boetse ho entse hore ho be le keketseho ea α7β1 ho mesifa ea masapo a mouse.
Phuputso ea morao tjena e bontšitse hore sarcospan overexpression e ntlafatsa ho hōla le glycosylation ea α-DG ka lisele tsa pelo ntle le galactosylaminotransferase 2 (Galgt2) knockdown ka mdx mouse ea DMD, kahoo ho fokotsa lefu la phenotype 101. Ho eketseha ha glycosylation ea motsoako oa dystroglycan ho ka ntlafatsa ho sebelisana le bothata ba dystroglycan ECM, ka hona e fokotsa lefu lena.Ho feta moo, ba bontšitse hore sarcospan overexpression e fokotsa ho sebelisana ha β1D integrin le DGCs, ho totobatsa karolo e ka bang teng bakeng sa sarcospan taolong ea integrin complexes101.
Li-Syntrophin ke lelapa la liprotheine tse nyane (58 kDa) tse fumanehang ho li-DGC, ka botsona ha li na ts'ebetso ea tlhaho ea enzymatic, mme li sebetsa joalo ka li-adapter tsa limolek'hule103,104.Li-isoform tse hlano (α-1, β-1, β-2, γ-1 le γ-2) li 'nile tsa khetholloa tse bontšang polelo e khethehileng ea lisele, e nang le α-1 isoform e hlahisoang haholo-holo ka mesifa e tsitsitseng ea 105.Li-syntrophin ke liprotheine tsa bohlokoa tsa adapter tse nolofalletsang puisano pakeng tsa dystrophin le limolek'hule tsa lipontšo, ho akarelletsa le neuronal nitric oxide synthase (nNOS) ka skeletal muscle106.α-syntrophin e sebelisana ka ho toba le dystrophin 16-17 spectrin repeat domain, e leng eona e tlamang ho nNOS106,107 PDZ-binding motif.
Li-Syntrophin li boetse li sebelisana le dystrobrevin ka libaka tse tlamang tsa PH2 le SU, hape li sebelisana le actin cytoskeleton 108.Ha e le hantle, li-sytrophin li bonahala li phetha karolo ea bohlokoa ka ho khetheha taolong ea cytoskeletal dynamics, 'me α le β isoforms li khona ho sebelisana ka ho toba le F-actin 108' me kahoo li ka 'na tsa e-ba le karolo ea ho laola tensegrity le biomechanics ea cellular. phello.Ho phaella moo, li-sytrophin li bontšitsoe ho laola cytoskeleton ka Rac1109.
Ho fetola maemo a syntrophin ho ka tsosolosa ts'ebetso, 'me phuputso ea morao-rao e sebelisang mini-dystrophin e bontšitse hore mohaho oa ΔR4-R23 / ΔCT o khonne ho tsosolosa α-syntrophin hammoho le liprotheine tse ling tsa DGC maemong a lekanang le a WT mdx cardiomyocytes.
Ntle le karolo ea bona ea ho laola cytoskeleton, li-sytrophin li boetse li ngotsoe hantle ho laola mechine ea ion 111,112,113.PDZ-tlamang motif ea syntrophin e laola cardiac voltage-dependent Nav1.5111 channel, e phethang karolo ea bohlokoa ho theha thabo ea pelo le conduction.Hoa thahasellisa hore ka mohlala oa mouse oa mdx, liteishene tsa Nav1.5 li ile tsa fumanoa li fokotsehile 'me li-arrhythmias tsa pelo li fumanoa liphoofolong tsa 111.Ho phaella moo, lelapa la mechanosensitive ion channels, the transient receptor potential channel (TRPC), e bontšitsoe hore e laoloa ke α1-syntrophin ka lisele tsa pelo 113 le TRPC6 inhibition e bontšitsoe ho ntlafatsa arrhythmias ka mokhoa oa mouse oa DMD112.Keketseho ea ts'ebetso ea TRPC6 ho DMD e tlalehiloe hore e baka li-arrhythmias tsa pelo, tse imolohang ha li kopantsoe le PKG 112.Ka mokhoa o ts'oanelang, ho fokotseha ha dystrophin ho khothalletsa phallo e otlolohileng ea [Ca2 +] i e sebetsang holimo ho TRPC6 ho e sebelisa, joalokaha ho bontšoa ka cardiomyocytes le vascular smooth muscle cell112,114.Hyperactivation ea TRPC6 ho otlolla e etsa hore e be mochine o moholo oa mochine le sepheo sa phekolo e ka bang teng ho DMD112,114.
Ho lahleheloa ke dystrophin ho lebisa ho lysis kapa khatello e tšoaeang ea DGC eohle e rarahaneng, ka tahlehelo e latelang ea mesebetsi e mengata ea mechanoprotective le mechanotransduction, e leng se bakang tlokotsi ea phenotype e bonoang meleng ea mesifa e tsitsitseng ho DMD.Ka hona, e ka ba ho utloahalang ho nahana hore li-RSK li sebetsa ka konsarete le hore likarolo tse ling li itšetlehile ka boteng le ho sebetsa ha likarolo tse ling.Sena ke 'nete ka ho khetheha bakeng sa dystrophin, e bonahalang e hlokahala bakeng sa kopano le sebaka sa sebaka sa sarcolemma complex ka cardiomyocytes.Karolo e 'ngoe le e' ngoe e phetha karolo e ikhethang ea ho kenya letsoho ho tsitsang ka kakaretso ea sarcolemma, ho kenngoa ha liprotheine tsa lisebelisoa tsa bohlokoa, ho laola mechine ea ion le liphatsa tsa lefutso, le ho lahleheloa ke protheine e le 'ngoe ho DGC ho lebisa ho senyeha ha myocardium eohle.
Joalokaha ho bontšitsoe ka holimo, liprotheine tse ngata tsa DGC li ameha ho mechanotransduction le pontšo, 'me dystrophin e loketse ka ho khetheha karolo ena.Haeba DGC e fumaneha likhopong, sena se tiisa maikutlo a hore e nka karolo ho mechanotransduction hammoho le li-interins.Ka hona, li-DGCs 'meleng li fetisoa ka matla a anisotropic le ho nka karolo ho rearrangement ea mechanosensory le cytoskeletal ea intracellular microenvironment, e lumellanang le mohlala oa tensegrity.Ntle le moo, Dp427m e sireletsa matla a kenang a biomechanical ka ho holisa pheta-pheto ea spectrin ka har'a sebaka sa eona sa mantlha sa mantlha, ka hona e sebetsa joalo ka mochini o sireletsang mochini ka ho boloka matla a 25 pN a sa feliseng matla holim'a sebaka se atolositsoeng sa 800 nm.Ka ho arohana, dystrophin e khona ho "buffer" matla a contraction-relaxation e hlahisoang ke cardiomyocytes10.Ka lebaka la mefuta-futa ea liprotheine le phospholipids tse sebelisanang le libaka tse pheta-phetoang tsa spectrin, hoa thahasellisa ho hakanya hore na ho pheta-pheta ha spectrin ho fetola kinetics e tlamang ea liprotheine tsa mechanosensitive ka mokhoa o tšoanang le oa talin116,117,118.Leha ho le joalo, sena ha se e-s'o tsejoe 'me lipatlisiso tse ling lia hlokahala.