Stainless Simbi 347 / 347H Welded coil Tubes zhemical chikamu, Basa re dystrophin glycoprotein complexes mu mechanotransduction yemhasuru masero.

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Dystrophin ndiyo puroteni huru yedystrophin-glycoprotein complex (DGC) mune skeletal muscle uye cardiomyocytes.Dystrophin inosunga actin cytoskeleton kune extracellular matrix (ECM).Kuputika kwekubatana pakati pe extracellular matrix uye intracellular cytoskeleton inogona kuva nemigumisiro yakaipa yehomeostasis ye skeletal muscle cells, zvichiita kuti muscular dystrophies iwande.Uye zvakare, kurasikirwa kweanoshanda maDGC anotungamira mukufambira mberi dilated cardiomyopathy uye kufa nguva isati yakwana.Dystrophin inoshanda sechitubu chemolecular uye DHA inoita basa rinokosha mukuchengetedza kuvimbika kwe sarcolemma.Zvakare, humbowo huri kuunganidza hunobatanidza DGC kune mechanistic kusaina, kunyangwe basa iri richiramba risinganzwisisike.Ichi chinyorwa chekuongorora chine chinangwa chekupa maonero emazuva ano eDGC uye basa rawo mu mechanotransduction.Isu tinotanga kukurukura hukama hwakaoma pakati pemhasuru cell mechanics uye basa, uye toongorora tsvakiridzo ichangobva kuitika pamusoro pebasa reiyo dystrophin glycoprotein yakaoma mu mechanotransduction uye kuchengetedza kwemhasuru cell biomechanical kuperera.Pakupedzisira, tinoongorora zvinyorwa zvemazuva ano kuti tinzwisise kuti DGC inoratidzira inopindirana sei ne mechanosignaling nzira yekujekesa zvingangoitika munguva yemberi yekupindira, nekutarisa zvakanyanya pa cardiomyopathy.
Masero ari mukukurukurirana nguva dzose ne microenvironment yavo, uye nzira mbiri-nhaurirano pakati pavo inokosha pakududzira uye kubatanidzwa kweruzivo rwebiomechanical.Biomechanics inodzora zviitiko zvakakosha zvinotevera (semuenzaniso, cytoskeletal rearrangements) nekudzora iyo yese cellular phenotype munzvimbo nenguva.Pakati pekuita uku mu cardiomyocytes inharaunda inodhura, nzvimbo iyo sarcolemma inobatanidza ne sarcomere inoumbwa ne integrin-talin-vinculin uye dystrophin-glycoprotein (DGC) complexes.Yakanamatira kune intracellular cytoskeleton, idzi discrete focal adhesions (FAs) dzinoparadzira cascade ye biomechanical uye biochemical cellular shanduko inodzora kusiyanisa, kuwanda, organogenesis, kutama, kufambira mberi kwechirwere, nezvimwe.Kushandurwa kwemasimba emagetsi kuita biochemical uye / kana (epi) genetic shanduko inozivikanwa se mechanotransduction1.
Iyo integrin transmembrane receptor 2 yagara ichizivikanwa kuti inotsigira iyo extracellular matrix mumasero uye inopindirana mukati nekunze kusaina.Mukuwirirana neinterins, maDGC anosunga ECM kune cytoskeleton, achigadzira chinongedzo chakakosha pakati pekunze nemukati mesero3.Yakazara-yakareba dystrophin (Dp427) inonyanya kuratidzwa mukati memoyo uye skeletal tsandanyama, asi inoonekwawo mumatishu epakati tsinga system, kusanganisira retina uye Purkinje tishu4.Kuchinja mu integrins uye DGC kunofungidzirwa kuti ndiyo zvikonzero zve muscular dystrophy uye progressive dilated cardiomyopathy (DCM) (Table 1) 5,6.Kunyanya, kuchinja kweDMD kukodha yepakati dystrophin protein DGCs inokonzeresa Duchenne muscular dystrophy (DMD)7.DGC inoumbwa nemasubcomplexes akati wandei anosanganisira α- uye β-dystroglycan (α/β-DG), sarcoglycan-spanin, dystrophin, uye dystrophin 8.
Dystrophin ipuroteni inonzi cytoskeletal yakavharidzirwa neDMD (Xp21.1-Xp22) inoita basa guru mukuchengetedza DGC.DGC inochengetedza kutendeseka kwe sarcolemma, iyo plasma membrane ye striated tsandanyama tishu.Dystrophin inowedzera kuderedza kukuvadzwa kunokonzerwa nekumisikidza nekuita sechitubu chemolecular uye molecular scaffold9,10.Yakazara-yakareba dystrophin ine huremu hwemamorekuru hwe427 kDa, zvisinei, nekuda kwevazhinji vanosimudzira mukati muDMD, kune akati wandei anongoitika truncated isoforms, kusanganisira Dp7111.
Mapuroteni ekuwedzera akave akaratidzwa kuti anowanikwa kune dystrophin, kusanganisira mechanotransducers yechokwadi yakadai se neuronal nitric oxide synthase (nNOS), Yes-associated protein (YAP), uye caveolin-3, nokudaro inomiririra zvikamu zvakakosha zvechiratidzo chemasero.Compounds 12, 13, 14. Pamusoro pekunamatira, nzira yemagetsi inobatanidza nekubatana pakati pemasero uye matrix, inoumbwa neintegrins uye zvinangwa zvadzo zvepasi, izvi zviviri zvinomiririra kuwirirana pakati pe "mukati" uye "kunze" kwesero. .Kuchengetedza izvi zvinonamira zvinonamira kubva mukuparadzwa zvisina kujairika kwakakosha kumaitiro emasero uye kurarama.Mukuwedzera, data inotsigira iyo dystrophin inogadzirisa ma mechanosensitive ion channels, kusanganisira kutambanudza-activated channels, kunyanya L-type Ca2 + chiteshi uye TRPC 15 nzira.
Kunyange zvazvo dystrophin yakakosha kune homeostatic basa re striated muscle cells, iyo chaiyo inotsigira nzira haina kujeka, kunyanya basa re dystrophin uye kukwanisa kwayo kuita se mechanosensor uye mechanical protector.Pamusana pekurasikirwa kwedystrophin, mibvunzo yakawanda isina kupindurwa yakamuka, kusanganisira: ndeye mechanosensitive mapuroteni akadai seYAP uye AMPK yakasvibiswa kune sarcolemma;Pane here crosstalk ine integrins, mamiriro ezvinhu anogona kutungamira kune abnormal mechanotransduction?Zvose izvi zvinogona kubatsira kune yakanyanya DCM phenotype inoonekwa kune varwere vane DMD.
Mukuwedzera, kushamwaridzana kwekuchinja mumaserura biomechanics nehuwandu hweDMD phenotype ine zvakakosha zvinokonzerwa nekliniki.DMD inonzi X-yakabatanidzwa muscular dystrophy inobata 1: 3500-5000 varume, inoratidzwa nekutanga kurasikirwa kwekufamba (<5 makore) uye inofambira mberi DCM ine chirevo chakanyanya kuipa kupfuura DCM yemamwe etiologies16,17,18.
Iyo biomechanics yekurasikirwa kwedystrophin haina kunyatsotsanangurwa, uye pano tinoongorora humbowo hunotsigira pfungwa yekuti dystrophin inonyatsoita basa re mechanoprotective, kureva kuchengetedza kuvimbika kwe sarcolemma, uye yakakosha mu mechanotransduction.Pamusoro pezvo, takaongorora humbowo hunoratidza kuti yakakosha crosstalk ine integrins, kunyanya kusunga laminin α7β1D mumasero akaomeswa mhasuru.
Kupinza uye kudzima ndiko kukonzeresa kuwanda kwekuchinja muDMD, ne72% yekuchinja kuri kukonzerwa nekuchinja kwakadaro19.Muchipatara, DMD inopa muhucheche (≤5 makore) ne hypotension, chiratidzo chakanaka chaGower, kunonoka kufambira mberi kwekuchinja kune zera, kuderera kwepfungwa, uye skeletal muscle atrophy.Kushungurudzika kwekufema kwakagara kwave kuri chikonzero chikuru chekufa kwevarwere veDMD, asi kugadziriswa kwekuchengetedza kwekutsigira (corticosteroids, kuenderera mberi kwakanaka kwemhepo yemhepo) kwakawedzera tarisiro yehupenyu muvarwere ava, uye zera repakati revarwere veDMD vakazvarwa mushure me1990 makore 28.1 20,21 ..Zvisinei, sezvo kupona kwemurwere kunowedzera, kufungidzira kwekufambira mberi kweDCM kwakanyanya kuipa kana ichienzaniswa nemamwe cardiomyopathies16, zvichiita kuti kupera kwemoyo kukundikana, iyo ikozvino ndiyo inonyanya kukonzera rufu, inoverengera inenge 50% yeDMD kufa17,18.
Progressive DCM inoratidzwa nekuwedzera kuruboshwe ventricular dilatation uye kutevedzera, ventricular kuonda, kuwedzera fibrofatty infiltration, kuderera kwe systolic basa, uye kuwedzera kuwanda kwearrhythmias.Dhigirii yeDCM muvarwere vane DMD inenge yepasi rose mukupera kwekuyaruka (90% kusvika kumakore gumi nemasere), asi iripo munenge 59% yevarwere vane makore gumi e8,22.Kugadzirisa nyaya iyi kwakakosha sezvo chikamu chekuruboshwe ventricular ejection chave kuderera zvishoma nezvishoma pamwero we1.6% pagore23.
Cardiac arrhythmias inowanzoitika kune varwere vane DMD, kunyanya sinus tachycardia uye ventricular tachycardia, uye ndiyo inokonzera kufa kamwe kamwe kwemwoyo22.Arrhythmias inokonzerwa nefibrofatty infiltration, kunyanya mu subbasal left ventricle, iyo inokanganisa kutenderera kwekudzoka pamwe chete ne [Ca2 +] i processing dysfunction uye ion channel dysfunction24,25.Kuzivikanwa kwekiriniki yemharidzo yemoyo kwakakosha, sezvo nzira dzekutanga dzekurapa dzinogona kunonoka kutanga kweDCM yakaoma.
Kukosha kwekurapa kusagadzikana kwemoyo uye skeletal muscle morbidity inoratidzwa mune chidzidzo chinonakidza chakashandisa mbeva yeDMD inonzi mdx26 kuti iongorore migumisiro yekuvandudza skeletal muscle tissue pasina kugadzirisa matambudziko emwoyo aripo muDMD.Pano, vanyori vakaratidza mhirizhonga ye5-fold kuwedzera kwekushaya simba kwemwoyo mushure mekuvandudzwa kweskeletal muscle, uye mbeva dzakave nekuderedza kukuru kwechikamu che ejection26.Kuvandudzwa kweskeletal tsandanyama basa kunobvumira kuita kwepamusoro kwemuviri kuisa kushushikana kwakawanda pamyocardium, zvichiita kuti ive nyore kune general dysfunction.Izvi zvinoratidzira kukosha kwekurapa varwere veDMD kazhinji uye kunyevera pamusoro pe skeletal muscle therapy chete.
DGCs dzinoita mamwe mabasa akati wandei, kureva, kupa kugadzikana kwechimiro kune sarcolemma, kuva molecular scaffold inoshanda sechiratidzo chekubatanidza, gadzirisa mechanosensitive ion chiteshi, musimboti we costal mechanotransduction, uye kutora chikamu mukufambiswa kwe lateral simba mudunhu re mbabvu (Fig. 1b)..Dystrophin inoita basa repakati mukukwanisa uku, uye nekuda kwekuvapo kwevazhinji vanosimudzira mukati, kune akati wandei akasiyana isoforms, imwe neimwe ichiita basa rakasiyana mumatishu akasiyana.Musiyano wematishu kutaura kweakasiyana dystrophin isoforms anotsigira pfungwa yekuti imwe neimwe isoform inoita basa rakasiyana.Semuenzaniso, nyama yemwoyo inoratidza hurefu hwakazara (Dp427m) pamwe chete nepfupi Dp71m isoform yedystrophin, nepo skeletal tissue inongoratidzira yekutanga yezviviri.Kucherechedzwa kwebasa rechikamu chega chega chinogona kuratidza kwete chete basa rayo remuviri, asiwo pathogenesis yemuscular dystrophy.
Schematic inomiririra ye-full-length dystrophin (Dp427m) uye diki, diki diki Dp71 isoform.Dystrophin ine 24 spectrin inodzokorora yakaparadzaniswa nemakumbo mana, pamwe chete ne-actin-binding domain (ABD), cysteine-rich (CR) domain, uye C-terminus (CT).Vakakosha vanosunga vanobatana vakaonekwa, kusanganisira microtubules (MTs) uye sarcolemma.Kune akawanda isoforms eDp71, Dp71m inoreva mhasuru tishu uye Dp71b inoreva tsinga isoform.Kunyanya, Dp71f inoreva cytoplasmic isoform ye neurons.b Dystrophin-glycoprotein complex (DHA) iri mu sarcolemma yose.Biomechanical mauto anochinja pakati peECM neF-actin.Ziva zvinogona kuyambuka pakati peDGCs uye integrin adhesion, Dp71 inogona kuita basa mukunamira kwakasimba.Yakagadzirwa neBiorender.com.
DMD ndiyo inonyanya kuzivikanwa muscular dystrophy uye inokonzerwa nekushanduka kweDMD.Zvisinei, kuti tinyatsonzwisisa kunzwisisa kwedu kwemazuva ano kwebasa re-anti-dystrophin, zvakakosha kuiisa mumamiriro ezvinhu eDGC yose.Saka, mamwe mapuroteni anoumbwa anozotsanangurwa muchidimbu.Mapuroteni ekuumbwa kweDGC akatanga kudzidzwa mukupera kwema1980, kunyanya kutarisisa kune dystrophin.Koenig27,28, Hoffman29 uye Ervasti30 vakawana zvakakosha nekuzivisa dystrophin, 427 kDa protein mu striated muscle31.
Mushure meizvozvo, mamwe madiki akaratidzwa kuve akabatana nedystrophin, kusanganisira sarcoglycan, iyo dystrophin transmembrane subcomplex, dysbrevin, uye syntrophins8, iyo pamwe chete inoumba yazvino DGC modhi.Ichi chikamu chichatanga kuparadzira humbowo hwebasa reDGC mukuona kwe mechanosensory uchiongorora zvikamu zvega zvega zvakadzama.
Iyo yakazara-yakareba dystrophin isoform iripo mu striated tsandanyama tishu Dp427m (semuenzaniso "m" kuti tsandanyama isiyanise kubva kuhuropi) uye ipuroteni hombe yakaita setsvimbo ine madomasi mana anoshanda ari pasi pe cardiomyocyte sarcolemma, kunyanya munzvimbo inodhura. 29, 32. Dp427m, yakavharwa neiyo DMD gene paXp21.1, ine 79 exons inogadzirwa pa 2.2 megabases uye saka ndiyo yakakura gene mune yedu genome8.
Vanoverengeka vemukati vanosimudzira muDMD vanogadzira akawanda truncated dystrophin isoforms, mamwe acho ari matushu chaiwo.Kuenzaniswa neDp427m, Dp71m yakaderedzwa zvakanyanya uye haina spectrin inodzokorora domain kana N-terminal ABD domain.Nekudaro, Dp71m inochengeta iyo C-terminal inosunga chimiro.Mune cardiomyocytes, basa reDp71m harina kujeka, asi rakaratidzwa kuti rinogara munzvimbo yeT tubules, zvichiratidza kuti inogona kubatsira kugadzirisa kubatanidza-kukurudzira kubatanidza 33,34,35.Kuruzivo rwedu, kuwanikwa kwechangobva kuitika kweDp71m munyama yemwoyo yakagamuchira kutariswa kushoma, asi zvimwe zvidzidzo zvinoratidza kuti yakabatana neakatambanudzwa-akabatidzwa ion migero, uye Masubuchi akataura kuti inogona kuita basa mukutonga kweNNOS33., 36. Mukuita kudaro, Dp71 yakagamuchira kunyanya kutarisisa neurophysiology uye tsvakurudzo yeplatelet, nzvimbo dzinogona kupa ruzivo rwebasa mu cardiomyocytes37,38,39.
Munyama yetsinga, iyo Dp71b isoform inonyanya kuratidzwa, ine gumi nemana isoforms yakashumwa38.Kubviswa kweDp71b, mutongi anokosha weaquaporin 4 uye Kir4.1 potassium migero munheyo yepakati, yakaratidzwa kushandura ropa-brain barriers permeability40.Tichifunga nezve basa reDp71b mune ion chiteshi mutemo, Dp71m inogona kuita basa rakafanana mucardiomyocytes.
Kuvapo kweDGC mu costal ganglia pakarepo kunoratidza basa mu mechanotransduction, uye zvechokwadi yakaratidzwa kuti iite co-localize ne integrin-talin-vinculin complexes 41.Uyezve, zvichipiwa kuti chikamu chinodhura ndicho chinotarisa che transverse mechanotransduction, nzvimbo yeDp427m pano inoratidzira basa rayo mukudzivirira masero kubva pakukanganiswa-kunokonzerwa nekukuvara.Kupfuurirazve, Dp427m inodyidzana ne actin uye iyo microtubule cytoskeleton, nekudaro ichipedzisa kubatana pakati peiyo intracellular nharaunda uye extracellular matrix.
Iyo N-terminus ine actin-binding domain 1 (ABD1) ine maviri calmodulin homology domains (CH) inodiwa pakudyidzana neF-actin uye anchoring iyo γ-actin isoform kune sarcolemma42,43.Dystrophin inogona kubatsira kune yakazara viscoelasticity ye cardiomyocytes nekubatanidza kune subsarcolemmal cytoskeleton, uye nzvimbo yayo mu costal ganglia inotsigira kubatanidzwa kwayo mu mechanotransduction pamwe ne mechanoprotection44,45.
Iyo yepakati core domain ine makumi maviri nemana-akaita seanodzokorora mapuroteni, rimwe nerimwe rinenge zana amino acid masara pakureba.Iyo spectrin inodzokororwa inopindirana neina hinge domains, ichipa iyo protein kuchinjika uye yakakwirira dhigirii yekuwedzera.Dystrophin spectrin inodzokorora inogona kuitika mukati mehutano hwehutano hwemasimba (15-30 pN) kubva ku21 nm kusvika ku84 nm, masimba anogoneka kune myosin contraction 46.Aya maficha eiyo spectrin inodzokorora domain inobvumira dystrophin kuita senge molecular shock absorber.
Iyo yepakati tsvimbo yeDp427m inovimbisa nzvimbo yayo mu sarcolemma, kunyanya, kuburikidza nehydrophobic uye electrostatic kusangana nephosphatidylserine 47,48.Sezvineiwo, iyo yepakati musimboti we dystrophin inopindirana zvakasiyana ne sarcolemma phospholipids mu skeletal uye cardiac tishu, zvichida kuratidza akasiyana matsutso maitiro.yakakosha, nepo skeletal tsandanyama dzinobatanidzwawo neR10-R1249.
Kusunga kune γ-actin cytoskeleton inoda iyo ABD2 spectrin inodzokorora 11-17 dunhu, iro rine basic amino acid zvisaririra uye rakasiyana kubva kuF-actin-binding CH domain.Microtubules inopindirana zvakananga neiyo core domain ye dystrophin, kusangana uku kunoda zvakasara zve spectrin kudzokorora 4-15 uye 20-23, uye kuvapo kweankyrin B kunodiwa kudzivirira kuumbwa kwe microtubules panzvimbo ino.Machubhu haapo 50,51,52.Mukaha pakati pe microtubules uye dystrophin yakaratidzwa kuwedzera DMD pathology nekuwedzera reactive oxygen marudzi (X-ROS).
Iyo CR domain kuburikidza neankyrin B imwe anchor ye sarcolemmal phospholipids52.Ankyrin-B uye ankyrin-G inodiwa kuti mbabvu igadzike yedystrophin/DGC, uye kusavapo kwavo kunoguma nekupararira sarcolemmal pateni yeDGC52.
Iyo CR domain ine WW inosunga domain inodyidzana zvakananga nePPxY inosunga motif ye β-DG.Nekunamatira kune dystrophin-glycan complex, dystrophin inopedzisa kubatana pakati pemukati nekunze kwesero54.Kubatana uku kwakakosha kune striated muscle, sezvinoratidzwa nechokwadi chokuti kukanganisa kwekubatana pakati peECM uye mukati mesero kunotungamirira kuhupenyu-kuderedza muscular dystrophy.
Pakupedzisira, iyo CT domain inzvimbo yakanyatsochengetedzwa inoumba helix yakakoswa uye yakakosha pakusunga ku-α-dystrobrevin uye α1-,β1-syntrophins55,56.α-dystrobrevin inosungira kune CT domain yedystrophin uye inopa kuwedzera kupikisa dystrophin mu sarcolemma57.
Munguva yekukura kwe embryonic uye fetal, Utrophin inoratidzirwa zvakanyanya mumatishu akasiyana siyana, kusanganisira endothelial masero, tsinga dzetsinga, uye striated tsandanyama tishu58.Utrophin inoratidzwa neUTRN iri pachromosome 6q uye inonzi dystrophin autolog ine 80% protein homology.Munguva yekuvandudzwa, utrophin inowanikwa munzvimbo ye sarcolemma asi inodzvinyirirwa zvakanyanya mumashure ekubereka ane striated muscle tissue, iyo inotsiviwa nedystrophin.Mushure mokuberekwa, nzvimbo ye utrophin inongogumira kune tendon uye neuromuscular junctions ye skeletal muscles58,59.
Utrophin vanosunga vanobatana vakafanana zvakanyanya neaya edystrophins, kunyangwe mamwe misiyano yakakosha yakatsanangurwa.Semuenzaniso, dystrophin inopindirana ne β-DG kuburikidza neWW domain yayo, iyo yakasimbiswa neZZ domain (yakanzi inokwanisa kusunga maviri zinc ions) mukati meC CT nzvimbo, apo cysteic acid yakasara 3307-3354 inonyanya kukosha pakubatana uku60. ., 61. Utrophin inosungirawo ku β-DG kuburikidza neWW / ZZ domain, asi masara chaiwo anotsigira kusangana uku anosiyana nedystrophin residues (3307-3345 mu dystrophin uye 3064-3102 mu utrophin) 60,61.Zvinonyanya kukosha, kusunga kweutrophin ku β-DG kwaive kunenge 2-yakaderera pasi kana ichienzaniswa nedystrophin 61. Dystrophin yakanzi inosunga kuF-actin kuburikidza ne spectrin inodzokorora 11-17, nepo nzvimbo dzakafanana mu utrophin dzisingakwanisi kusunga kuF-actin, kunyange pa. yakanyanya kuwanda, asi inogona kupindirana kuburikidza neCh-domains yavo.Chiito 62,63,64.Pakupedzisira, kusiyana nedystrophin, utrophin haigoni kusunga kune microtubules51.
Biomechanically, utrophin spectrin inodzokororwa ine yakasarudzika inofumuka pateni ichienzaniswa nedystrophin65.Utrophin-spectrin inodzokorora kutumirwa kune masimba akakwirira, akafanana netitin asi kwete dystrophin65.Izvi zvinopindirana nekugara kwayo uye basa mukuparidzirwa kwesimba rakasimba rakasimba pamakona e tendon, asi inogona kuita kuti utrophin isanyanya kukodzera kuita sechitubu chemolecular mu buffering forces inokonzerwa nechibvumirano 65.Kutorwa pamwe chete, idzi data dzinoratidza kuti mechanotransduction uye mechanobuffering masimba anogona kuchinjwa pamberi peutrophin overexpression, kunyanya kupihwa vakasiyana vanosunga vanobatana / nzira, zvisinei izvi zvinoda kumwe kuongorora.
Kubva pakuona kwekushanda, chokwadi chokuti utrophin inotendwa kuva nemigumisiro yakafanana kune dystrophin inoita kuti ive chinangwa chekurapa cheDMD66,67.Kutaura zvazviri, vamwe varwere veDMD vakaratidzwa kuti vakanyanyisa utrophin, zvichida senzira yekubhadhara, uye phenotype yakadzorerwa kubudirira mumuenzaniso we mouse ne utrophin overexpression 68.Kunyange zvazvo kukwidziridzwa kweutrophin inzira yekurapa inogona kunge iri nzira yekurapa, kufunga nezvekusiyana kwepamutemo uye kushanda pakati peutrophin nedystrophin uye kushandiswa kwekukonzera kuwedzeredza uku nekugadziriswa kwakakodzera pamwe chete ne sarcolemma kunoita kuti nzira yenguva refu ye utrophin isati yanyatsojeka.Zvinonyanya kukosha, vatakuri vevakadzi vanoratidza maitiro e-mosaic ekutaura kweutrophin, uye chiyero pakati pedystrophin uye utrophin inogona kukanganisa dhigirii ye dilated cardiomyopathy muvarwere ava, 69 kunyange zvazvo murine mienzaniso yevatakuri vakaratidza..
The dystroglycan subcomplex ine mapuroteni maviri, α- uye β-dystroglycan (α-, β-DG), zvose zvakanyorwa kubva kuDAG1 gene uye mushure mekushandura-shanduro yakanamatira muzvikamu zviviri zveprotein 71.α-DG yakanyanyisa glycosylated mu extracellular aspect yeDGCs uye inopindirana zvakananga neproline residues mu laminin α2 pamwe chete ne agrin72 uye picaculin73 uye CT / CR nzvimbo yedystrophin73,74,75,76.O-yakabatana glycosylation, kunyanya yemaserine residues, inodiwa pakudyidzana kwayo neECM.Iyo glycosylation nzira inosanganisira akawanda enzymes ayo anochinja anotungamira muscular dystrophy (ona zvakare Tafura 1).Izvi zvinosanganisira O-mannosyltransferase POMT2, fucutin uye fucutin-related protein (FKRP), maviri ribitol phosphotransferases anowedzera tandem ribitol phosphates kune core glycan, uye puroteni yeKUMURU1 inowedzera xylose uye glucose.Linear uronic acid polysaccharide, inozivikanwawo sematrix glycan pamagumo eglycan77.FKRP inobatanidzwawo mukusimudzirwa nekuchengetedza kweECM, uye kuchinja mairi kunokonzera kuderera kwekutaura kwelaminin α2 uye α-DG77,78,79.Pamusoro pezvo, FKRP inogona zvakare kutungamira kuumbwa kwebasal lamina uye cardiac extracellular matrix kuburikidza neglycosylated fibronectin 80.
β-DG ine PPxY inosunga motif inoisa zvakananga munharaunda uye sequesters YAP12.Uku ndiko kutsvaga kunonakidza sezvo zvichireva kuti DGC inoronga cardiomyocyte cell cycle.α-DH muineonatal cardiomyocytes inopindirana neagrin, iyo inokurudzira moyo patsva uye DGC76 lysis nekuda kwekukura kwesero.Sezvo cardiomyocytes ichikura, aggrin kutaura kunoderera mukufarira laminin, iyo inofungidzirwa kuti inobatsira pakusungwa kwesero76.Morikawa12 yakaratidza kuti kugogodza kaviri kwedystrophin uye salvador, isina kunaka regulator yeYAP, inotungamira kune hyperproliferation ye cardiomyocytes mune infarct-inokonzera rumen.Izvi zvakatungamira kune inonakidza pfungwa yekuti YAP manipulation inogona kuve yakakosha yekiriniki mukudzivirira kurasikirwa kwetishu mushure memyocardial infarction.Saka, agrin-induced DGC lysis inogona kumiririra axis inobvumira kuti YAP activation uye inokwanisa nzira yekuvandudzwa kwemoyo.
Mechanically, α- uye β-DG inofanirwa kuchengetedza kuwirirana pakati pe sarcolemma uye basal layer 81.Ose ari maviri α-DG uye α7 integrins anobatsira mukumanikidza kugadzirwa mugomba remari, uye kurasikirwa kwe-α-DG kunokonzera kupatsanurwa kwesarcolemma kubva kune basal lamina, zvichisiya skeletal tsandanyama tishu panjodzi yekukanganisa-induced kukuvara.Sezvakatsanangurwa kare, iyo dystroglycan complex inogadzirisa kushanduka kwese kweDGCs, uko kusungirirwa ku cognate ligand laminin kunoguma ne tyrosine phosphorylation yePPPY-binding motif ye β-DG892.Tyrosine phosphorylation pano inosimudzira dystrophin disassembly, iyo inofambisa iyo DGC yakaoma.Physiologically, iyi nzira yakanyatsogadziriswa, iyo isipo muscular dystrophy82, kunyange zvazvo nzira dziri pasi dzinotungamirira nzira iyi hadzina kunyatsonzwisiswa.
Cyclic stretch yakaratidzwa kuti iite ERK1/2 uye AMPK nzira kuburikidza neiyo dystrophin yakaoma uye yakabatana protein plectin83.Pamwe chete, plectin uye dystroglycan inotarisirwa kwete kungoita se scaffold, asiwo kutora chikamu mu mechanotransduction, uye kugogodza kweplectin kunotungamirira kuderera kwebasa reERK1 / 2 uye AMPK83.Plectin inosungirawo ku cytoskeletal yepakati filament desmin, uye desmin overexpression yakaratidzwa kuvandudza chirwere che phenotype mu mdx: desmin uye mdx mice, DMD84 double knockout mouse model.Nekubatana ne β-DG, plectin inosunga zvisina kunanga DGC kune ichi chikamu che cytoskeleton.Mukuwedzera, dystroglycan inopindirana nekukura factor receptor-binding protein 2 (Grb2), iyo inozivikanwa kuti inobatanidzwa mune cytoskeletal rearrangements85.Ras activation ne integrin yakaratidzwa kuve yakayananiswa kuburikidza neGrb2, iyo inogona kupa nzira inogoneka yekuyambuka pakati pe integrins neDGC86.
Kuchinja kwemajini anobatanidzwa mu-α-DH glycosylation kunotungamirira kune inonzi muscular dystrophy.Dystroglycanopathies inoratidza kliniki heterogeneity asi inonyanya kukonzerwa nekuvhiringidza kwekubatana pakati pe-α-DG uye laminin α277.Dystrophiglicanoses inokonzerwa nekuchinja kwekutanga muDAG1 kazhinji kushoma zvakanyanya, pamwe nekuti iri embryonic lethal87, zvichisimbisa kukosha kwekushamwaridzana kweserura neECM.Izvi zvinoreva kuti zvirwere zvakawanda zvedystrophic glycan zvinokonzerwa nechipiri cheprotein mutations inobatanidza neglycosylation.Semuenzaniso, shanduko muPOMT1 inokonzeresa yakanyanya kuomarara yeWalker-Warburg syndrome, iyo inoratidzirwa neanencephaly uye zvakanyanya kupfupikiswa hupenyu hunotarisirwa (pasi pemakore matatu)88.Zvisinei, kuchinja kweFKRP kunonyanya kuratidza semakumbo-girdle muscular dystrophy (LGMD), iyo inowanzo (asi kwete nguva dzose) yakapfava.Nekudaro, shanduko muFKRP dzakaratidzwa kuve chikonzero chisingawanzo yeWWS89.Machinjiro mazhinji akaonekwa muFKRP, iyo muvambi mutation (c.826> A) inowanzokonzera LGMD2I90.
LGMD2I inonzi mild muscular dystrophy iyo pathogenesis inobva pakukanganiswa kwekubatana pakati pe extracellular matrix uye intracellular cytoskeleton.Zvisina kujeka hukama pakati pe genotype uye phenotype muvarwere vane shanduko mumajini aya, uye zvechokwadi pfungwa iyi inoshanda kune mamwe mapuroteni eDSC.Sei vamwe varwere vane FKRP mutations vachiratidza chirwere che phenotype chinoenderana neWWS vamwe vaine LGMD2I?Mhinduro kumubvunzo uyu inogona kunge iri mu i) ndeipi nhanho ye glycosylation nzira inobatwa nekuchinja, kana ii) chiyero che hypoglycosylation pane chero nhanho yakapihwa.Hypoglycosylation ye-α-DG inogona kuramba ichibvumira imwe dhigirii yekudyidzana neECM zvichiita kuti pave nehunyoro hwese phenotype, nepo kuparadzaniswa kubva kune yepasi membrane kunowedzera kuoma kwechirwere phenotype.Varwere vane LGMD2I vanogadzirawo DCM, kunyange izvi zvisinganyanyi kunyorwa pane DMD, zvichikurudzira kukurumidza kwekunzwisisa kuchinja uku mumamiriro ezvinhu e-cardiomyocytes.
Iyo sarcospan-sarcoglycan subcomplex inokurudzira kuumbwa kweDHA uye inopindirana zvakananga ne β-DH.Kune mana unidirectional sarcoglycans munyama yemwoyo: α, β, γ, uye δ91.Ichangobva kutsanangurwa kuti c.218C>T missense mutation in exon 3 yeSGCA gene uye chikamu cheheterozygous deletion mu exons 7-8 chinokonzera LGMD2D92.Zvisinei, munyaya iyi, vanyori havana kuongorora cardiac phenotype.
Mamwe mapoka akawana kuti SGCD mu porcine93 uye mouse94 modhi inoguma nekuderedzwa kweprotein kutaura mu sarcoglycan subcomplex, kukanganisa chimiro chese cheDGC uye chinotungamira kuDCM.Mukuwedzera, 19% yevarwere vose vane SGCA, SGCB, kana SGCG mutations vakanzi vane dilated cardiomyopathy, uye 25% yevarwere vose vaidawo rubatsiro rwekufema95.
Recessive mutations mu sarcoglycan (SG) δ inokonzeresa kuderedzwa kana kusavapo kwakakwana kwe sarcoglycan complexes uye nokudaro DGC munyama yemwoyo uye ine mutoro weLGMD uye yakabatana nayo DCM96.Sezvineiwo, inotonga-yakashata shanduko muSG-δ yakanangana neiyo cardiovascular system uye ndiyo inokonzera mhuri dilated cardiomyopathy97.SG-δ R97Q uye R71T dominant-negative mutations dzakaratidzwa dzakadzikama kuratidzwa mumakonzo cardiomyocytes pasina kukanganisa kwakanyanya kweiyo yakazara DGC98.Zvisinei, masero emwoyo anotakura kuchinja uku anonyanya kukanganisa kukuvadzwa kwe sarcolemma, permeability, uye mechanical dysfunction pasi pe mechanical stress, inopindirana neDCM98 phenotype.
Sarcospan (SSPN) ndeye 25 kDa tetraspanin inowanikwa mu sarcoglycan subcomplex uye inofungidzirwa kuti inoshanda seprotein scaffold99,100.Seprotein scaffold, SSPN inogadzirisa nzvimbo uye glycosylation ye-α-DG99,101.Kuwedzeredza kweSSPN mumhando dzemouse kwakawanikwa kuwedzera kusunga pakati pemhasuru uye laminin 102.Pamusoro pezvo, SSPN yakaratidza kudyidzana neinterins, zvichiratidza dhigirii rekuyambuka pakati pemiviri yembabvu commissures, DGC, uye integrin-talin-vinculin glycoprotein chimiro100,101,102.Knockdown yeSSPN yakakonzerawo kuwedzera kwe α7β1 mune mouse skeletal muscle.
Ongororo ichangobva kuitika yakaratidza kuti sarcospan overexpression inowedzera kukura uye glycosylation ye-α-DG munyama yemwoyo yakazvimiririra yegalactosylaminotransferase 2 (Galgt2) knockdown mu mdx mouse model yeDMD, nokudaro kuderedza chirwere che phenotype 101. Kuwedzera glycosylation ye dystroglycan yakaoma inogona kuwedzera kupindirana kwedystroglycan ECM, nekudaro zvakanyanya kuderedza chirwere.Uyezve, vakaratidza kuti sarcospan overexpression inoderedza kupindirana kwe β1D integrin neDGCs, kuratidza basa rinobvira re sarcospan mukugadzirisa kwe integrin complexes101.
Syntrophins imhuri yediki (58 kDa) mapuroteni anogara kuDGCs, haana iwo ega ane intrinsic enzymatic chiitiko, uye anoshanda semamolecular adapter103,104.Zvishanu isoforms (α-1, β-1, β-2, γ-1 uye γ-2) zvakaonekwa zvichiratidza mataurirwo-akananga kutaura, ne-α-1 isoform inonyanya kuratidzwa mumasumbu akaomeswa 105.Syntrophins inokosha adapta mapuroteni anobatsira kutaurirana pakati pedystrophin uye kuisa mamorekuru, kusanganisira neuronal nitric oxide synthase (nNOS) mu skeletal muscle106.α-syntrophin inopindirana zvakananga nedystrophin 16-17 spectrin repeat domain, iyo inosungira kune nNOS106,107 PDZ-binding motif.
Syntrophins inodyidzanawo nedystrobrevin kuburikidza nePH2 uye SU binding domains, uye ivo vanobatanawo ne actin cytoskeleton 108.Zvechokwadi, ma syntrophins anoita seanoita basa rinokosha mukugadzirisa kwe cytoskeletal dynamics, uye α uye β isoforms inokwanisa kuwirirana zvakananga neF-actin 108 uye nokudaro inogona kuita basa mukugadzirisa kwekusimba uye biomechanics ye cellular. effect.Mukuwedzera, ma syntrophins akaratidzwa kudzora cytoskeleton kuburikidza neRac1109.
Modulating syntrophin mazinga anogona kudzorera basa, uye kuongorora kwechangobva kuitwa kushandisa mini-dystrophin kwakaratidza kuti ΔR4-R23 / ΔCT kuvaka yakakwanisa kudzorera α-syntrophin pamwe chete nemamwe mapuroteni eDGC kusvika kumazinga akaenzana neWT mdx cardiomyocytes.
Mukuwedzera kune basa ravo mukugadzirisa kwe cytoskeleton, syntrophins yakanyorwawo zvakanaka mukugadzirisa kweion channels 111,112,113.Iyo PDZ-binding motif ye syntrophins inodzora cardiac voltage-dependent Nav1.5111 chiteshi, iyo inobata basa rakakosha pakugadzira cardiac excitability uye conduction.Zvinofadza, mu mdx mouse model, Nav1.5 migero yakawanikwa yakaderedzwa uye cardiac arrhythmias yakawanikwa mumhuka 111.Mukuwedzera, mhuri ye mechanosensitive ion channels, iyo inononoka receptor inogona chiteshi (TRPC), yakaratidzwa kuti inotungamirirwa ne α1-syntrophin muhutano hwemwoyo 113 uye TRPC6 inhibition yakaratidzwa kuvandudza arrhythmias muDMD112 mouse model.Kuwedzera kweTRPC6 basa muDMD yakashumwa kuti inokonzera cardiac arrhythmias, iyo inosunungurwa kana yakabatanidzwa nePKG 112.Mechanically, dystrophin depletion inokurudzira kutambanudza-induced influx ye [Ca2+] i inoshanda kumusoro kweTRPC6 kuti iite, sezvinoratidzwa mu cardiomyocytes uye vascular smooth muscle cells112,114.Hyperactivation yeTRPC6 kutambanudza inoita kuti ive mechanosensor yakakura uye inogona kurapa chinangwa muDMD112,114.
Kurasikirwa kwedystrophin kunotungamirira ku lysis kana kudzvinyirirwa kweDGC yose yakaoma, nekurasikirwa kunotevera kwemaitiro akawanda e mechanoprotective uye mechanotransduction, zvichiita kuti njodzi ye phenotype ionekwe mumasumbu akaomeswa muDMD.Naizvozvo, zvingava zvine musoro kufunga kuti maRSK anoshanda mukonti uye kuti zvikamu zvega zvega zvinoenderana nekuvapo uye kushanda kwezvimwe zvikamu.Izvi zvinonyanya kuitika kune dystrophin, iyo inoratidzika seyo inodiwa pakuunganidza uye kuisa nzvimbo ye sarcolemma complex mu cardiomyocytes.Chikamu chega chega chinoita basa rakasiyana-siyana mukubatsira kugadzikana kwese sarcolemma, kugadzikwa kwemapuroteni akakosha ekuwedzera, kudzora nzira dzeion uye gene expression, uye kurasikirwa kweprotein imwe chete muDGC kunotungamirira mukusagadzikana kwemyocardium yose.
Sezvakaratidzwa pamusoro apa, mapuroteni akawanda eDGC anobatanidzwa mu mechanotransduction uye kuisa chiratidzo, uye dystrophin inonyanya kukodzera basa iri.Kana DGC iri mumbabvu, izvi zvinotsigira pfungwa yekuti inotora chikamu mu mechanotransduction pamwe chete ne integrins.Nokudaro, DGCs mumuviri inopinda anisotropic simba rekufambisa uye kutora chikamu mune mechanosensory uye cytoskeletal rearrangement ye intracellular microenvironment, inopindirana nemuenzaniso wekusimba.Pamusoro pezvo, Dp427m inobhura mauto anouya ebiomechanical nekuwedzera spectrin inodzokorora mukati mepakati pedomendi, nekudaro ichiita semakanoprotector nekuchengetedza 25 pN yekusunungura simba pamusoro peiyo yakawedzera 800 nm renji.Nekuparadzanisa, dystrophin inokwanisa "kuvharisa" simba rekugadzirisa-relaxation rinobudiswa ne cardiomyocytes10.Tichifunga nezvekusiyana-siyana kweprotein uye phospholipids inopindirana ne spectrin inodzokorora domains, zvinonakidza kufungidzira kana spectrin inodzokorora kusunungura inoshandura kinetics inosunga yemaprotein e mechanosensitive nenzira yakafanana neye talin116,117,118.Zvisinei, izvi hazvisati zvazivikanwa uye kumwe kuongorora kunodiwa.