Bakin Karfe 347 / 347H Welded Coil Tubus zhemical bangaren, Matsayin dystrophin glycoprotein hadaddun a cikin mechanotransduction na tsoka Kwayoyin.

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Dystrophin shine babban furotin na hadaddun dystrophin-glycoprotein (DGC) a cikin tsokar kwarangwal da cardiomyocytes.Dystrophin yana ɗaure cytoskeleton na actin zuwa matrix extracellular (ECM).Rushewar haɗin kai tsakanin matrix extracellular da cytoskeleton na ciki na iya haifar da mummunan sakamako ga homeostasis na ƙwayoyin tsoka na kwarangwal, wanda ke haifar da adadin dystrophy na muscular.Bugu da ƙari, asarar DGCs masu aiki yana haifar da ci gaba mai lalacewa na cardiomyopathy da mutuwa da wuri.Dystrophin yana aiki azaman bazarar kwayoyin halitta kuma DHA tana taka muhimmiyar rawa wajen kiyaye amincin sarcolemma.Haka kuma, shaida tana tara alaƙar DGC zuwa siginar injina, kodayake wannan rawar har yanzu ba a fahimta sosai ba.Wannan labarin bita yana nufin samar da ra'ayi na zamani game da DGCs da rawar da suke takawa a cikin injina.Da farko mun tattauna hadaddun alaƙa tsakanin injiniyoyin ƙwayoyin tsoka da aiki, sannan mu sake nazarin binciken kwanan nan game da rawar da hadaddun glycoprotein na dystrophin a cikin injina transduction da kiyaye amincin ƙwayoyin ƙwayoyin tsoka.A ƙarshe, mun sake nazarin wallafe-wallafen yanzu don fahimtar yadda alamar DGC ta shiga tsakani tare da hanyoyin sarrafa kayan aiki don nuna yiwuwar abubuwan shiga tsakani a nan gaba, tare da mayar da hankali kan ciwon zuciya.
Kwayoyin suna cikin sadarwa akai-akai tare da ƙananan ƙwayoyin cuta, kuma tattaunawa ta hanyoyi biyu a tsakanin su yana da mahimmanci don fassarar da haɗa bayanan kwayoyin halitta.Biomechanics yana sarrafa mahimmin abubuwan da suka faru na gaba (misali, gyare-gyaren cytoskeletal) ta hanyar sarrafa nau'in salon salula gaba ɗaya a sarari da lokaci.Tsakanin wannan tsari a cikin cardiomyocytes shine yanki na farashi, yankin da sarcolemma ke haɗuwa da sarcomere wanda ya ƙunshi integrin-talin-vinculin da dystrophin-glycoprotein (DGC).Haɗe zuwa cytoskeleton na ciki, waɗannan maɗaukakin maɗaukaki masu hankali (FAs) suna yaɗa sauye-sauye na ƙwayoyin cuta da ƙwayoyin cuta waɗanda ke sarrafa bambance-bambance, haɓakawa, organogenesis, ƙaura, ci gaban cuta, da ƙari.Juyawar sojojin biomechanical zuwa biochemical da/ko (epi) canje-canjen kwayoyin halitta ana kiransa mechanotransduction1.
Mai karɓar mai karɓa na integrin 2 ya daɗe da saninsa don ƙulla matrix na extracellular a cikin sel kuma yana daidaita siginar ciki da waje.A layi daya tare da integrins, DGCs suna ɗaure ECM zuwa cytoskeleton, suna kafa muhimmiyar hanyar haɗi tsakanin waje da ciki na tantanin halitta3.Dystrophin mai cikakken tsayi (Dp427) an bayyana shi da farko a cikin ƙwayar zuciya da kwarangwal, amma kuma ana lura dashi a cikin kyallen jikin tsarin juyayi na tsakiya, gami da retina da Purkinje tissue4.Maye gurbi a cikin integrins da DGC ana tsammanin su ne abubuwan da ke haifar da dystrophy na muscular da ci gaban dilated cardiomyopathy (DCM) (Table 1)5,6.Musamman, maye gurbi na DMD da ke ɓoye furotin dystrophin na tsakiya DGCs yana haifar da dystrophy na muscular Duchenne (DMD)7.DGC ya ƙunshi ƙananan ƙananan abubuwa da yawa ciki har da α- da β-dystroglycan (α/β-DG), sarcoglycan-spanin, dystrophin, da dystrophin 8.
Dystrophin shine furotin cytoskeletal wanda DMD (Xp21.1-Xp22) ke yi wanda ke taka muhimmiyar rawa wajen kiyaye DGC.DGC yana kula da mutuncin sarcolemma, membrane plasma na ƙwayar tsoka mai tsauri.Dystrophin yana ƙara rage lalacewa ta hanyar raguwa ta hanyar aiki azaman bazarar kwayoyin halitta da saffold molecular9,10.Dystrophin mai cikakken tsayi yana da nauyin kwayoyin halitta na 427 kDa, duk da haka, saboda yawancin masu tallata ciki a cikin DMD, akwai nau'i-nau'i da yawa da ke faruwa ta halitta, ciki har da Dp7111.
An nuna sunadaran na'urorin haɗi zuwa dystrophin, ciki har da mechanotransducers na gaskiya irin su neuronal nitric oxide synthase (nNOS), furotin da ke hade da Yes (YAP), da caveolin-3, don haka wakiltar mahimman sassa na siginar salula.Haɗaɗɗen 12, 13, 14. Baya ga mannewa, tsarin salula wanda ke hade da hulɗar tsakanin sel da matrix, wanda aka kafa ta hanyar integrins da maƙasudin su na ƙasa, waɗannan ɗakunan biyu suna wakiltar haɗin tsakanin "ciki" da "waje" na tantanin halitta. .Kare waɗannan mannewa mai mahimmanci daga lalacewa mara kyau yana da mahimmanci ga halayen sel da rayuwa.Bugu da ƙari, goyon bayan bayanan cewa dystrophin shine mai daidaitawa na tashoshin ion na injiniya, ciki har da tashoshi masu kunnawa, musamman tashoshi na L-type Ca2 + da tashoshi na TRPC 15.
Ko da yake dystrophin yana da mahimmanci ga aikin homeostatic na ƙwayoyin tsoka masu tsauri, daidaitattun hanyoyin tallafi ba su fito fili ba, musamman rawar dystrophin da ikonsa na aiki azaman injiniyoyi da kariyar injina.Saboda asarar dystrophin, tambayoyin da ba a amsa ba sun taso, ciki har da: sunadaran sunadarai irin su YAP da AMPK sun ɓace zuwa sarcolemma;Shin akwai crosstalk tare da integrins, yanayi da zai iya haifar da rashin daidaituwa na inji?Duk waɗannan fasalulluka na iya ba da gudummawa ga mummunan yanayin phenotype na DCM da aka gani a cikin marasa lafiya tare da DMD.
Bugu da ƙari, haɗin kai na canje-canje a cikin kwayoyin halitta na salula tare da cikakken DMD phenotype yana da mahimmancin tasiri na asibiti.DMD shine dystrophy na muscular da ke da alaƙa da X wanda ke shafar 1: 3500-5000 maza, wanda ke nuna farkon asarar motsi (<5 shekaru) da ci gaba DCM tare da tsinkaye mafi muni fiye da DCM na sauran etiologies16,17,18.
Ba a yi cikakken bayanin sinadarai na asarar dystrophin ba, kuma a nan mun sake nazarin shaidar da ke goyan bayan ra'ayi cewa dystrophin hakika yana taka rawar kariya, watau kiyaye mutuncin sarcolemma, kuma yana da mahimmanci a cikin injina.Bugu da ƙari, mun sake nazarin shaidun da ke ba da shawara mai mahimmanci ta hanyar sadarwa tare da integrins, musamman maɗaurin laminin α7β1D a cikin ƙwayoyin tsoka masu tsauri.
Shigarwa da gogewa suna da alhakin babban adadin maye gurbi a cikin DMD, tare da kashi 72% na maye gurbi ya haifar da irin waɗannan maye gurbi19.A asibiti, DMD yana nunawa a cikin jariri (≤5 shekaru) tare da hypotension, alamar Gower mai kyau, jinkirin ci gaba na canje-canje masu alaka da shekaru, jinkirin tunani, da kuma atrophy na skeletal tsoka.Matsalolin numfashi a tarihi shine babban dalilin mutuwa a cikin marasa lafiya na DMD, amma ingantaccen kulawar tallafi (corticosteroids, ci gaba da matsa lamba mai kyau na iska) ya karu da tsawon rayuwa a cikin waɗannan marasa lafiya, kuma matsakaicin shekarun marasa lafiya na DMD da aka haifa bayan 1990 shine 28.1 shekaru 20,21 ..Duk da haka, yayin da rayuwa mai haƙuri ya karu, tsinkayen ci gaba na DCM yana da matukar muni idan aka kwatanta da sauran cardiomyopathies16, wanda ke haifar da gazawar zuciya na ƙarshe, wanda a halin yanzu shine babban dalilin mutuwa, yana lissafin kusan 50% na mutuwar DMD17,18.
DCM mai ci gaba yana da alaƙa da haɓaka haɓakar ventricular na hagu da kuma yarda, ɓacin rai na ventricular, ƙara yawan shigar fibrofatty, rage aikin systolic, da ƙara yawan arrhythmias.Matsayin DCM a cikin marasa lafiya tare da DMD kusan kusan duniya ne a ƙarshen samartaka (90% zuwa 18 shekaru), amma yana cikin kusan 59% na marasa lafiya ta shekaru 10 na shekaru8,22.Magance wannan batu yana da mahimmanci yayin da ɓangarorin fitar da jijiyoyi na hagu ke raguwa akai-akai akan adadin 1.6% a kowace shekara23.
arrhythmias na zuciya ya zama ruwan dare a cikin marasa lafiya tare da DMD, musamman sinus tachycardia da tachycardia na ventricular, kuma sune sanadin mutuwar zuciya na kwatsam22.Arrhythmias shine sakamakon fibrofatty infiltration, musamman ma a cikin ƙananan ventricle na hagu na subbasal, wanda ke lalata tsarin dawowa da kuma [Ca2 +] i aiki tabarbarewar aiki da tashar tashar ion24,25.Gane bayyanar cututtukan zuciya na asibiti yana da mahimmanci, saboda dabarun jiyya na farko na iya jinkirta farawa na DCM mai tsanani.
Muhimmancin kula da cututtukan zuciya da cututtukan ƙwayar cuta an nuna su a cikin wani bincike mai ban sha'awa wanda ya yi amfani da samfurin linzamin kwamfuta na DMD da ake kira mdx26 don nazarin sakamakon inganta ƙwayar ƙwayar ƙwayar ƙwayar cuta ba tare da magance matsalolin zuciya na zuciya da ke cikin DMD ba.Anan, marubutan sun nuna karuwa mai ban mamaki 5-ninka karuwa a cikin rashin aikin zuciya bayan ingantawa a cikin tsokar kwarangwal, kuma mice sun sami raguwa mai yawa a cikin juzu'in fitarwa26.Ingantacciyar aikin tsokar kwarangwal yana ba da damar yin aiki mafi girma don sanya ƙarin damuwa a kan myocardium, yana sa ya fi sauƙi ga rashin aiki na gaba ɗaya.Wannan yana nuna mahimmancin kula da marasa lafiya na DMD gabaɗaya da kuma yin taka tsantsan game da maganin ƙwanƙwasa ƙwanƙwasa kaɗai.
DGCs suna yin ƙarin ayyuka da yawa, wato, samar da kwanciyar hankali ga sarcolemma, zama ɓangarorin ƙwayoyin cuta waɗanda ke aiki azaman hanyar haɗin sigina, daidaita tashoshin ion na injina, ainihin kayan aikin tsada, da shiga cikin watsa ƙarfin gefe a cikin yankin hakarkarinsa (Hoto na 1b)..Dystrophin yana taka muhimmiyar rawa a cikin wannan ƙarfin, kuma saboda kasancewar yawancin masu haɓakawa na ciki, akwai nau'i-nau'i daban-daban, kowannensu yana taka rawa a cikin kyallen takarda.Bambance-bambancen nama na nau'ikan isoforms na dystrophin daban-daban suna goyan bayan ra'ayi cewa kowane isoform yana taka rawa daban.Misali, nama na zuciya yana bayyana cikakken tsayin (Dp427m) da kuma guntun Dp71m isoform na dystrophin, yayin da kwarangwal nama ke bayyana na farkon biyun.Lura da rawar kowane subttype zai iya bayyana ba kawai aikin halittar halittu ba, har ma da pathogene na tsoka dystrophy.
Misalin tsari na dystrophin mai cikakken tsayi (Dp427m) da ƙarami, tsattsage Dp71 isoform.Dystrohinhin yana da Specrin mai maimaita shekaru hudu sun rabu da madaukai huɗu, da kuma yanki mai-aiki (ABR), wani yanki mai-rics (CT).An gano mahimman abokan haɗin gwiwa, gami da microtubules (MTs) da sarcolemma.Akwai isoforms da yawa na Dp71, Dp71m yana nufin ƙwayar tsoka kuma Dp71b yana nufin isoform na nama mai juyayi.Musamman, Dp71f yana nufin isoform na cytoplasmic na neurons.b Ƙungiyar dystrophin-glycoprotein (DHA) tana cikin sarcolemma gaba ɗaya.Ƙwararrun ƙwayoyin halitta suna canzawa tsakanin ECM da F-actin.Yi la'akari da yuwuwar tattaunawa tsakanin DGCs da mannewar haɗin gwiwa, Dp71 na iya taka rawa a cikin mannewa mai hankali.An ƙirƙira tare da Biorender.com.
DMD shine dystrophy na muscular da ya fi kowa kuma ana haifar dashi ta maye gurbin DMD.Koyaya, don cikakken godiya da fahimtarmu na yanzu game da rawar anti-dystrophin, yana da mahimmanci a sanya shi cikin mahallin DGC gabaɗaya.Don haka, sauran abubuwan gina jiki za a yi bayanin su a taƙaice.An fara nazarin abubuwan gina jiki na DGC a ƙarshen 1980s, tare da kulawa ta musamman ga dystrophin.Koenig27,28, Hoffman29 da Ervasti30 sun yi wani muhimmin bincike ta hanyar gano dystrophin, furotin 427 kDa a cikin tsoka mai rauni31.
Daga baya, an nuna wasu ƙananan abubuwan haɗin gwiwa tare da dystrophin, ciki har da sarcoglycan, da dystrophin transmembrane subcomplex, dysbrevin, da syntrophins8, wanda tare ya zama samfurin DGC na yanzu.Wannan sashe zai fara yada shaidar rawar da DGC ke takawa a cikin fahimtar injiniyoyi yayin nazarin abubuwan da aka haɗa dalla-dalla.
Cikakken dystrophin isoform mai cikakken tsayi wanda ke cikin ƙwayar tsoka mai tsauri shine Dp427m (misali "m" don tsoka don bambanta ta daga kwakwalwa) kuma babban furotin ne mai siffar sanda tare da yankuna huɗu masu aiki waɗanda ke ƙarƙashin sarcolemma na cardiomyocyte, musamman a cikin yankin costal. 29, 32. Dp427m, wanda DMD gene codeed akan Xp21.1, ya ƙunshi 79 exons da aka samar a 2.2 megabases kuma don haka shine mafi girma a cikin genome8.
Yawancin masu tallata cikin gida a cikin DMD suna samar da isoforms na dystrophin da yawa da aka yanke, wasu daga cikinsu takamaiman nama ne.Idan aka kwatanta da Dp427m, Dp71m yana da mahimmanci sosai kuma ba shi da yankin maimaicin spectrin ko yankin N-terminal ABD.Koyaya, Dp71m yana riƙe da tsarin ɗaurin C-terminal.A cikin cardiomyocytes, rawar Dp71m ba a sani ba, amma an nuna shi don ganowa a cikin T tubules, yana ba da shawarar cewa zai iya taimakawa wajen daidaita haɗin kai-hantsi na 33,34,35.Don saninmu, binciken da aka yi kwanan nan na Dp71m a cikin ƙwayar zuciya ya sami kulawa kaɗan, amma wasu nazarin sun nuna cewa yana da alaƙa da tashoshi na ion mai kunnawa, kuma Masubuchi ya nuna cewa yana iya taka rawa a cikin tsarin nNOS33., 36. A cikin yin haka, Dp71 ya sami kulawa mai mahimmanci a cikin neurophysiology da bincike na platelet, yankunan da zasu iya ba da haske game da rawar da ke cikin cardiomyocytes37,38,39.
A cikin nama mai juyayi, Dp71b isoform yawanci ana bayyana shi, tare da isoforms 14 da aka ruwaito38.Goge Dp71b, muhimmin mai kula da tashoshin aquaporin 4 da Kir4.1 potassium a cikin tsarin jijiya na tsakiya, an nuna shi don canza shingen shinge na jini-kwakwalwa40.Ganin rawar Dp71b a cikin ka'idojin tashar ion, Dp71m na iya taka irin wannan rawar a cikin cardiomyocytes.
Kasancewar DGC a cikin ganglia costal nan da nan yana nuna rawar da ke cikin injina, kuma hakika an nuna shi tare da haɗin gwiwar integrin-talin-vinculin complexes 41.Bugu da ƙari, idan aka ba da cewa ɓangaren costal shine abin da ke mayar da hankali ga injinan transverse, ƙaddamar da Dp427m a nan yana nuna rawar da yake takawa wajen kare kwayoyin halitta daga lalacewa mai lalacewa.Bugu da ari, Dp427m yana hulɗa tare da actin da microtubule cytoskeleton, ta haka ne ya kammala haɗin tsakanin yanayin ciki da kuma matrix extracellular.
N-terminus mai ɗauke da actin-binding domain 1 (ABD1) ya ƙunshi yankuna biyu na calmodulin homology (CH) waɗanda ake buƙata don hulɗa tare da F-actin da ƙaddamar da isoform na γ-actin zuwa sarcolemma42,43.Dystrophin na iya ba da gudummawa ga cikakkiyar viscoelasticity na cardiomyocytes ta hanyar haɗawa da cytoskeleton na subsarcolemmal, kuma kasancewarsa a cikin ganglia costal yana goyan bayan sa hannu a cikin injina da kuma mechanoprotection44,45.
Babban yanki na tsakiya ya ƙunshi sunadaran sinadarai masu kama da maimaitawa guda 24, kowannensu kusan 100 ragowar amino acid a tsayi.Ana maimaita maimaitawar spectrin tare da yanki huɗu na hinge, yana ba da sassaucin furotin da babban matakin haɓaka.Dystrophin spectrin maimaitawa zai iya bayyana a cikin kewayon physiological kewayon sojojin (15-30 pN) wanda ya karu daga 21 nm zuwa 84 nm, sojojin da za a iya cimmawa don ƙaddamar da myosin 46.Waɗannan fasalulluka na yankin maimaita spectrin suna ba da damar dystrophin yayi aiki azaman abin ɗaukar girgiza kwayoyin halitta.
Tsakanin sanda na Dp427m yana tabbatar da kasancewarsa a cikin sarcolemma, musamman, ta hanyar hulɗar hydrophobic da electrostatic tare da phosphatidylserine 47,48.Abin sha'awa shine, tsakiyar tsakiya na dystrophin yana hulɗar daban-daban tare da sarcolemma phospholipids a cikin kwarangwal da ƙwayar zuciya, mai yiwuwa yana nuna nau'o'in bazara daban-daban.m, yayin da kwarangwal tsokoki kuma suna hade da R10-R1249.
Daure ga cytoskeleton na γ-actin yana buƙatar spectrin ABD2 maimaita yankin 11-17, wanda ya ƙunshi ragowar amino acid na asali kuma ya bambanta da yankin F-actin-binding CH.Microtubules suna hulɗa kai tsaye tare da ainihin yankin dystrophin, wannan hulɗar yana buƙatar ragowar spectrin maimaita 4-15 da 20-23, kuma ana buƙatar kasancewar ankyrin B don hana samuwar microtubules a wannan rukunin yanar gizon.Tubes ba su nan 50,51,52.An nuna rata tsakanin microtubules da dystrophin don haɓaka ilimin halittar DMD ta hanyar haɓaka nau'in oxygen mai amsawa (X-ROS).
Yankin CR ta hanyar ankyrin B shine wani anka don sarcolemmal phospholipids52.Ana buƙatar Ankyrin-B da ankyrin-G don ƙayyadaddun haƙarƙarin dystrophin/DGC, kuma rashin su yana haifar da yanayin sarcolemmal mai yaduwa na DGC52.
Yankin CR ya ƙunshi yanki mai ɗaurin WW wanda ke hulɗa kai tsaye tare da PPxY dauri motif na β-DG.Ta hanyar haɗawa da hadaddun dystrophin-glycan, dystrophin yana kammala haɗin gwiwa tsakanin ciki da waje na cell54.Wannan haɗin yana da mahimmanci ga tsokar tsoka, kamar yadda shaida ta gaskiyar cewa rushewar haɗin gwiwa tsakanin ECM da ciki na tantanin halitta yana haifar da dystrophy na muscular mai iyakacin rai.
A ƙarshe, yankin CT yanki ne da aka kiyaye shi sosai wanda ke samar da helix ɗin da aka murɗa kuma yana da mahimmanci don ɗaure ga α-dystrobrevin da α1-, β1-syntrophins55,56.α-dystrobrevin yana ɗaure zuwa yankin CT na dystrophin kuma yana ba da ƙarin juriya ga dystrophin a cikin sarcolemma57.
Yayin ci gaban amfrayo da tayin, Utrophin yana bayyana ko'ina a cikin kyallen takarda daban-daban, gami da sel na endothelial, nama mai juyayi, da tsokar tsoka58.Utrophin yana bayyana ta UTRN wanda ke kan chromosome 6q kuma shine autolog dystrophin tare da homology na furotin 80%.A lokacin haɓakawa, an gano utrophin a cikin sarcolemma amma an danne shi sosai a cikin ƙwayar tsoka mai rauni bayan haihuwa, inda aka maye gurbinsa da dystrophin.Bayan haihuwa, ƙaddamarwar utrophin yana iyakance ga tendons da neuromuscular junctions na skeletal tsokoki58,59.
Abokan haɗin Utrophin suna kama da na dystrophins, kodayake an bayyana wasu bambance-bambance masu mahimmanci.Misali, dystrophin yana hulɗa tare da β-DG ta hanyar yankin WW, wanda yankin ZZ ya daidaita (mai suna don ikonsa na ɗaure ions zinc guda biyu) a cikin yankin CT ɗin sa, inda ragowar cysteic acid 3307-3354 ke da mahimmanci ga wannan hulɗar60. ., 61. Utrophin kuma yana ɗaure zuwa β-DG ta hanyar WW / ZZ yankin, amma ainihin ragowar da ke tallafawa wannan hulɗar ya bambanta da ragowar dystrophin (3307-3345 a cikin dystrophin da 3064-3102 a utrophin) 60,61.Mahimmanci, ɗaurin utrophin zuwa β-DG ya kasance kusan 2-ninka ƙasa idan aka kwatanta da dystrophin 61. An ba da rahoton Dystrophin don ɗaure zuwa F-actin ta hanyar spectrin maimaita 11-17, yayin da irin wannan rukunin yanar gizon a cikin utrophin ba zai iya ɗaure zuwa F-actin ba, har ma a babban taro, amma suna iya yin hulɗa ta hanyar CH-domains.Aiki 62,63,64.A ƙarshe, sabanin dystrophin, utrophin ba zai iya ɗaure zuwa microtubules51 ba.
A biomechanically, utrophin spectrin maimaita suna da keɓantaccen tsarin bayyanawa idan aka kwatanta da dystrophin65.Utrophin-spectrin yana maimaita turawa a manyan runduna, kama da titin amma ba dystrophin65 ba.Wannan ya yi daidai da yanayinsa da rawar da yake takawa wajen watsa ƙarfin roba mai ƙarfi a mahaɗar tendon, amma yana iya sa utrophin ya zama ƙasa da dacewa don yin aiki azaman bazarar ƙwayoyin cuta a cikin ƙarfin buffering wanda aka jawo ta hanyar raguwa 65.A hade, waɗannan bayanan suna ba da shawarar cewa za a iya canza canjin injina da ƙarfin injina a gaban yawan wuce gona da iri na utrophin, musamman da aka ba abokan tarayya / injiniyoyi daban-daban, duk da haka wannan yana buƙatar ƙarin binciken gwaji.
Daga ra'ayi na aiki, gaskiyar cewa an yi imanin cewa utrophin yana da irin wannan tasiri ga dystrophin ya sa ya zama maƙasudin magani ga DMD66,67.A gaskiya ma, wasu marasa lafiya na DMD an nuna su don haɓakar utrophin, mai yiwuwa a matsayin tsarin ramawa, kuma an sami nasarar dawo da phenotype a cikin ƙirar linzamin kwamfuta tare da utrophin overexpression 68.Yayin da haɓakar utrophin zai iya zama dabarun warkewa, la'akari da bambancin aiki da aiki tsakanin utrophin da dystrophin da kuma amfanin haifar da wannan wuce gona da iri tare da daidaitaccen wuri tare da sarcolemma ya sa tsarin dogon lokaci na utrophin har yanzu ba a sani ba.Musamman ma, masu ɗaukar mata suna nuna alamar mosaic na maganganun utrophin, kuma rabo tsakanin dystrophin da utrophin na iya rinjayar digiri na cardiomyopathy a cikin waɗannan marasa lafiya, 69 ko da yake nau'in murine na masu ɗaukar kaya sun nuna..
Dystroglycan subcomplex ya ƙunshi sunadaran guda biyu, α- da β-dystroglycan (α-, β-DG), dukansu an rubuta su daga kwayoyin DAG1 sannan kuma bayan fassarar sun rataye a cikin nau'o'in sunadarai guda biyu 71.α-DG yana da glycosylated sosai a cikin sashin salula na DGCs kuma yana hulɗa kai tsaye tare da ragowar proline a cikin laminin α2 da kuma agrin72 da picaculin73 da yankin CT / CR na dystrophin73,74,75,76.Ana buƙatar glycosylation mai alaƙa da O, musamman na ragowar serine, don hulɗar sa tare da ECM.Hanyar glycosylation ta ƙunshi enzymes da yawa waɗanda maye gurbi suna haifar da dystrophy na tsoka (duba kuma Table 1).Waɗannan sun haɗa da O-mannosyltransferase POMT2, fucutin da furotin da ke da alaƙa (FKRP), ribitol phosphotransferases guda biyu waɗanda ke ƙara tandem ribitol phosphates zuwa ainihin glycan, da furotin LARGE1 wanda ke ƙara xylose da glucose.Linear uronic acid polysaccharide, wanda kuma aka sani da matrix glycan a ƙarshen glycan77.FKRP kuma yana shiga cikin haɓakawa da kiyaye ECM, kuma maye gurbi a cikinta yana haifar da raguwar maganganun laminin α2 da α-DG77,78,79.Bugu da ƙari, FKRP na iya jagorantar samuwar basal lamina da matrix extracellular na zuciya ta hanyar glycosylated fibronectin 80.
β-DG ya ƙunshi PPxY dauri motif wanda kai tsaye localizes da sequesters YAP12.Wannan bincike ne mai ban sha'awa kamar yadda yake nuna cewa DGC tana daidaita zagayowar tantanin halitta na cardiomyocyte.α-DH a cikin cardiomyocytes neonatal yana hulɗa tare da agrin, wanda ke inganta farfadowar zuciya da kuma DGC76 lysis saboda balaga ta cell.Yayin da cardiomyocytes suka girma, maganganun aggrin yana raguwa don jin dadin laminin, wanda ake tunanin zai taimaka wajen kama tsarin kwayar halitta76.Morikawa12 ya nuna cewa ƙwanƙwasa sau biyu na dystrophin da salvador, mai kula da YAP mara kyau, yana haifar da haɓakar hauhawar jini na cardiomyocytes a cikin rumen da ke haifar da infarct.Wannan ya haifar da ra'ayi mai ban sha'awa cewa magudi na YAP na iya zama darajar asibiti don hana asarar nama bayan ciwon zuciya na zuciya.Don haka, agin-induced DGC lysis na iya wakiltar axis wanda ke ba da damar kunna YAP kuma hanya ce mai yuwuwa don farfadowar zuciya.
Mechanically, α- da β-DG ana buƙatar don kula da hulɗar tsakanin sarcolemma da basal Layer 81.Dukansu α-DG da α7 integrins suna ba da gudummawar haɓakar ƙarfi a cikin ganglion costal, kuma asarar α-DG yana haifar da rabuwa da sarcolemma daga lamina basal, yana barin ƙwayar ƙwanƙwasa mai rauni ga lalacewar lalacewa.Kamar yadda aka bayyana a baya, hadaddun dystroglycan yana daidaita juzu'in juzu'i na DGCs, inda ɗaure zuwa cognate ligand laminin sakamakon a cikin tyrosine phosphorylation na PPPY-dauri motif na β-DG892.Tyrosine phosphorylation anan yana haɓaka rarrabawar dystrophin, wanda ke jujjuya hadadden DGC.A ilimin halittar jiki, wannan tsari yana da tsari sosai, wanda ba ya cikin dystrophy na muscular82, ko da yake ba a fahimci hanyoyin da ke da alaƙa da wannan tsari ba.
An nuna shimfiɗar cyclic don kunna hanyoyin ERK1/2 da AMPK ta hanyar hadaddun dystrophin da furotin mai alaƙa da plectin83.Tare, ana buƙatar plectin da dystroglycan ba kawai don yin aiki a matsayin abin rufe fuska ba, har ma don shiga cikin mechanotransduction, kuma ƙwanƙwasa na plectin yana haifar da raguwar ayyukan ERK1/2 da AMPK83.Plectin kuma yana ɗaure ga cytoskeletal matsakaici filament desmin, kuma desmin overexpression da aka nuna don inganta cutar phenotype a mdx:desmin da mdx mice, DMD84 biyu knockout linzamin kwamfuta model.Ta hanyar hulɗa tare da β-DG, plectin a kaikaice yana ɗaure DGC zuwa wannan ɓangaren cytoskeleton.Bugu da kari, dystroglycan yana hulɗa tare da furotin mai ɗaure mai karɓa mai girma factor 2 (Grb2), wanda aka sani yana shiga cikin sake tsara tsarin cytoskeletal85.Ras kunnawa ta integrin an nuna ana yin sulhu ta hanyar Grb2, wanda zai iya samar da yuwuwar hanya don tsaka-tsaki tsakanin integrins da DGC86.
Maye gurbi a cikin kwayoyin halittar da ke cikin α-DH glycosylation suna haifar da abin da ake kira dystrophy na muscular.Dystroglycanopathies suna nuna bambancin asibiti amma galibi ana haifar da su ta hanyar rushewa a cikin hulɗar tsakanin α-DG da laminin α277.Dystrophiglicanoses da ke haifar da maye gurbi na farko a cikin DAG1 gabaɗaya ba safai ba ne, mai yiwuwa saboda suna mutuwa na amfrayo87, don haka yana tabbatar da buƙatar haɗin kan salula tare da ECM.Wannan yana nufin cewa yawancin cututtuka na glycan dystrophic suna haifar da maye gurbin furotin na biyu da ke hade da glycosylation.Alal misali, maye gurbi a cikin POMT1 yana haifar da ciwo mai tsanani na Walker-Warburg, wanda ke da alamun anencephaly kuma ya rage tsawon rai (kasa da shekaru 3)88.Koyaya, maye gurbin FKRP galibi yana bayyana azaman dystrophy na muscular-girdle (LGMD), wanda yawanci (amma ba koyaushe) yana da sauƙi ba.Koyaya, an nuna maye gurbi a cikin FKRP don zama sanadin da ba kasafai ba na WWS89.An gano maye gurbi da yawa a cikin FKRP, wanda wanda ya kafa maye gurbi (c.826>A) ya fi haifar da LGMD2I90.
LGMD2I wani ɗan ƙaramin rauni ne na muscular dystrophy wanda pathogenesis ya dogara ne akan rushewar haɗin da ke tsakanin matrix extracellular da cytoskeleton na ciki.Karamin bayyananniyar dangantaka tsakanin genotype da phenotype a cikin marasa lafiya tare da maye gurbi a cikin waɗannan kwayoyin halitta, kuma hakika wannan ra'ayi yana da amfani ga sauran sunadaran DSC.Me yasa wasu marasa lafiya tare da maye gurbin FKRP ke nuna nau'in cuta mai kama da WWS yayin da wasu ke da LGMD2I?Amsar wannan tambayar na iya kasancewa a cikin i) wane mataki na hanyar glycosylation ne maye gurbi ya shafa, ko ii) matakin hypoglycosylation a kowane mataki.Hypoglycosylation na α-DG na iya har yanzu ba da damar ɗan ƙaramin hulɗa tare da ECM wanda ke haifar da mafi ƙarancin phenotype gabaɗaya, yayin da rabuwa daga membrane na ginshiƙi yana ƙaruwa da tsananin cutar phenotype.Marasa lafiya tare da LGMD2I kuma suna haɓaka DCM, kodayake wannan bai cika rubuce ba fiye da DMD, yana motsa gaggawar fahimtar waɗannan maye gurbi a cikin mahallin cardiomyocytes.
Sarcospan-sarcoglycan subcomplex yana inganta samuwar DHA kuma yana hulɗa kai tsaye tare da β-DH.Akwai sarcoglycans guda hudu unidirectional a cikin nama na zuciya: α, β, γ, da δ91.An bayyana kwanan nan cewa c.218C>T kuskuren maye gurbi a cikin exon 3 na kwayar halitta ta SGCA da wani ɓangaren heterozygous shafe a cikin exons 7-8 yana haifar da LGMD2D92.Duk da haka, a cikin wannan yanayin, marubutan ba su kimanta phenotype na zuciya ba.
Sauran ƙungiyoyi sun gano cewa SGCD a cikin nau'ikan porcine93 da mouse94 suna haifar da raguwar furcin furotin a cikin sarcoglycan subcomplex, rushe tsarin gaba ɗaya na DGCs kuma yana haifar da DCM.Bugu da ƙari, 19% na duk marasa lafiya tare da SGCA, SGCB, ko SGCG maye gurbi an ba da rahoton cewa suna da cututtukan zuciya, kuma 25% na duk marasa lafiya suna buƙatar tallafin numfashi95.
Sauye-sauyen maye gurbi a cikin sarcoglycan (SG) δ yana haifar da raguwa ko cikakkiyar rashi na sarcoglycan complexes kuma saboda haka DGC a cikin nama na zuciya kuma suna da alhakin LGMD da haɗin gwiwar DCM96.Abin sha'awa, maye gurbi-mara kyau a cikin SG-δ sun keɓanta ga tsarin zuciya da jijiyoyin jini kuma sune sanadin familial dilated cardiomyopathy97.An nuna SG-δ R97Q da R71T sauye-sauye-korau masu rinjaye da za a iya bayyana su a tsaye a cikin ɓangarorin cardiomyocytes ba tare da lahani mai mahimmanci na jimlar DGC98 ba.Duk da haka, ƙwayoyin zuciya waɗanda ke ɗauke da waɗannan maye gurbi sun fi dacewa da lalacewa ta sarcolemma, rashin ƙarfi, da rashin aiki na inji a ƙarƙashin damuwa na inji, daidai da nau'in DCM98 phenotype.
Sarcospan (SSPN) tetraspanin 25 kDa ne wanda aka keɓe a cikin sarcoglycan subcomplex kuma an yi imanin yana aiki azaman sikelin furotin99,100.A matsayin sinadari na furotin, SSPN yana daidaita yanayin wuri da glycosylation na α-DG99,101.An sami karuwar SSPN a cikin ƙirar linzamin kwamfuta don ƙara ɗaure tsakanin tsoka da laminin 102.Bugu da ƙari, an nuna SSPN don yin hulɗa tare da integrins, yana ba da shawarar matakin haɗin kai tsakanin commissures biyu na haƙarƙari, DGC, da integrin-talin-vinculin glycoprotein tsarin100,101,102.Knockdown na SSPN kuma ya haifar da karuwa a cikin α7β1 a cikin tsokar kwarangwal na linzamin kwamfuta.
Wani binciken da aka yi a baya-bayan nan ya nuna cewa sarcospan overexpression yana haɓaka balaga da glycosylation na α-DG a cikin nama na zuciya da kansa ba tare da galactosylaminotransferase 2 (Galgt2) knockdown a cikin wani mdx linzamin kwamfuta model na DMD, game da shi rage cutar phenotype 101. Ƙara glycosylation na hadaddun na iya haɓaka hadaddun dystroglycan. ECM, don haka ya fi rage cutar.Bugu da ƙari, sun nuna cewa sarcospan overexpression yana rage hulɗar β1D integrin tare da DGCs, yana nuna yiwuwar tasiri ga sarcospan a cikin tsari na integrin complexes101.
Syntrophins iyali ne na ƙananan sunadaran (58 kDa) waɗanda ke daidaitawa zuwa DGCs, ba su da kansu suna da aikin enzymatic na ciki, kuma suna aiki azaman adaftar kwayoyin halitta103,104.An gano nau'i-nau'i guda biyar (α-1, β-1, β-2, γ-1 da γ-2) suna nuna ƙayyadaddun maganganun nama, tare da α-1 isoform wanda aka fi sani da shi a cikin ƙwayar tsoka na 105.Syntrophins sune mahimman sunadaran adaftar da ke sauƙaƙe sadarwa tsakanin dystrophin da siginar sigina, gami da neuronal nitric oxide synthase (nNOS) a cikin tsokar skeletal106.α-syntrophin yana hulɗa kai tsaye tare da yankin maimaita dystrophin 16-17 spectrin, wanda hakan ya ɗaure zuwa nNOS106,107 PDZ-binding motif.
Syntrophins kuma suna hulɗa tare da dystrobrevin ta hanyar PH2 da SU, kuma suna hulɗa tare da actin cytoskeleton 108.Lalle ne, syntrophins suna da alama suna taka muhimmiyar rawa a cikin ka'idodin cytoskeletal kuzarin kawo cikas, kuma α da β isoforms suna iya yin hulɗa kai tsaye tare da F-actin 108 kuma don haka wataƙila suna taka rawa a cikin ka'idodin tensegrity da biomechanics na salon salula. tasiri.Bugu da ƙari, an nuna syntrophins don tsara cytoskeleton ta hanyar Rac1109.
Daidaita matakan syntrophin na iya dawo da aiki, kuma binciken da aka yi kwanan nan ta amfani da mini-dystrophin ya nuna cewa ginin ΔR4-R23 / ΔCT ya iya mayar da α-syntrophin da sauran sunadaran DGC zuwa matakan da suka dace da WT mdx cardiomyocytes.
Baya ga rawar da suke takawa a cikin tsari na cytoskeleton, syntrophins kuma an rubuta su da kyau a cikin ka'idodin tashoshin ion 111,112,113.Ma'anar PDZ-binding motif na syntrophins yana daidaita tashar tashar Nav1.5111 mai dogara da ƙarfin zuciya, wanda ke taka muhimmiyar rawa wajen kafa ƙarfin zuciya da gudanarwa.Abin sha'awa, a cikin samfurin linzamin kwamfuta na mdx, an gano tashoshi Nav1.5 da aka rushe kuma an sami arrhythmias na zuciya a cikin dabbobi 111.Bugu da ƙari, dangin tashoshi na ion masu amfani da kayan aiki, tashar tashar tashar mai karɓa ta wucin gadi (TRPC), an nuna cewa an tsara shi ta hanyar α1-syntrophin a cikin ƙwayar zuciya na 113 da kuma hana TRPC6 don inganta arrhythmias a cikin samfurin linzamin kwamfuta na DMD112.Ƙara yawan ayyukan TRPC6 a cikin DMD an bayar da rahoto don haifar da arrhythmias na zuciya, wanda aka sauke lokacin da aka haɗa shi da PKG 112.Mechanically, dystrophin depletion yana haɓaka haɓakar haɓakar haɓakar [Ca2 +] i wanda ke aiki sama da TRPC6 don kunna shi, kamar yadda aka nuna a cikin cardiomyocytes da ƙwayoyin tsoka mai santsi na jijiyoyin jini112,114.Haɓakawa na TRPC6 don shimfiɗawa ya sa ya zama babban injiniyoyi da maƙasudin warkewa a cikin DMD112,114.
Asarar dystrophin yana haifar da lysis ko alamar murƙushewa na gaba ɗaya hadaddun DGC, tare da asarar aikin injiniyoyi da yawa da ke haifar da bala'i da aka gani a cikin tsokar tsoka a cikin DMD.Sabili da haka, yana iya zama mai ma'ana a yi la'akari da cewa RSKs suna aiki tare kuma cewa ɗayan abubuwan haɗin gwiwa sun dogara da kasancewa da aiki na wasu abubuwan.Wannan shi ne ainihin gaskiya ga dystrophin, wanda ya bayyana cewa ana buƙata don haɗuwa da ƙaddamarwa na sarcolemma hadaddun a cikin cardiomyocytes.Kowane bangare yana taka muhimmiyar rawa wajen ba da gudummawa ga haɓakar sarcolemma gabaɗaya, ƙayyadaddun abubuwan sunadarai masu mahimmanci, ka'idojin tashoshi ion da maganganun kwayoyin halitta, da asarar furotin guda ɗaya a cikin DGC yana haifar da dysregulation na gabaɗayan myocardium.
Kamar yadda aka nuna a sama, yawancin sunadaran DGC suna shiga cikin injina da sigina, kuma dystrophin ya dace da wannan rawar.Idan DGC yana cikin haƙarƙari, wannan yana tabbatar da ra'ayin cewa yana shiga cikin injina tare da integrins.Don haka, DGCs a jiki suna juyar da canjin ƙarfin anisotropic kuma suna shiga cikin injiniyoyi da sake tsara tsarin cytoskeletal na microenvironment na ciki, daidai da ƙirar tensegrity.Bugu da kari, Dp427m yana ba da damar shigowar sojojin biomechanical ta hanyar faɗaɗa maimaitawar spectrin a cikin babban yanki na tsakiya, ta haka yana aiki azaman injiniyoyi ta hanyar kiyaye ƙarfin 25 pN mai jujjuyawa akan iyakar 800 nm.Ta hanyar rarrabuwa, dystrophin zai iya "buffer" ƙarfin kwantar da hankali da cardiomyocytes ke samarwa.Ganin bambance-bambancen sunadaran da phospholipids waɗanda ke yin hulɗa tare da spectrin maimaita yanki, yana da ban sha'awa don yin hasashen ko maimaitawar spectrin yana canza ɗaurin kinetics na sunadaran injiniyoyi ta hanyar kama da na kula da116,117,118.Duk da haka, har yanzu ba a tantance wannan ba kuma ana buƙatar ƙarin bincike.