Insimbi Engagqwali 347 / 347H Ikhoyili eshisiwe Amashubhu we-zhemical ingxenye, Indima ye-dystrophin glycoprotein complexes ku-mechanotransduction yamaseli emisipha

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I-Dystrophin iyiphrotheni eyinhloko ye-dystrophin-glycoprotein complex (DGC) kumisipha yamathambo nama-cardiomyocytes.I-Dystrophin ibophezela i-actin cytoskeleton ku-matrix ye-extracellular (ECM).Ukuqhekeka kokuxhumana phakathi kwe-matrix engaphandle kwe-extracellular kanye ne-cytoskeleton ye-intracellular kungaba nemiphumela elimazayo ye-homeostasis yamangqamuzana emisipha yohlaka lwamathambo, okuholela enanini le-muscular dystrophies.Ukwengeza, ukulahlekelwa kwama-DGC asebenzayo kuholela ekukhuleni kwenhliziyo okunwebekayo nokufa ngaphambi kwesikhathi.I-Dystrophin isebenza njengentwasahlobo yamangqamuzana futhi i-DHA idlala indima ebalulekile ekugcineni ubuqotho be-sarcolemma.Ngaphezu kwalokho, ubufakazi buyanda obuxhumanisa i-DGC nokusayina kwemishini, nakuba le ndima isalokhu iqondwa kabi.Lesi sihloko sokubuyekeza sihlose ukunikeza umbono wesimanje wama-DGC kanye nendima yawo ku-mechanotransduction.Siqale sixoxe ngobudlelwano obuyinkimbinkimbi phakathi kwemishini yamangqamuzana emisipha nomsebenzi, bese sibuyekeza ucwaningo lwakamuva mayelana nendima ye-dystrophin glycoprotein eyinkimbinkimbi ku-mechanotransduction nokugcinwa kobuqotho be-biomechanical ye-muscle.Okokugcina, sibuyekeza izincwadi zamanje ukuze siqonde ukuthi ukusayinda kwe-DGC kuhlangana kanjani nezindlela ze-mechanosignaling ukuze kugqanyiswe amaphuzu angaba khona okungenelela esikhathini esizayo, ngokugxila ikakhulukazi ku-cardiomyopathy.
Amaseli ahlala exhumana ne-microenvironment yawo, futhi ingxoxo yezindlela ezimbili phakathi kwawo iyadingeka ukuze kuchazwe nokuhlanganiswa kolwazi lwe-biomechanical.I-Biomechanics ilawula izenzakalo ezibalulekile ezilandelayo (isb., ukuhlela kabusha i-cytoskeletal) ngokulawula i-phenotype yeselula iyonke emkhathini nesikhathi.Okubalulekile kule nqubo ku-cardiomyocytes isifunda esibizayo, isifunda lapho i-sarcolemma ixhumeka khona ku-sarcomere eyakhiwe yi-integrin-talin-vinculin kanye ne-dystrophin-glycoprotein (DGC) complexes.Enamathiselwe ku-cytoskeleton ye-intracellular, lawa ma-discrete focal adhesion (FAs) asakaza i-cascade yezinguquko zeselula ze-biomechanical kanye ne-biochemical ezilawula ukuhlukana, ukwanda, i-organogenesis, ukufuduka, ukuqhubekela phambili kwezifo, nokuningi.Ukuguqulwa kwamandla e-biomechanical abe yi-biochemical kanye/noma (epi) izinguquko zofuzo kwaziwa ngokuthi i-mechanotransduction1.
I-integrin transmembrane receptor 2 sekuyisikhathi eside yaziwa ngokumisa i-matrix engaphandle kwamaseli kumaseli futhi ilamula kokubili ukusayina kwangaphakathi nangaphandle.Ngokuhambisana nama-interins, ama-DGC abophezela i-ECM ku-cytoskeleton, asungula isixhumanisi esibalulekile phakathi kwengaphandle nangaphakathi kweseli3.I-dystrophin yobude obugcwele (i-Dp427) iboniswa ngokuyinhloko emisipha yenhliziyo neyohlaka lwamathambo, kodwa futhi ibonakala ezicutshini zesistimu yezinzwa emaphakathi, okuhlanganisa i-retina ne-Purkinje tissue4.Ukuguqulwa kwama-interins kanye ne-DGC kucatshangwa ukuthi yizimbangela ze-muscular dystrophy kanye ne-progressive dilated cardiomyopathy (DCM) (Ithebula 1)5,6.Ikakhulukazi, izinguquko ze-DMD ezifaka ikhodi yephrotheni ye-dystrophin emaphakathi DGCs kubangela i-Duchenne muscular dystrophy (DMD)7.I-DGC yakhiwe ama-subcomplexes amaningana ahlanganisa i-α- ne-β-dystroglycan (α/β-DG), i-sarcoglycan-spanin, i-dystrophin, ne-dystrophin 8.
I-Dystrophin iphrotheni ye-cytoskeletal efakwe ikhodi yi-DMD (Xp21.1-Xp22) edlala indima ebalulekile ekugcineni i-DGC.I-DGC igcina ubuqotho be-sarcolemma, ulwelwesi lwe-plasma lwezicubu ze-striated muscle.I-Dystrophin iqhubeka inciphisa umonakalo obangelwa ukufinyela ngokusebenza njengentwasahlobo yamangqamuzana kanye ne-scaffold yamangqamuzana9,10.I-dystrophin yobude obugcwele inesisindo samangqamuzana esingu-427 kDa, nokho, ngenxa yabagqugquzeli abaningi bangaphakathi ku-DMD, kukhona ama-isoform ambalwa avele ngokwemvelo ancishisiwe, okuhlanganisa ne-Dp7111.
Amaprotheni asesekeli aboniswe ukuthi atholakala ku-dystrophin, kuhlanganise nama-mechanotransducers weqiniso afana ne-neuronal nitric oxide synthase (nNOS), i-Yes-associated protein (YAP), ne-caveolin-3, ngaleyo ndlela imele izingxenye ezibalulekile zokubonisa amaselula.I-Compounds 12, 13, 14. Ngaphezu kokunamathela, indlela yeselula ehlotshaniswa nokusebenzisana phakathi kwamaseli kanye ne-matrix, eyakhiwe ama-interins kanye nokuhlosiwe kwawo komfula, lezi zinhlanganisela ezimbili zimelela ukuxhumana phakathi "kwangaphakathi" kanye "nangaphandle" kweseli. .Ukuvikela lezi zinto ezigxilile ekubhujisweni okungavamile kubalulekile ekuziphatheni kweseli nasekusindeni.Ngaphezu kwalokho, ukusekelwa kwedatha ukuthi i-dystrophin iyi-modulator yeziteshi ze-ion ze-mechanosensitive, kufaka phakathi iziteshi ezivuliwe, ikakhulukazi iziteshi ze-L-type Ca2 + kanye neziteshi ze-TRPC 15.
Nakuba i-dystrophin ibalulekile emsebenzini we-homeostatic wamangqamuzana emisipha e-striated, izindlela eziqondile zokusekela azicaci kahle, ikakhulukazi indima ye-dystrophin kanye nekhono layo lokusebenza njenge-mechanosensor kanye nomvikeli wemishini.Ngenxa yokulahlekelwa kwe-dystrophin, kuye kwavela imibuzo eminingana engaphenduliwe, okuhlanganisa: ingabe amaprotheni e-mechanosensitive afana ne-YAP ne-AMPK adutshulwe ku-sarcolemma;Ingabe kukhona i-crosstalk nama-interins, izimo ezingaholela ku-mechanotransduction engavamile?Zonke lezi zici zingase zibe nomthelela ku-DCM phenotype ebonakala ezigulini ezine-DMD.
Ukwengeza, ukuhlotshaniswa kwezinguquko ku-biomechanics yamaselula ne-phenotype ye-DMD iyonke kunemiphumela ebalulekile yomtholampilo.I-DMD i-X-linked muscular dystrophy ethinta amadoda angu-1: 3500-5000, ebonakala ngokulahlekelwa ukuhamba kwangaphambi kwesikhathi (I-biomechanics yokulahlekelwa kwe-dystrophin ayizange ichazwe ngokugcwele, futhi lapha sibuyekeza ubufakazi obusekela umbono wokuthi i-dystrophin ngempela idlala indima ye-mechanoprotective, okungukuthi ukugcina ubuqotho be-sarcolemma, futhi ibalulekile ku-mechanotransduction.Ngaphezu kwalokho, sibuyekeze ubufakazi obuphakamisa i-crosstalk ebalulekile nama-interins, ikakhulukazi abopha i-lamin α7β1D kumaseli emisipha e-striated.
Ukufaka nokususwa kwezakhi zofuzo kunesibopho senani elikhulu lokuguqulwa kwezakhi zofuzo ku-DMD, no-72% wezinguquko ezibangelwa izinguquko ezinjalo19.Ngokomtholampilo, i-DMD yethula ebuntwaneni (≤5 iminyaka) nge-hypotension, isibonakaliso esihle sika-Gower, ukulibaziseka kokuqhubekela phambili kwezinguquko ezihlobene nobudala, ukukhubazeka kwengqondo, kanye ne-skeletal muscle atrophy.Ukucindezeleka kokuphefumula ngokomlando bekuyimbangela ehamba phambili yokufa kweziguli ze-DMD, kodwa ukunakekelwa okuthuthukisiwe okusekelayo (i-corticosteroids, ukucindezela okuqhubekayo kwe-airway) kuye kwenyusa isikhathi sokuphila kulezi ziguli, futhi iminyaka emaphakathi yeziguli ze-DMD ezalwe ngemva kuka-1990 yiminyaka engu-28.1 20 ,21 ..Kodwa-ke, njengoba ukusinda kwesiguli kwanda, ukubikezelwa kwe-DCM eqhubekayo kubi kakhulu uma kuqhathaniswa nezinye i-cardiomyopathies16, okuholela ekuhlulekeni kwenhliziyo yesigaba sokuphela, okwamanje okuyimbangela ehamba phambili yokufa, okubalelwa cishe i-50% yokufa kwe-DMD17,18.
I-DCM eqhubekayo ibonakala ngokwanda kokunwetshwa kwe-ventricular yesokunxele nokuhambisana, ukuncipha kwe-ventricular, ukwanda kokungena kwe-fibrofatty, ukwehla kokusebenza kwe-systolic, nokwanda kwemvamisa ye-arrhythmias.Izinga le-DCM ezigulini ezine-DMD licishe lifike endaweni yonke lapho sekwephuzile (90% kuya ku-18 ubudala), kodwa likhona cishe ku-59% weziguli ngeminyaka eyi-10 yobudala8,22.Ukubhekana nalolu daba kubalulekile njengoba ingxenye ye-ventricular ejection yesokunxele iye yehla kancane kancane ngezinga le-1.6% ngonyaka23.
I-cardiac arrhythmias ivamile ezigulini ezine-DMD, ikakhulukazi i-sinus tachycardia kanye ne-ventricular tachycardia, futhi iyimbangela yokufa kwenhliziyo kungazelelwe22.I-Arrhythmias iwumphumela wokungena kwe-fibrofatty, ikakhulukazi ku-ventricle yesokunxele engaphansi kwe-basal, ephazamisa ukujikeleza kokubuya kanye [ne-Ca2+]i yokucubungula ukungasebenzi kanye nokungasebenzi kahle kwesiteshi se-ion24,25.Ukuqashelwa kwesethulo senhliziyo yomtholampilo kubalulekile, njengoba amasu okwelapha kusenesikhathi angase abambezele ukuqala kwe-DCM enzima.
Ukubaluleka kokwelapha ukungasebenzi kahle kwenhliziyo kanye ne-skeletal muscle morbidity kuboniswa esifundweni esithakazelisayo esasebenzisa imodeli yegundane ye-DMD ebizwa ngokuthi i-mdx26 ukutadisha imiphumela yokuthuthukisa izicubu ze-skeletal muscle ngaphandle kokubhekana nezinkinga zenhliziyo ezingaphansi ezikhona ku-DMD.Lapha, abalobi babonise ukwanda kwe-paradoxical 5-fold in dysfunction yenhliziyo ngemva kokuthuthukiswa kwemisipha yamathambo, futhi amagundane abe nokunciphisa okukhulu kwe-ejection fraction26.Ukusebenza okuthuthukisiwe kwemisipha yamathambo kuvumela umsebenzi ophezulu womzimba ukubeka ubunzima obuningi ku-myocardium, okwenza kube lula ukungasebenzi kahle okuvamile.Lokhu kuqokomisa ukubaluleka kokwelapha iziguli ze-DMD ngokujwayelekile kanye nezixwayiso ngokwelashwa kwemisipha yamathambo kuphela.
Ama-DGC enza imisebenzi eminingana eyengeziwe, okungukuthi, ukunikeza ukuzinza kwesakhiwo ku-sarcolemma, abe isikafula samangqamuzana esisebenza njengesixhumanisi sokubonisa, silawule iziteshi ze-ion ze-mechanosensitive, umnyombo we-costal mechanotransduction, futhi ubambe iqhaza ekudlulisweni kwamandla ahlangene esifundeni izimbambo (Fig. 1b)..I-Dystrophin idlala indima ebalulekile kuleli khono, futhi ngenxa yokuba khona kwabagqugquzeli abaningi bangaphakathi, kunama-isoform amaningana ahlukene, ngalinye lidlala indima ehlukile ezicutshini ezahlukene.Ukubonakaliswa kwezicubu ezihlukene ze-dystrophin isoforms ehlukene kusekela umbono wokuthi isoform ngayinye idlala indima ehlukile.Isibonelo, izicubu zenhliziyo ziveza ubude obugcwele (i-Dp427m) kanye ne-Dp71m emfishane ye-isoform ye-dystrophin, kuyilapho izicubu zamathambo zizwakalisa eyokuqala kokubili.Ukubhekwa kwendima ye-subtype ngayinye kungembuli nje kuphela umsebenzi wayo wokuphila, kodwa futhi ne-pathogenesis ye-muscular dystrophy.
Ukumelwa okuhleliwe kwe-dystrophin yobude obugcwele (Dp427m) kanye ne-isoform encane, efinyeziwe ye-Dp71.I-Dystrophin inokuphinda okungu-24 kwe-spectrin ehlukaniswe izihibe ezine, kanye nesizinda esibopha i-actin (ABD), isizinda se-cysteine-rich (CR), kanye ne-C-terminus (CT).Abalingani ababalulekile ababophezelayo bakhonjwe, okuhlanganisa ama-microtubules (MTs) kanye ne-sarcolemma.Kunama-isoform amaningi e-Dp71, i-Dp71m isho izicubu zemisipha bese i-Dp71b isho i-isoform yezicubu zezinzwa.Ikakhulukazi, i-Dp71f ibhekisela ku-cytoplasmic isoform yama-neurons.b I-dystrophin-glycoprotein complex (DHA) itholakala ku-sarcolemma iyonke.Amandla e-Biomechanical ashintsha phakathi kwe-ECM ne-F-actin.Qaphela ukungqubuzana okungaba khona phakathi kwe-DGC kanye nokunamathela kwe-integrin, i-Dp71 ingase idlale indima ekugxilweni kokunamathela.Idalwe nge-Biorender.com.
I-DMD iyi-dystrophy yemisipha evame kakhulu futhi ibangelwa ukuguquka kwezakhi ku-DMD.Nokho, ukwazisa ngokugcwele ukuqonda kwethu kwamanje kwendima ye-anti-dystrophin, kubalulekile ukuyibeka kumongo we-DGC iyonke.Ngakho-ke, amanye amaprotheni ayingxenye azochazwa kafushane.Ukwakheka kwamaprotheni e-DGC kwaqala ukufundwa ngasekupheleni kweminyaka yawo-1980, kugxilwe ikakhulukazi ku-dystrophin.I-Koenig27,28, Hoffman29 kanye ne-Ervasti30 bathole into ebalulekile ngokuhlonza i-dystrophin, iphrotheni engu-427 kDa ku-striated muscle31.
Kamuva, amanye ama-subcomplexes aboniswa ukuthi ahlotshaniswa ne-dystrophin, okuhlanganisa i-sarcoglycan, i-dystrophin transmembrane subcomplex, i-dysbrevin, ne-sytrophins8, ehlangene akha imodeli yamanje ye-DGC.Lesi sigaba sizoqala sisakaze ubufakazi bendima ye-DGC ekuboneni kwemishini ngenkathi sihlola izingxenye ezingazodwana ngokuningiliziwe.
I-dystrophin isoform yobude obugcwele ekhona kumathishu emisipha e-striated yi-Dp427m (isb. “m” ukuze umsipha ukuze uyihlukanise nobuchopho) futhi iyiphrotheni enkulu emise okwenduku enezizinda ezine ezisebenzayo ezitholakala ngaphansi kwe-cardiomyocyte sarcolemma, ikakhulukazi endaweni yezindleko. 29, 32. I-Dp427m, efakwe ikhodi yofuzo lwe-DMD ku-Xp21.1, iqukethe ama-exons angu-79 akhiqizwa ngamamegabase angu-2.2 futhi ngaleyo ndlela iyisakhi sofuzo esikhulu kunazo zonke ku-genome8 yethu.
Abagqugquzeli abambalwa bangaphakathi ku-DMD bakhiqiza ama-isoform amaningi e-dystrophin anciphile, amanye awo aqondene nezicubu ezithile.Uma iqhathaniswa ne-Dp427m, i-Dp71m incishisiwe kakhulu futhi ayinaso isizinda esiphindayo se-spectrin noma isizinda se-N-terminal ABD.Nokho, i-Dp71m igcina isakhiwo sokubopha i-C-terminal.Ku-cardiomyocytes, indima ye-Dp71m ayicacile, kodwa iboniswe ukuthi ifakwe endaweni ye-T tubules, iphakamisa ukuthi ingasiza ekulawuleni ukuhlangana kwe-excitation-contraction 33,34,35.Ngolwazi lwethu, ukutholakala kwakamuva kwe-Dp71m ezicutshini zenhliziyo zithole ukunakwa okuncane, kodwa ezinye izifundo ziphakamisa ukuthi zihlotshaniswa neziteshi ze-ion ezinwetshiwe, futhi uMasubuchi uphakamise ukuthi kungase kube nendima ekulawuleni i-nNOS33., 36. Ngokwenza kanjalo, i-Dp71 ithole ukunakwa okuphawulekayo ku-neurophysiology kanye nocwaningo lwe-platelet, izindawo ezingase zinikeze ukuqonda ngendima ye-cardiomyocytes37,38,39.
Ezicutshini zezinzwa, i-Dp71b isoform ivezwa kakhulukazi, kubikwe ama-isoform ayi-14.Ukususwa kwe-Dp71b, isilawuli esibalulekile se-aquaporin 4 kanye neziteshi ze-potassium ze-Kir4.1 ohlelweni lwezinzwa olumaphakathi, kuye kwaboniswa ukushintsha ukungakwazi ukungena kwesithiyo segazi nobuchopho40.Njengoba kunikezwe indima ye-Dp71b ekulawuleni isiteshi se-ion, i-Dp71m ingase idlale indima efanayo kuma-cardiomyocytes.
Ukuba khona kwe-DGC ku-costal ganglia ngokushesha kubonisa indima ku-mechanotransduction, futhi ngempela kuboniswe ukuhlanganisa indawo ne-integrin-talin-vinculin complexes 41.Ngaphezu kwalokho, uma kubhekwa ukuthi ingxenye yezindleko igxile ku-mechanotransduction eguquguqukayo, ukwenziwa kwasendaweni kwe-Dp427m lapha kugqamisa indima yayo ekuvikeleni amaseli emonakalweni obangelwa ukufinyela.Ngaphezu kwalokho, i-Dp427m isebenzisana ne-actin kanye ne-microtubule cytoskeleton, ngaleyo ndlela iqedela ukuxhumana phakathi kwemvelo ye-intracellular kanye ne-matrix engaphandle kweseli.
I-N-terminus equkethe isizinda esibophezelayo se-actin 1 (ABD1) siqukethe izizinda ezimbili ze-callodulin homology (CH) ezidingekayo ukuze kusetshenziswe i-F-actin nokunamathisela i-γ-actin isoform ku-sarcolemma42,43.I-Dystrophin ingase ibe nomthelela ku-viscoelasticity yonke ye-cardiomyocytes ngokunamathisela ku-cytoskeleton ye-subsarcolemmal, futhi indawo yayo ku-costal ganglia isekela ukubandakanyeka kwayo ku-mechanotransduction kanye ne-mechanoprotection44,45.
Isizinda esimaphakathi siqukethe amaprotheni aphindayo afana ne-spectrin angama-24, ngalinye linezinsalela ze-amino acid eziyi-100 ngobude.Ukuphinda kwe-spectrin kuhlanganiswe nezizinda ezine zamahinge, okunikeza ukuguquguquka kwephrotheni kanye nezinga eliphezulu lokunwebeka.Ukuphindaphinda kwe-Dystrophin spectrin kungavela ngaphakathi kohla lwe-physiological yamandla (15-30 pN) ukusuka ku-21 nm kuya ku-84 nm, amandla afinyelelekayo ekufinyezweni kwe-myosin 46.Lezi zici zesizinda esiphindayo se-spectrin sivumela i-dystrophin ukuthi isebenze njenge-absorbitor ye-molecular shock.
I-central rod ye-Dp427m iqinisekisa ukuthi indawo yayo ku-sarcolemma, ikakhulukazi, ngokusebenzisana kwe-hydrophobic kanye ne-electrostatic ne-phosphatidylserine 47,48.Kuyathakazelisa ukuthi i-central core ye-dystrophin isebenzisana ngokuhlukile ne-sarcolemma phospholipids ezicutshini zamathambo nezenhliziyo, okungenzeka zibonise amaphethini entwasahlobo ahlukene.okubucayi, kuyilapho izicubu zamathambo nazo zihlotshaniswa no-R10-R1249.
Ukubophezela ku-γ-actin cytoskeleton kudinga i-ABD2 spectrin impinda 11–17 isifunda, esiqukethe izinsalela eziyisisekelo ze-amino acid futhi ehlukile kusizinda se-CH esibopha i-F-actin.Ama-Microtubules asebenzisana ngokuqondile nesizinda esiyinhloko se-dystrophin, lokhu kusebenzisana kudinga izinsalela ze-spectrin ephindaphinda i-4-15 kanye ne-20-23, futhi ukuba khona kwe-ankyrin B kuyadingeka ukuvimbela ukwakheka kwama-microtubules kule sayithi.Amashubhu awekho ku-50,51,52.Igebe phakathi kwama-microtubules ne-dystrophin likhonjiswe ukuthi libhebhethekisa ukugula kwe-DMD ngokwandisa izinhlobo ze-oxygen esebenzayo (X-ROS).
Isizinda se-CR nge-ankyrin B singesinye isikhonkwane se-sarcolemmal phospholipids52.I-Ankyrin-B ne-ankyrin-G ziyadingeka ukuze izimbambo zibe zasendaweni ze-dystrophin/DGC, futhi ukungabikho kwazo kuholela kuphethini ehlukile ye-sarcolemmal ye-DGC52.
Isizinda se-CR siqukethe isizinda esibophezelayo se-WW esisebenzisana ngokuqondile ne-PPxY motif ebophayo ye-β-DG.Ngokunamathisela ku-dystrophin-glycan complex, i-dystrophin iqedela isixhumanisi phakathi kwangaphakathi nangaphandle kweseli54.Lokhu kuxhumana kubalulekile emisipha e-striated, njengoba kufakazelwa yiqiniso lokuthi ukuphazamiseka kokuxhumana phakathi kwe-ECM nengaphakathi leseli kuholela ekunciphiseni ukuphila kwe-muscular dystrophy.
Ekugcineni, isizinda se-CT siyindawo egcinwe kakhulu eyenza i-helix ehlanganisiwe futhi ibalulekile ekubopheni i-α-dystrobrevin kanye ne-α1-,β1-syntrophins55,56.I-α-dystrobrevin ibophezela kusizinda se-CT se-dystrophin futhi inikeza ukumelana okwengeziwe kwe-dystrophin ku-sarcolemma57.
Ngesikhathi sokukhula kwe-embryonic kanye ne-fetus, i-Utrophin iboniswa kabanzi ezicutshini ezihlukahlukene, okuhlanganisa amaseli e-endothelial, izicubu zezinzwa, nezicubu zemisipha ezihlutshiwe58.I-Utrophin iboniswa yi-UTRN etholakala ku-chromosome 6q futhi iyi-autolog ye-dystrophin enama-protein homology angu-80%.Ngesikhathi sokuthuthukiswa, i-utrophin ifakwa endaweni ye-sarcolemma kodwa icindezelwa ngokuphawulekayo kuzicubu zemisipha engemuva kokubeletha, lapho ithathelwa indawo yi-dystrophin.Ngemva kokuzalwa, indawo ye-utrophin inqunyelwe kuma-tendon kanye ne-neuromuscular junctions ye-skeletal muscles58,59.
Ozakwethu ababopha i-Utrophin bafana kakhulu nalawo ama-dystrophin, nakuba kuchaziwe umehluko oyinhloko.Isibonelo, i-dystrophin isebenzisana ne-β-DG ngokusebenzisa isizinda sayo se-WW, esizinziswa isizinda se-ZZ (eqanjwe amandla ayo okubopha ama-ion amabili e-zinc) ngaphakathi kwesifunda sayo se-CT, lapho izinsalela ze-cysteic acid 3307-3354 zibaluleke kakhulu kulokhu kusebenzisana60 ., 61. I-Utrophin iphinde ibophe ku-β-DG ngesizinda se-WW/ZZ, kodwa izinsalela eziqondile ezisekela lokhu kusebenzisana zihluke ezinsalela ze-dystrophin (3307-3345 ku-dystrophin kanye ne-3064-3102 ku-utrophin) 60,61.Okubalulekile, ukubophezela kwe-utrophin ku-β-DG bekucishe kube ngaphansi ngokuphindwe kabili uma kuqhathaniswa ne-dystrophin 61. I-Dystrophin kubikwe ukuthi ibophezela ku-F-actin nge-spectrin ephindaphinda i-11-17, kuyilapho amasayithi afanayo ku-utrophin engakwazi ukubophezela ku-F-actin, ngisho naku-F-actin. ukugxilisa ingqondo okuphezulu, kodwa bangasebenzisana ngokusebenzisa izizinda zabo ze-CH.Isenzo 62,63,64.Okokugcina, ngokungafani ne-dystrophin, i-utrophin ayikwazi ukubopha kuma-microtubules51.
Ngokwe-Biomechanical, ukuphinda kwe-utrophin spectrin kunephethini engabonakali ehlukile uma kuqhathaniswa ne-dystrophin65.I-Utrophin-spectrin iphinda ukuthunyelwa kumandla aphezulu, afana ne-titin kodwa hhayi i-dystrophin65.Lokhu kuhambisana nendawo yayo kanye nendima ekudlulisweni kwamandla okunwebeka aqinile ezimpahleni ze-tendon, kodwa kungenza i-utrophin ingafanelekile ukusebenza njengentwasahlobo yamangqamuzana kumandla okuphazamisayo okubangelwa ukufinyezwa kwe-65.Ihlanganiswe ndawonye, ​​le datha iphakamisa ukuthi i-mechanotransduction kanye namakhono we-mechanobuffering angase ashintshwe lapho kukhona i-utrophin overexpression, ikakhulukazi uma kunikezwe ozakwethu/izindlela zokubopha ezihlukene, nokho lokhu kudinga ucwaningo olwengeziwe lokuhlola.
Ngokombono wokusebenza, iqiniso lokuthi i-utrophin kukholakala ukuthi inemiphumela efanayo ne-dystrophin iyenza ibe inhloso yokwelashwa engaba khona ye-DMD66,67.Eqinisweni, ezinye iziguli ze-DMD ziye zaboniswa ukuthi zine-overexpress utrophin, mhlawumbe njengendlela yokubuyisela, futhi i-phenotype ibuyiselwe ngempumelelo kumodeli yegundane nge-utrophin overexpression 68.Nakuba ukukhushulwa kwe-utrophin kuyindlela yokwelapha okungenzeka ibe yindlela yokwelapha, ukucatshangelwa komehluko osemthethweni nokusebenzayo phakathi kwe-utrophin ne-dystrophin kanye nokusetshenziswa kokwenza lokhu kuchazwa ngokweqile nokwenziwa kwasendaweni okufanele eduze kwe-sarcolemma kwenza isu lesikhathi eside le-utrophin lingacaci.Ngokuphawulekayo, abathwali besifazane babonisa iphethini ye-mosaic ye-utrophin expression, futhi isilinganiso phakathi kwe-dystrophin ne-utrophin singathonya izinga le-cardiomyopathy enwetshiwe kulezi ziguli, i-69 nakuba izibonelo ze-murine zabathwali zibonisiwe..
I-subcomplex ye-dystroglycan iqukethe amaprotheni amabili, i-α- ne-β-dystroglycan (α-, β-DG), womabili alotshwe kusukela kufuzo lwe-DAG1 bese emva kokuhumusha ahlukaniseke abe izingxenye ezimbili zamaprotheni 71.I-α-DG ine-glycosylated kakhulu kusici esingaphandle kwamaseli e-DGC futhi isebenzisana ngokuqondile nezinsalela ze-proline ku-laminin α2 kanye ne-agrin72 ne-picaculin73 kanye nesifunda se-CT/CR se-dystrophin73,74,75,76.I-O-linked glycosylation, ikakhulukazi izinsalela ze-serine, iyadingeka ekusebenzisaneni kwayo ne-ECM.Umzila we-glycosylation uhlanganisa ama-enzyme amaningi okuguquguquka kwawo kuholela ku-muscular dystrophy (bheka futhi Ithebula 1).Lokhu kufaka phakathi i-O-mannosyltransferase POMT2, i-fucutin ne-fucutin-related protein (FKRP), ama-ribitol phosphotransferase amabili anezela i-tandem ribitol phosphates ku-core glycan, kanye ne-LARGE1 protein enezela i-xylose ne-glucose.Umugqa we-uronic acid polysaccharide, owaziwa nangokuthi i-matrix glycan ekugcineni kwe-glycan77.I-FKRP iphinde ihileleke ekuthuthukiseni nasekugcinweni kwe-ECM, futhi ukuguqulwa kwayo kuholela ekunciphiseni ukubonakaliswa kwe-laminin α2 ne-α-DG77,78,79.Ngaphezu kwalokho, i-FKRP ingaphinde iqondise ukwakheka kwe-basal lamina kanye ne-cardiac extracellular matrix ngokusebenzisa i-glycosylated fibronectin 80.
I-β-DG iqukethe i-PPxY motif ebophayo eyenza ibe ngokwendawo ngokuqondile futhi ilandelela i-YAP12.Lokhu kutholakala okuthakazelisayo njengoba kusho ukuthi i-DGC ilawula umjikelezo weseli ye-cardiomyocyte.I-α-DH ku-cardiomyocyte yengane isebenzisana ne-agrin, ekhuthaza ukuvuselelwa kwenhliziyo kanye ne-DGC76 lysis ngenxa yokuvuthwa kwamaseli.Njengoba i-cardiomyocyte ikhula, i-aggrin expression iyehla ivuna i-laminin, okucatshangwa ukuthi inomthelela ekuboshweni komjikelezo wamaseli76.I-Morikawa12 ibonise ukuthi ukunqotshwa kabili kwe-dystrophin ne-salvador, isilawuli esingalungile se-YAP, kuholela ekwandeni kwe-cardiomyocyte ku-rumen ebangela i-infarct.Lokhu kuholele embonweni othokozisayo wokuthi ukukhohlisa kwe-YAP kungaba wusizo emtholampilo ekuvimbeleni ukulahleka kwezicubu ngemuva kwe-myocardial infarction.Ngakho, i-agrin-induced DGC lysis ingase imele i-eksisi evumela ukuqaliswa kwe-YAP futhi iyindlela engaba khona yokuvuselelwa kwenhliziyo.
Ngomshini, i-α- ne-β-DG iyadingeka ukuze kugcinwe ukusebenzisana phakathi kwe-sarcolemma ne-basal layer 81.Kokubili ama-α-DG kanye ne-α7 integrins afaka isandla ekukhiqizeni amandla ku-ganglion ebizayo, futhi ukulahlekelwa kwe-α-DG kubangela ukuhlukaniswa kwe-sarcolemma ku-basal lamina, okushiya izicubu zemisipha yohlaka zibe sengozini yokulimala okubangelwa ukufinyela.Njengoba kuchazwe ngaphambilini, inkimbinkimbi ye-dystroglycan ilawula inzuzo iyonke ye-DGCs, lapho ukubophezela ku-cognate ligand laminin kuphumela ku-tyrosine phosphorylation ye-PPPY-binding motif ye-β-DG892.I-Tyrosine phosphorylation lapha ikhuthaza i-dystrophin disassembly, ephenya inkimbinkimbi ye-DGC.I-Physiologically, le nqubo ilawulwa kakhulu, engekho ku-muscular dystrophy82, nakuba izindlela eziyisisekelo ezilawula le nqubo aziqondi ngokugcwele.
Ukwelulwa kwe-Cyclic kuboniswe ukwenza kusebenze izindlela ze-ERK1/2 kanye ne-AMPK ngokusebenzisa i-dystrophin complex kanye ne-protein plectin83 ehlobene.Ndawonye, ​​i-plectin ne-dystroglycan zidingekile ukuthi ingagcini nje ngokusebenza njenge-scaffold, kodwa futhi nokubamba iqhaza ku-mechanotransduction, futhi ukugoqa kwe-plectin kuholela ekwehleni komsebenzi we-ERK1/2 ne-AMPK83.I-Plectin iphinde ibophezele ku-cytoskeletal intermediate filament desmin, futhi i-desmin overexpression iye yaboniswa ukuthuthukisa i-phenotype yesifo ku-mdx: desmin kanye namagundane e-mdx, imodeli yegundane eliphindwe kabili le-DMD84.Ngokusebenzisana ne-β-DG, i-plectin ibophezela ngokungaqondile i-DGC kule ngxenye ye-cytoskeleton.Ngaphezu kwalokho, i-dystroglycan isebenzisana ne-protein factor receptor-binding binding protein 2 (Grb2), eyaziwa ngokubandakanyeka ekuhleleni kabusha kwe-cytoskeletal85.Ukwenziwa kusebenze kwe-Ras nge-integrin kuboniswe ukuthi kulamula nge-Grb2, enganikeza indlela engaba khona ye-crosstalk phakathi kwama-interins ne-DGC86.
Ukuguqulwa kwezakhi zofuzo ezihilelekile ku-α-DH glycosylation kuholela kulokho okubizwa ngokuthi i-muscular dystrophy.I-Dystroglycanopathies ibonisa ukuhluka komtholampilo kodwa ikakhulukazi ibangelwa ukuphazamiseka ekusebenzisaneni phakathi kwe-α-DG ne-laminin α277.Ama-Dystrophiglicanoses okubangelwa ukuguqulwa kwezakhi zofuzo okuyinhloko ku-DAG1 ngokuvamile ayivelakancane ngokwedlulele, mhlawumbe ngenxa yokuthi ayabulala ama-embryonic87, ngaleyo ndlela aqinisekisa isidingo sokuhlangana kwamaselula ne-ECM.Lokhu kusho ukuthi izifo eziningi ze-dystrophic glycan zibangelwa ukuguqulwa kwamaprotheni esibili okuhambisana ne-glycosylation.Isibonelo, ukuguqulwa kwezakhi zofuzo ku-POMT1 kubangela isifo se-Walker-Warburg esinzima kakhulu, esibonakala nge-anencephaly kanye nesikhathi sokuphila esifinyeziwe ngokuphawulekayo (ngaphansi kweminyaka engu-3)88.Kodwa-ke, ukuguqulwa kwe-FKRP kubonakala kakhulu njenge-limb-girdle muscular dystrophy (LGMD), okuvamise (kodwa hhayi njalo) ukuba mnene uma kuqhathaniswa.Kodwa-ke, ukuguqulwa kwezakhi zofuzo ku-FKRP kukhonjiswe njengembangela eyivelakancane ye-WWS89.Ukuguqulwa okuningi kukhonjwe ku-FKRP, lapho ukuguqulwa komsunguli (c.826>A) kuvame ukubangela i-LGMD2I90.
I-LGMD2I iyi-dystrophy yemisipha ethambile uma kuqhathaniswa ne-pathogenesis yayo isuselwa ekuphazamisekeni kokuxhumana phakathi kwe-matrix engaphandle kweseli kanye ne-intracellular cytoskeleton.Akucaci kakhulu ubudlelwano phakathi kwe-genotype kanye ne-phenotype ezigulini ezinokuguqulwa kwalezi zakhi zofuzo, futhi ngempela lo mqondo uyasebenza kwamanye amaprotheni e-DSC.Kungani ezinye iziguli ezinezinguquko ze-FKRP zibonisa i-phenotype yesifo ehambisana ne-WWS kuyilapho ezinye zine-LGMD2I?Impendulo yalo mbuzo ingase ilele kokuthi i) yisiphi isinyathelo sendlela ye-glycosylation ethintwa ukuguqulwa, noma ii) izinga le-hypoglycosylation kunoma yisiphi isinyathelo.I-Hypoglycosylation ye-α-DG isengase ivumele izinga elithile lokusebenzelana ne-ECM okuholela ku-phenotype evamile emnene, kuyilapho ukuhlukana nolwelwesi olungaphansi kwandisa ukuqina kwe-phenotype yesifo.Iziguli ezine-LGMD2I nazo zithuthukisa i-DCM, nakuba lokhu kubhalwe kancane kune-DMD, okugqugquzela ukuphuthuma kokuqonda lezi zinguquko kumongo we-cardiomyocytes.
I-subcomplex ye-sarcospan-sarcoglycan ikhuthaza ukwakheka kwe-DHA futhi ixhumana ngokuqondile ne-β-DH.Kunama-sarcoglycans amane angaqondile kuzicubu zenhliziyo: α, β, γ, kanye no-δ91.Kusanda kuchazwa ukuthi ukuguqulwa kwe-c.218C>T okuyiphutha ku-exon 3 yofuzo lwe-SGCA kanye nokususwa kwe-heterozygous ngokwengxenye kuma-exons 7–8 kubangela i-LGMD2D92.Kodwa-ke, kulokhu, abalobi abazange bahlole i-phenotype yenhliziyo.
Amanye amaqembu athole ukuthi i-SGCD kumamodeli we-porcine93 kanye ne-mouse94 iphumela ekubonisweni kweprotheyini encishisiwe ku-sarcoglycan subcomplex, ephazamisa ukwakheka okuphelele kwama-DGC futhi okuholela ku-DCM.Ngaphezu kwalokho, i-19% yazo zonke iziguli ezine-SGCA, SGCB, noma i-SGCG zokuguqulwa kwabikwa ukuthi zine-cardiomyopathy enwetshiwe, futhi i-25% yazo zonke iziguli nazo zazidinga ukwesekwa kokuphefumula95.
Ukuguqulwa okweqile ku-sarcoglycan (SG) δ kubangela ukuncipha noma ukungabikho ngokuphelele kwezakhiwo ze-sarcoglycan futhi yingakho i-DGC kuzicubu zenhliziyo futhi inesibopho se-LGMD kanye ne-DCM96 yayo ehlotshaniswa nayo.Kuyathakazelisa ukuthi ukuguqulwa okunamandla-okubi ku-SG-δ kuqondile ohlelweni lwenhliziyo nemithambo yegazi futhi kuyimbangela ye-family dilated cardiomyopathy97.Ukuguqulwa kwe-SG-δ R97Q kanye ne-R71T kokubusa-negative kuboniswe ukuthi kuvezwe ngokuqinile kumagundane e-cardiomyocyte ngaphandle kokonakala okubalulekile kwengqikithi ye-DGC98.Kodwa-ke, amangqamuzana enhliziyo aphethe lezi zinguquko angathinteka kakhulu ekulimaleni kwe-sarcolemma, ukufinyeleleka, kanye nokungasebenzi kahle kwemishini ngaphansi kokucindezeleka komshini, okuhambisana ne-DCM98 phenotype.
I-Sarcospan (SSPN) iyi-tetraspanin engu-25 kDa ebekwe endaweni engaphansi kwe-sarcoglycan futhi kukholakala ukuthi isebenza njenge-scaffold yamaprotheni99,100.Njenge-scaffold yamaprotheni, i-SSPN iqinisa ukwenziwa kwasendaweni kanye ne-glycosylation ye-α-DG99,101.Ukweqisa kwe-SSPN kumamodeli wegundane kutholakale ukwandisa ukubopha phakathi kwemisipha ne-laminin 102.Ngaphezu kwalokho, i-SSPN ikhonjiswe ukuthi isebenzisana nama-interins, iphakamisa izinga le-crosstalk phakathi kwe-commissures yezimbambo ezimbili, i-DGC, kanye nesakhiwo se-integrin-talin-vinculin glycoprotein100,101,102.I-Knockdown ye-SSPN iphinde yaphumela ekwenyukeni kwe-α7β1 kumsipha wamathambo wegundane.
Ucwaningo lwakamuva lubonise ukuthi i-sarcospan overexpression ithuthukisa ukuvuthwa kanye ne-glycosylation ye-α-DG kuzicubu zenhliziyo ngaphandle kwe-galactosylaminotransferase 2 (Galgt2) knockdown kumodeli yegundane ye-mdx ye-DMD, ngaleyo ndlela inciphise isifo se-phenotype 101. Ukwenyuka kwe-glycosylation ye-dystroglycan complex kungase kuthuthukise ukusebenzisana kwe-dystroglycan I-ECM, ngaleyo ndlela inciphisa kakhulu lesi sifo.Ngaphezu kwalokho, babonise ukuthi i-sarcospan overexpression inciphisa ukusebenzisana kwe-β1D integrin nama-DGC, okugqamisa indima engaba khona ye-sarcospan kulawulo lwe-integrin complexes101.
Ama-Syntrophin awumndeni wamaprotheni amancane (58 kDa) atholakala kuma-DGC, wona ngokwawo awanawo umsebenzi we-enzymatic wangaphakathi, futhi asebenza njengama-adaptha wamangqamuzana103,104.Ama-isoforms amahlanu (α-1, β-1, β-2, γ-1 kanye ne-γ-2) ahlonziwe abonisa inkulumo ethize yezicubu, ne-α-1 isoform evezwe kakhulu kumathishu e-striated muscle 105.Ama-Syntrophin abalulekile amaprotheni e-adaptha enza kube lula ukuxhumana phakathi kwe-dystrophin nama-molecule abonisa izimpawu, kuhlanganise neuronal nitric oxide synthase (nNOS) ku-skeletal muscle106.I-α-syntrophin isebenzisana ngokuqondile nesizinda esiphindayo se-dystrophin 16-17, yona ebophezela ku-nNOS106,107 PDZ-binding motif.
Ama-Syntrophin aphinde ahlanganyele ne-dystrobrevin ngezizinda ezibophezelayo ze-PH2 ne-SU, futhi aphinde ahlanganyele ne-actin cytoskeleton 108.Ngempela, ama-sytrophin abonakala edlala indima ebaluleke kakhulu ekulawulweni kwe-cytoskeletal dynamics, futhi i-α kanye ne-β isoforms iyakwazi ukuxhumana ngokuqondile ne-F-actin 108 futhi ngaleyo ndlela ibambe iqhaza ekulawuleni ukuqina kanye ne-biomechanics yeselula. umphumela.Ngaphezu kwalokho, ama-sytrophin abonisiwe ukuthi alawula i-cytoskeleton nge-Rac1109.
Ukulinganisa amazinga e-syntrophin kungabuyisela ukusebenza, futhi ucwaningo lwakamuva olusebenzisa i-mini-dystrophin lubonise ukuthi ukwakhiwa kwe-ΔR4-R23/ΔCT kwakwazi ukubuyisela i-α-syntrophin kanye namanye amaprotheni e-DGC kumazinga aqhathaniswa ne-WT mdx cardiomyocytes.
Ngaphandle kwendima yabo ekulawuleni i-cytoskeleton, ama-sytrophin nawo abhalwe kahle ekulawuleni iziteshi ze-ion 111,112,113.I-PDZ-binding motif yama-sytrophin ilawula isiteshi se-Nav1.5111 esincike ku-voltage yenhliziyo, esidlala indima ebalulekile ekusunguleni ukujabula kwenhliziyo nokuqhuba.Kuyathakazelisa ukuthi kumodeli yegundane ye-mdx, iziteshi ze-Nav1.5 zitholwe zilawulwa futhi ama-arrhythmias enhliziyo atholakala ezilwaneni ze-111.Ukwengeza, umndeni weziteshi ze-ion ze-mechanosensitive, isiteshi esingaba khona se-receptor yesikhashana (TRPC), siboniswe ukuthi silawulwa yi-α1-syntrophin kuzicubu zenhliziyo ye-113 kanye ne-TRPC6 inhibition iboniswe ukuthuthukisa i-arrhythmias kumodeli yegundane ye-DMD112.Ukwenyuka komsebenzi we-TRPC6 ku-DMD kuye kwabikwa ukuthi kubangele ama-arrhythmias enhliziyo, akhululwa lapho ehlanganiswa ne-PKG 112.Ngomshini, ukuncipha kwe-dystrophin kukhuthaza ukungena kwe-stretch-induced ye- [Ca2+]i esebenza phezulu kwe-TRPC6 ukuze isebenze, njengoba kuboniswe kuma-cardiomyocytes namaseli e-vascular smooth muscle cell112,114.I-Hyperactivation ye-TRPC6 ukuze iselule iyenza i-mechanosensor enkulu kanye nethagethi yokwelapha engaba khona ku-DMD112,114.
Ukulahlekelwa kwe-dystrophin kuholela ku-lysis noma ukucindezelwa okumakiwe kwayo yonke inkimbinkimbi ye-DGC, nokulahlekelwa okulandelayo kwemisebenzi eminingi ye-mechanoprotective kanye ne-mechanotransduction, okuholela ku-phenotype eyinhlekelele ebonakala ezicutshini ze-striated muscle ku-DMD.Ngakho-ke, kungase kube nengqondo ukucabangela ukuthi ama-RSK asebenza ekhonsathini nokuthi izingxenye ngazinye zincike ebukhoneni nasekusebenzeni kwezinye izingxenye.Lokhu kuyiqiniso ikakhulukazi nge-dystrophin, ebonakala idingeka ekuhlanganiseni nasekufakweni kwendawo ye-sarcolemma complex kuma-cardiomyocytes.Ingxenye ngayinye idlala indima eyingqayizivele ekufaka isandla ekuzinziseni okuphelele kwe-sarcolemma, ukwenziwa kwasendaweni kwamaprotheni ayisisetshenziswa esibalulekile, ukulawulwa kweziteshi ze-ion kanye nokubonakaliswa kwezakhi zofuzo, nokulahlekelwa kwephrotheni eyodwa ku-DGC kuholela ekungasebenzi kahle kwe-myocardium yonke.
Njengoba kuboniswe ngenhla, amaprotheni amaningi e-DGC ahilelekile ku-mechanotransduction kanye nokusayina, futhi i-dystrophin ifaneleka ngokukhethekile kule ndima.Uma i-DGC itholakala ezimbanjeni, lokhu kuqinisekisa umbono wokuthi ibamba iqhaza ku-mechanotransduction kanye nama-interins.Ngakho-ke, ama-DGC ngokomzimba adluliswa amandla e-anisotropic futhi abambe iqhaza ekuhleleni kabusha kwe-mechanosensory kanye ne-cytoskeletal ye-intracellular microenvironment, ehambisana nemodeli ye-tensegrity.Ngaphezu kwalokho, i-Dp427m ivimba amandla angenayo e-biomechanical ngokwandisa izibukeli eziphindaphindwayo ngaphakathi kwesizinda sayo esimaphakathi, ngaleyo ndlela isebenze njenge-mechanoprotector ngokugcina amandla angu-25 pN akhululayo phezu kwebanga elingu-800 nm elinwetshiwe.Ngokuhlukana, i-dystrophin iyakwazi "ukuvimbela" amandla okunciphisa-ukuphumula akhiqizwa ama-cardiomyocytes10.Uma kubhekwa ukwehlukahlukana kwamaprotheni nama-phospholipids asebenzisana nezizinda eziphindayo ze-spectrin, kuyathakazelisa ukuqagela ukuthi ingabe ukuphinda ukuhlehlisa kwe-spectrin kuyayishintsha yini i-kinetics ebophezelayo yama-mechanosensitive proteins ngendlela efana ne-talin116,117,118.Nokho, lokhu akukakanqunywa futhi kusadingeka uphenyo olwengeziwe.