Stainless Steel 347 / 347H Welded coil Tubes zhemical component, Ntchito ya dystrophin glycoprotein complexes mu mechanotransduction ya minofu maselo

Zikomo pochezera Nature.com.Mukugwiritsa ntchito msakatuli wokhala ndi chithandizo chochepa cha CSS.Kuti mudziwe zambiri, tikupangira kuti mugwiritse ntchito msakatuli wosinthidwa (kapena kuletsa Compatibility Mode mu Internet Explorer).Kuphatikiza apo, kuti tiwonetsetse chithandizo chopitilira, tikuwonetsa tsambalo popanda masitayilo ndi JavaScript.
Masilayidi owonetsa zolemba zitatu pa slide iliyonse.Gwiritsani ntchito mabatani akumbuyo ndi ena kuti mudutse zithunzi, kapena mabatani owongolera masilayidi kumapeto kuti mudutse silayidi iliyonse.

Dystrophin ndiye puloteni yayikulu ya dystrophin-glycoprotein complex (DGC) mu minofu ya chigoba ndi cardiomyocytes.Dystrophin imamanga actin cytoskeleton ku matrix a extracellular (ECM).Kuphulika kwa kugwirizana pakati pa matrix a extracellular ndi cytoskeleton ya intracellular ikhoza kukhala ndi zotsatira zowonongeka kwa homeostasis ya maselo a minofu ya chigoba, zomwe zimapangitsa kuti muscular dystrophies.Kuphatikiza apo, kutayika kwa ma DGC ogwira ntchito kumabweretsa kukulitsa mtima kwamtima komanso kufa msanga.Dystrophin imagwira ntchito ngati kasupe wa maselo ndipo DHA imagwira ntchito yofunika kwambiri posunga umphumphu wa sarcolemma.Kuphatikiza apo, umboni ukuchulukirachulukira kulumikiza DGC ndi kusaina kwamakina, ngakhale gawo ili silikumveka bwino.Nkhani yowunikirayi ikufuna kupereka mawonekedwe amakono a ma DGC ndi gawo lawo mu mechanotransduction.Choyamba timakambirana za mgwirizano wovuta pakati pa makina a maselo a minofu ndi ntchito, ndikuwunikanso kafukufuku waposachedwapa pa ntchito ya dystrophin glycoprotein complex mu mechanotransduction ndi kusamalira minofu ya biomechanical integrity.Pomaliza, tikuwunikanso zolemba zomwe zilipo kuti timvetsetse momwe ma signature a DGC amalumikizirana ndi njira zamakina kuti awonetsere zomwe zingachitike m'tsogolomu, makamaka makamaka pamtima wamtima.
Maselo amalankhulana nthawi zonse ndi microenvironment yawo, ndipo kukambirana njira ziwiri pakati pawo ndikofunikira kuti kutanthauzira ndi kuphatikiza chidziwitso cha biomechanical.Biomechanics imayang'anira zochitika zazikulu zotsatila (mwachitsanzo, cytoskeletal rearrangements) polamulira phenotype yonse ya ma cell mumlengalenga ndi nthawi.Pakatikati mwa njirayi mu cardiomyocytes ndi dera lamtengo wapatali, dera limene sarcolemma imagwirizanitsa ndi sarcomere yopangidwa ndi integrin-talin-vinculin ndi dystrophin-glycoprotein (DGC) complexes.Zophatikizidwa ndi cytoskeleton ya intracellular, ma discrete focal adhesions (FAs) amafalitsa kusintha kwa ma cell a biomechanical ndi biochemical omwe amawongolera kusiyanitsa, kuchulukana, organogenesis, kusamuka, kupita patsogolo kwa matenda, ndi zina zambiri.Kutembenuka kwa mphamvu za biomechanical kukhala biochemical ndi / kapena (epi) kusintha kwachibadwa kumadziwika kuti mechanotransduction1.
Integrated transmembrane receptor 2 yakhala ikudziwika kuti imakhazikitsa matrix a extracellular m'maselo ndikuyimira ma signature amkati ndi akunja.Mofanana ndi ma integrins, ma DGC amamanga ECM ku cytoskeleton, kukhazikitsa ulalo wofunikira pakati pa kunja ndi mkati mwa cell3.Dystrophin yotalika (Dp427) imawonetsedwa makamaka mu mtima ndi chigoba cha minofu, komanso imawonedwanso m'magulu apakati a mitsempha, kuphatikizapo retina ndi Purkinje tissue4.Kusintha kwa ma integrins ndi DGC kumaganiziridwa kuti ndizomwe zimayambitsa matenda a muscular dystrophy ndi progressive dilated cardiomyopathy (DCM) (Table 1) 5,6.Makamaka, masinthidwe a DMD omwe amalowetsa mapuloteni apakati a dystrophin DGCs amachititsa Duchenne muscular dystrophy (DMD)7.DGC imapangidwa ndi ma subcomplexes angapo kuphatikiza α- ndi β-dystroglycan (α/β-DG), sarcoglycan-spanin, dystrophin, ndi dystrophin 8.
Dystrophin ndi puloteni ya cytoskeletal yosungidwa ndi DMD (Xp21.1-Xp22) yomwe imatenga gawo lalikulu pakusunga DGC.DGC imasunga kukhulupirika kwa sarcolemma, nembanemba ya plasma ya minofu ya striated.Dystrophin imachepetsanso kuwonongeka komwe kumachitika chifukwa cha kukomoka pochita ngati kasupe wa mamolekyulu ndi ma cell scaffold9,10.Dystrophin yotalika kwambiri imakhala ndi molekyulu yolemera 427 kDa, komabe, chifukwa cha olimbikitsa ambiri mkati mwa DMD, pali ma isoform angapo opangidwa mwachilengedwe, kuphatikiza Dp7111.
Mapuloteni owonjezera awonetsedwa kuti akupezeka ku dystrophin, kuphatikizapo mechanotransducers enieni monga neuronal nitric oxide synthase (nNOS), mapuloteni otchedwa Yes-associated (YAP), ndi caveolin-3, motero akuyimira zigawo zofunika kwambiri za zizindikiro za ma cell.Mapangidwe a 12, 13, 14. Kuphatikiza pa kumatira, njira yama cell yomwe imagwirizanitsidwa ndi kuyanjana pakati pa maselo ndi matrix, opangidwa ndi integrins ndi zolinga zawo zapansi, zovuta ziwirizi zimayimira mawonekedwe pakati pa "mkati" ndi "kunja" kwa selo. .Kuteteza zomatirazi ku chiwonongeko chachilendo ndikofunikira pamachitidwe a cell ndi kupulumuka.Kuonjezera apo, deta imathandiza kuti dystrophin ndi modulator ya makina a ion mechanosensitive, kuphatikizapo njira zotambasula, makamaka L-mtundu wa Ca2 + ndi TRPC 15.
Ngakhale kuti dystrophin ndi yofunikira pa ntchito ya homeostatic ya maselo a striated minofu, njira zolondola zothandizira sizidziwika bwino, makamaka ntchito ya dystrophin ndi mphamvu yake yochita ngati mechanosensor ndi wotetezera makina.Chifukwa cha kutayika kwa dystrophin, mafunso angapo osayankhidwa abuka, kuphatikizapo: ndi mapuloteni a mechanosensitive monga YAP ndi AMPK omwe amasokonekera ku sarcolemma;Kodi pali crosstalk yokhala ndi ma integrins, zochitika zomwe zingayambitse mechanotransduction yachilendo?Zonsezi zikhoza kuthandizira kuopsa kwa DCM phenotype yomwe imawoneka mwa odwala omwe ali ndi DMD.
Kuphatikiza apo, kuyanjana kwa kusintha kwa ma biomechanics am'manja ndi DMD phenotype yonse kumakhala ndi zofunikira zachipatala.DMD ndi X-linked muscular dystrophy yomwe imakhudza amuna a 1: 3500-5000, omwe amadziwika ndi kutayika koyambirira (<5 zaka) ndi DCM yopita patsogolo yomwe ili ndi chidziwitso choyipa kwambiri kuposa DCM ya etiologies ina16,17,18.
Ma biomechanics a dystrophin imfa sanafotokozedwe mokwanira, ndipo apa tikuwunikanso umboni wotsimikizira kuti dystrophin imagwiradi ntchito ya mechanoprotective, mwachitsanzo, kusunga umphumphu wa sarcolemma, ndipo n'kofunika kwambiri pa mechanotransduction.Kuphatikiza apo, tidawunikiranso umboni wosonyeza kuti crosstalk yofunika kwambiri ndi ma integrins, makamaka kumangiriza laminin α7β1D m'maselo a striated minofu.
Kulowetsa ndi kuchotsa ndizomwe zimayambitsa kuchuluka kwa masinthidwe mu DMD, pomwe 72% ya masinthidwe amadza chifukwa cha masinthidwe otere19.Zachipatala, DMD imapezeka ali wakhanda (≤5 zaka) ndi hypotension, chizindikiro chabwino cha Gower, kuchedwa kwa kusintha kokhudzana ndi ukalamba, kusokonezeka maganizo, ndi kufooka kwa minofu ya chigoba.Kupsyinjika kwa kupuma kwakhala kumayambitsa imfa kwa odwala a DMD, koma chithandizo chothandizira (corticosteroids, kuthamanga kwa mpweya wabwino nthawi zonse) kwawonjezera nthawi ya moyo kwa odwalawa, ndipo zaka zapakati za odwala DMD omwe anabadwa pambuyo pa 1990 ndi zaka 28.1 20,21 ..Komabe, pamene kupulumuka kwa odwala kumawonjezeka, chidziwitso cha DCM yopita patsogolo ndi yoipitsitsa kwambiri poyerekeza ndi ena a cardiomyopathies16, zomwe zimayambitsa kulephera kwa mtima kumapeto, zomwe pakalipano zimayambitsa imfa, zomwe zimawerengera pafupifupi 50% ya kufa kwa DMD17,18.
Progressive DCM imadziwika ndi kuwonjezeka kwa kumanzere kwa ventricular dilatation ndi kutsata, kupatulira kwa ventricular, kuwonjezeka kwa fibrofatty kulowa, kuchepa kwa systolic, ndi kuwonjezeka kwafupipafupi kwa arrhythmias.Mlingo wa DCM mwa odwala omwe ali ndi DMD umakhala pafupifupi padziko lonse lapansi kumapeto kwa unyamata (90% mpaka 18 wazaka zakubadwa), koma amapezeka pafupifupi 59% ya odwala omwe ali ndi zaka 10 zakubadwa8,22.Kuthana ndi vutoli ndikofunikira chifukwa kagawo kakang'ono ka kumanzere kwa ventricular ejection wakhala ukutsika pang'onopang'ono pamlingo wa 1.6% pachaka23.
Cardiac arrhythmias ndi yofala kwa odwala omwe ali ndi DMD, makamaka sinus tachycardia ndi ventricular tachycardia, ndipo ndizomwe zimayambitsa kufa mwadzidzidzi kwa mtima22.Arrhythmias ndi zotsatira za kulowetsedwa kwa fibrofatty, makamaka mu subbasal left ventricle, zomwe zimasokoneza maulendo obwereza komanso [Ca2+] i processing dysfunction ndi ion channel dysfunction24,25.Kuzindikirika kwa kuwonetsa kwachipatala kwamtima ndikofunikira, chifukwa njira zochiritsira zoyambilira zimatha kuchedwetsa kuyambika kwa DCM yoopsa.
Kufunika kochiza matenda a mtima ndi matenda a mitsempha ya mitsempha kumasonyezedwa mu phunziro lochititsa chidwi lomwe linagwiritsa ntchito mbewa ya DMD yotchedwa mdx26 kuti iphunzire zotsatira za kupititsa patsogolo minofu ya chigoba popanda kuthana ndi mavuto a mtima omwe alipo mu DMD.Apa, olembawo adawonetsa kuwonjezereka kwapang'onopang'ono kwa 5 kwa vuto la mtima pambuyo pakusintha kwachigoba, ndipo mbewa zidachepetsa kwambiri gawo la ejection26.Kuchita bwino kwa minofu ya chigoba kumathandizira kuchita masewera olimbitsa thupi kwambiri kuyika mphamvu zambiri pa myocardium, ndikupangitsa kuti ikhale yovuta kwambiri.Izi zikuwonetseratu kufunika kochiza odwala a DMD ambiri ndikuchenjeza za mankhwala a chigoba okha.
Ma DGC amachita ntchito zina zowonjezera, zomwe ndi, kupereka kukhazikika kwa sarcolemma, kukhala scaffold ya molekyulu yomwe imakhala ngati ulalo wolumikizira, kuwongolera njira zama mechanosensitive ion, maziko a costal mechanotransduction, ndikutenga nawo gawo pakufalitsa mphamvu yakutsogolo mdera la nthiti (mkuyu 1b)..Dystrophin imakhala ndi gawo lalikulu pa lusoli, ndipo chifukwa cha kukhalapo kwa olimbikitsa ambiri amkati, pali ma isoform angapo, aliyense akugwira ntchito yosiyana m'magulu osiyanasiyana.Kufotokozera kwa minofu yamitundu yosiyanasiyana ya dystrophin isoforms kumathandizira lingaliro lakuti isoform iliyonse imagwira ntchito yosiyana.Mwachitsanzo, minofu yamtima imasonyeza kutalika kwake (Dp427m) komanso Dp71m yaifupi ya isoform ya dystrophin, pamene chigoba chimangosonyeza choyamba mwa ziwirizo.Kuyang'ana ntchito ya subtype iliyonse sikungawulule osati momwe thupi limagwirira ntchito, komanso matenda a muscular dystrophy.
Kuyimilira kwadongosolo kwa dystrophin (Dp427m) yayitali komanso yaying'ono, yodulidwa Dp71 isoform.Dystrophin ili ndi ma 24 spectrin obwereza olekanitsidwa ndi malupu anayi, komanso domain-binding domain (ABD), cysteine-rich (CR) domain, ndi C-terminus (CT).Othandizana nawo ofunikira adadziwika, kuphatikiza ma microtubules (MTs) ndi sarcolemma.Pali ma isoform ambiri a Dp71, Dp71m amatanthauza minofu ya minofu ndipo Dp71b imatanthawuza minofu yamanjenje ya isoform.Makamaka, Dp71f imanena za cytoplasmic isoform ya neurons.b Dystrophin-glycoprotein complex (DHA) ili mu sarcolemma yonse.Mphamvu za biomechanical zimasintha pakati pa ECM ndi F-actin.Zindikirani kuthekera kwapang'onopang'ono pakati pa DGCs ndi integrin adhesion, Dp71 ikhoza kutengapo gawo pakumatira kwapakati.Adapangidwa ndi Biorender.com.
DMD ndi matenda omwe amapezeka kwambiri muscular dystrophy ndipo amayamba chifukwa cha masinthidwe a DMD.Komabe, kuti timvetsetse bwino momwe titha kumvetsetsa za ntchito ya anti-dystrophin, ndikofunikira kuti tiyike muzochitika za DGC yonse.Chifukwa chake, ma protein ena omwe ali nawo adzafotokozedwa mwachidule.Mapuloteni a DGC adayamba kuphunziridwa kumapeto kwa zaka za m'ma 1980, makamaka ku dystrophin.Koenig27,28, Hoffman29 ndi Ervasti30 adapeza zofunikira pozindikira dystrophin, mapuloteni a 427 kDa mu striated muscle31.
Pambuyo pake, ma subcomplexes ena adawonetsedwa kuti amalumikizidwa ndi dystrophin, kuphatikiza sarcoglycan, dystrophin transmembrane subcomplex, dysbrevin, ndi syntrophins8, zomwe pamodzi zimapanga mtundu waposachedwa wa DGC.Gawoli lidzayamba kufalitsa umboni wa ntchito ya DGC mu kulingalira kwa mechanosensory pamene ikuyang'ana zigawozo mwatsatanetsatane.
Dystrophin isoform yotalikirapo yomwe imapezeka mu minofu ya striated ndi Dp427m (mwachitsanzo "m" kuti minofu isiyanitse ndi ubongo) ndipo ndi puloteni yayikulu yooneka ngati ndodo yokhala ndi madera anayi ogwirira ntchito omwe ali pansi pa cardiomyocyte sarcolemma, makamaka kudera la costal. 29, 32. Dp427m, yolembedwa ndi jini ya DMD pa Xp21.1, imakhala ndi ma exons 79 opangidwa pa 2.2 megabases motero ndiye jini yayikulu kwambiri mu genome8 yathu.
Othandizira angapo amkati mu DMD amapanga ma isoform angapo a truncated a dystrophin, ena omwe amakhala enieni.Poyerekeza ndi Dp427m, Dp71m imachepetsedwa kwambiri ndipo ilibe domain yobwereza ya spectrin kapena N-terminal ABD domain.Komabe, Dp71m imasunga zomangira za C-terminal.Mu cardiomyocytes, ntchito ya Dp71m sichidziwika bwino, koma yasonyezedwa kuti imapezeka mu T tubules, kutanthauza kuti ikhoza kuthandizira kugwirizanitsa 33,34,35.Kudziwa kwathu, kupezeka kwaposachedwa kwa Dp71m mu minofu ya mtima sikulandira chidwi chochepa, koma kafukufuku wina amasonyeza kuti amagwirizana ndi njira za ion zotambasula, ndipo Masubuchi adanena kuti zikhoza kukhala ndi gawo pakuwongolera nNOS33., 36. Pochita zimenezi, Dp71 yalandira chidwi chachikulu mu neurophysiology ndi kafukufuku wa mapulateleti, madera omwe angapereke chidziwitso cha gawo la cardiomyocytes37,38,39.
M'minyewa yamanjenje, Dp71b isoform imawonetsedwa kwambiri, ndi ma isoform 14 akuti38.Kuchotsedwa kwa Dp71b, chowongolera chofunikira cha aquaporin 4 ndi njira za potaziyamu za Kir4.1 m'kati mwa dongosolo la mitsempha, zasonyezedwa kuti zisintha zotchinga zamagazi-ubongo permeability40.Poganizira za gawo la Dp71b pakuwongolera njira za ion, Dp71m itha kukhala ndi gawo lofanana mu cardiomyocytes.
Kukhalapo kwa DGC mu ganglia yamtengo wapatali nthawi yomweyo kumasonyeza gawo la mechanotransduction, ndipo ndithudi zasonyezedwa kuti zigwirizane ndi integrin-talin-vinculin complexes 41.Komanso, poganizira kuti gawo la mtengo ndilomwe limayang'ana pa mechanotransduction yodutsa, kukhazikitsidwa kwa Dp427m pano kukuwonetsa ntchito yake poteteza maselo kuti asawonongeke.Kuphatikiza apo, Dp427m imalumikizana ndi actin ndi microtubule cytoskeleton, potero kumaliza kulumikizana pakati pa chilengedwe cha intracellular ndi extracellular matrix.
N-terminus yomwe ili ndi actin-binding domain 1 (ABD1) imakhala ndi madera awiri a calmodulin homology (CH) omwe amafunikira kuti agwirizane ndi F-actin ndikumangirira γ-actin isoform ku sarcolemma42,43.Dystrophin ikhoza kuthandizira kuti ma cardiomyocyte awonongeke kwambiri pogwirizanitsa ndi subsarcolemmal cytoskeleton, ndipo malo ake mu ganglia yamtengo wapatali amathandizira kukhudzidwa kwake mu mechanotransduction komanso mechanoprotection44,45.
Pakatikati pakatikati pamakhala mapuloteni 24 obwereza ngati ma spectrin, omwe ali pafupifupi 100 amino acid zotsalira m'litali.Kubwereza kwa spectrin kumalowetsedwa ndi madera anayi a hinge, kupereka kusinthasintha kwa mapuloteni komanso kuwonjezereka kwakukulu.Kubwereza kwa Dystrophin spectrin kumatha kufalikira mkati mwa mphamvu zambiri (15-30 pN) kuchokera ku 21 nm mpaka 84 nm, mphamvu zomwe zingatheke kuti myosin contraction 46 .Mawonekedwe awa a spectrin kubwereza domain amalola dystrophin kukhala ngati ma cell shock absorber.
Ndodo yapakati ya Dp427m imatsimikizira kukhazikika kwake mu sarcolemma, makamaka, kudzera muzochita za hydrophobic ndi electrostatic ndi phosphatidylserine 47,48.Chochititsa chidwi n'chakuti pakati pakatikati pa dystrophin amalumikizana mosiyana ndi sarcolemma phospholipids m'mafupa a chigoba ndi mtima, mwinamwake akuwonetseratu zosiyana za masika.zovuta, pomwe minofu ya chigoba imalumikizidwanso ndi R10-R1249.
Kumanga ku γ-actin cytoskeleton kumafuna ABD2 spectrin kubwereza 11-17 dera, lomwe lili ndi zotsalira za amino acid ndipo zimasiyana ndi F-actin-binding CH domain.Ma microtubules amalumikizana mwachindunji ndi gawo lalikulu la dystrophin, kuyanjana kumeneku kumafuna zotsalira za spectrin kubwereza 4-15 ndi 20-23, ndi kukhalapo kwa ankyrin B kumafunika kuteteza mapangidwe a microtubules pamalo ano.Machubu kulibe 50,51,52.Kusiyana pakati pa ma microtubules ndi dystrophin kwawonetsedwa kuti kumakulitsa matenda a DMD powonjezera mitundu ya okosijeni (X-ROS).
Dera la CR kudzera pa ankyrin B ndi nangula wina wa sarcolemmal phospholipids52.Ankyrin-B ndi ankyrin-G amafunikira kuti nthiti ikhale ya dystrophin/DGC, ndipo kusapezeka kwawo kumabweretsa mawonekedwe a sarcolemmal a DGC52.
Dongosolo la CR lili ndi dera lomangiriza la WW lomwe limalumikizana mwachindunji ndi PPxY yomangiriza motif ya β-DG.Pophatikizana ndi dystrophin-glycan complex, dystrophin imamaliza kulumikizana pakati ndi kunja kwa selo54.Kulumikizana kumeneku ndikofunika kwambiri kwa minofu yowonongeka, monga umboni wakuti kusokonezeka kwa mgwirizano pakati pa ECM ndi mkati mwa selo kumabweretsa moyo wolepheretsa muscular dystrophy.
Potsirizira pake, dera la CT ndi dera lotetezedwa kwambiri lomwe limapanga helix yozungulira ndipo ndi yofunika kwambiri kuti imangirire ku α-dystrobrevin ndi α1-,β1-syntrophins55,56.α-dystrobrevin imamangiriza ku CT domain ya dystrophin ndipo imapereka kukana kowonjezereka kwa dystrophin mu sarcolemma57.
Pakukula kwa embryonic ndi fetal, Utrophin imawonetsedwa kwambiri m'magulu osiyanasiyana, kuphatikiza ma cell a endothelial, minofu yamanjenje, ndi minofu ya striated58.Utrophin imawonetsedwa ndi UTRN yomwe ili pa chromosome 6q ndipo ndi dystrophin autolog yokhala ndi 80% protein homology.Panthawi ya chitukuko, utrophin imapezeka mu sarcolemma koma imaponderezedwa kwambiri mu minofu ya postnatal striated muscle, kumene imasinthidwa ndi dystrophin.Pambuyo pa kubadwa, malo a utrophin amangokhala ndi tendons ndi neuromuscular junctions of skeletal muscle58,59.
Omwe amamangirira a Utrophin amafanana kwambiri ndi a dystrophins, ngakhale kusiyana kwakukulu kwafotokozedwa.Mwachitsanzo, dystrophin imagwirizana ndi β-DG kupyolera mu dera lake la WW, lomwe limakhazikika ndi dera la ZZ (lotchedwa kuti limatha kumangirira ma ion awiri a zinc) mkati mwa chigawo chake cha CT, kumene cysteic acid zotsalira 3307-3354 ndizofunikira kwambiri pakuchita izi60 ., 61. Utrophin imamangirizanso ku β-DG kudzera pa WW / ZZ domain, koma zotsalira zenizeni zomwe zimathandizira kuyanjana kumeneku zimasiyana ndi zotsalira za dystrophin (3307-3345 mu dystrophin ndi 3064-3102 mu utrophin) 60,61.Chofunika kwambiri, kumanga kwa utrophin ku β-DG kunali pafupifupi 2-fold pansi poyerekeza ndi dystrophin 61. Dystrophin yanenedwa kuti imamangiriza ku F-actin kudzera mu spectrin kubwereza 11-17, pamene malo ofanana mu utrophin sangathe kumanga ku F-actin, ngakhale pa okwera kwambiri, koma amatha kulumikizana kudzera m'magawo awo a CH.Ntchito 62,63,64.Pomaliza, mosiyana ndi dystrophin, utrophin sangathe kumangirira ku ma microtubules51.
Biomechanically, kubwereza kwa utrophin spectrin kumakhala ndi mawonekedwe osadziwika bwino poyerekeza ndi dystrophin65.Utrophin-spectrin imabwereza kutumizidwa ku mphamvu zapamwamba, zofanana ndi titin koma osati dystrophin65.Izi zimagwirizana ndi malo ake komanso ntchito yofalitsa mphamvu zolimba zolimba pamagulu a tendon, koma zingapangitse utrophin kukhala wosayenerera kukhala ngati kasupe wa mamolekyu mu mphamvu zowonongeka zomwe zimayambitsidwa ndi mgwirizano wa 65.Kutengedwa palimodzi, deta iyi imasonyeza kuti mphamvu za mechanotransduction ndi mechanobuffering zikhoza kusinthidwa pamaso pa utrophin overexpression, makamaka kupatsidwa mabwenzi / njira zosiyana siyana, komabe izi zimafuna kufufuza kwina koyesera.
Kuchokera kumalo ogwirira ntchito, mfundo yakuti utrophin imakhulupirira kuti imakhala ndi zotsatira zofanana ndi dystrophin imapangitsa kuti ikhale chithandizo chamankhwala cha DMD66,67.Ndipotu, odwala ena a DMD awonetsedwa kuti ali ndi overexpress utrophin, mwinamwake ngati njira yobwezera, ndipo phenotype yabwezeretsedwa bwino mu chitsanzo cha mbewa ndi utrophin overexpression 68.Ngakhale kuti kuwonjezeka kwa utrophin ndi njira yochiritsira yotheka, kulingalira za kusiyana kovomerezeka ndi ntchito pakati pa utrophin ndi dystrophin ndi zothandiza zomwe zimapangitsa kuti izi zikhale zomveka bwino ndi malo oyenerera pamodzi ndi sarcolemma zimapangitsa kuti njira yayitali ya utrophin isadziwikebe.Mwachidziwitso, zonyamulira za akazi zimasonyeza mawonekedwe a mosaic a mawu a utrophin, ndipo chiŵerengero cha pakati pa dystrophin ndi utrophin chingakhudze mlingo wa dilated cardiomyopathy mwa odwalawa, 69 ngakhale kuti murine zitsanzo za zonyamulira zasonyeza..
Dystroglycan subcomplex imakhala ndi mapuloteni awiri, α- ndi β-dystroglycan (α-, β-DG), onse olembedwa kuchokera ku jini ya DAG1 ndiyeno pambuyo pake amamangiriridwa kukhala mapuloteni awiri a 71.α-DG imakhala ndi glycosylated kwambiri mu gawo la extracellular la DGCs ndipo imagwirizana mwachindunji ndi zotsalira za proline mu laminin α2 komanso agrin72 ndi picaculin73 ndi CT/CR dera la dystrophin73,74,75,76.O-linked glycosylation, makamaka zotsalira za serine, zimafunika kuti zigwirizane ndi ECM.Njira ya glycosylation imaphatikizapo michere yambiri yomwe masinthidwe ake amatsogolera ku muscular dystrophy (onaninso Gulu 1).Izi zikuphatikizapo O-mannosyltransferase POMT2, fucutin ndi fucutin-related protein (FKRP), ma ribitol phosphotransferase awiri omwe amawonjezera tandem ribitol phosphates ku core glycan, ndi mapuloteni a LARGE1 omwe amawonjezera xylose ndi shuga.Linear uronic acid polysaccharide, yomwe imadziwikanso kuti matrix glycan kumapeto kwa glycan77.FKRP imakhudzidwanso ndi chitukuko ndi kukonzanso kwa ECM, ndipo kusintha kwake kumayambitsa kuchepa kwa mawu a laminin α2 ndi α-DG77,78,79.Kuphatikiza apo, FKRP imathanso kuwongolera mapangidwe a basal lamina ndi matrix amtima a extracellular kudzera mu glycosylated fibronectin 80.
β-DG ili ndi PPxY yomangiriza motif yomwe imapezeka mwachindunji ndikutsata YAP12.Izi ndizosangalatsa chifukwa zikutanthauza kuti DGC imayang'anira ma cell a cardiomyocyte.α-DH mu neonatal cardiomyocytes imagwirizana ndi agrin, zomwe zimalimbikitsa kusinthika kwa mtima ndi DGC76 lysis chifukwa cha kusasitsa maselo.Pamene ma cardiomyocytes akukula, mawu a aggrin amachepetsa mokomera laminini, yomwe imaganiziridwa kuti imathandizira kumangidwa kwa selo76.Morikawa12 adawonetsa kuti kugwetsa kawiri kwa dystrophin ndi salvador, chowongolera cholakwika cha YAP, kumabweretsa kuchulukitsa kwa ma cardiomyocytes mu rumen yomwe imayambitsa infarct.Izi zidadzetsa lingaliro losangalatsa loti kusintha kwa YAP kungakhale kothandiza popewa kutayika kwa minofu pambuyo pa infarction ya myocardial.Choncho, agrin-induced DGC lysis akhoza kuimira axis yomwe imalola kuti YAP iyambe kugwira ntchito ndipo ndi njira yotheka kukonzanso mtima.
Mwachimake, α- ndi β-DG amafunikira kuti asunge mgwirizano pakati pa sarcolemma ndi basal layer 81.Zonse za α-DG ndi α7 integrins zimathandizira kukakamiza kupanga mu ganglion yamtengo wapatali, ndipo kutayika kwa α-DG kumayambitsa kulekanitsa kwa sarcolemma kuchokera ku basal lamina, ndikusiya minofu ya chigoba kukhala pangozi yowonongeka.Monga tafotokozera kale, zovuta za dystroglycan zimayang'anira chiwongoladzanja chonse cha DGCs, komwe kumangiriza kwa ligand laminin kumabweretsa tyrosine phosphorylation ya PPPY-binding motif ya β-DG892.Tyrosine phosphorylation apa imalimbikitsa dystrophin disassembly, yomwe imatembenuza DGC complex.Physiologically, njirayi imayendetsedwa kwambiri, yomwe ilibe muscular dystrophy82, ngakhale kuti njira zomwe zimayendetsa ndondomekoyi sizikumveka bwino.
Kutambasula kwa cyclic kwawonetsedwa kuti yambitsa ERK1/2 ndi AMPK njira kudzera mu dystrophin complex ndi protein plectin83 yogwirizana.Pamodzi, plectin ndi dystroglycan amafunikira osati kuchita ngati scaffold, komanso kutenga nawo mbali mu mechanotransduction, ndipo kugogoda kwa plectin kumabweretsa kuchepa kwa ntchito ya ERK1/2 ndi AMPK83.Plectin imamangirizanso ku cytoskeletal intermediate filament desmin, ndipo desmin overexpression yasonyezedwa kuti imathandizira matenda a phenotype mu mdx: desmin ndi mdx mbewa, DMD84 double knockout mouse model.Polumikizana ndi β-DG, plectin imamangiriza DGC ku gawo ili la cytoskeleton.Kuonjezera apo, dystroglycan imagwirizana ndi kukula kwa receptor-binding protein 2 (Grb2), yomwe imadziwika kuti imakhudzidwa ndi cytoskeletal rearrangements85.Kutsegula kwa Ras ndi integrin kwawonetsedwa kuti kukhale pakati pa Grb2, yomwe ingapereke njira yotheka ya crosstalk pakati pa integrins ndi DGC86.
Kusintha kwa majini omwe amaphatikizidwa mu α-DH glycosylation kumabweretsa zomwe zimatchedwa muscular dystrophy.Dystroglycanopathies amasonyeza kusiyanasiyana kwachipatala koma makamaka amayamba chifukwa cha kusokonezeka kwa mgwirizano pakati pa α-DG ndi laminin α277.Dystrophiglicanoses omwe amayamba chifukwa cha masinthidwe oyambira mu DAG1 nthawi zambiri amakhala osowa kwambiri, mwina chifukwa amapha embryonic lethal87, motero amatsimikizira kufunikira kolumikizana ndi ma cell ndi ECM.Izi zikutanthauza kuti matenda ambiri a dystrophic glycan amayamba chifukwa cha kusintha kwa mapuloteni achiwiri okhudzana ndi glycosylation.Mwachitsanzo, masinthidwe amtundu wa POMT1 amachititsa matenda oopsa kwambiri a Walker-Warburg, omwe amadziwika ndi anencephaly komanso kufupikitsa nthawi ya moyo (osakwana zaka 3)88.Komabe, kusintha kwa FKRP kumawoneka ngati limb-girdle muscular dystrophy (LGMD), yomwe nthawi zambiri imakhala (koma osati nthawi zonse) yofatsa.Komabe, masinthidwe mu FKRP awonetsedwa kuti ndi chifukwa chosowa cha WWS89.Zosintha zambiri zadziwika mu FKRP, pomwe kusintha koyambitsa (c.826>A) kumayambitsa LGMD2I90.
LGMD2I ndi yocheperako muscular dystrophy yomwe pathogenesis yake imachokera ku kusokonezeka kwa kulumikizana pakati pa matrix a extracellular ndi intracellular cytoskeleton.Zosamveka bwino ndi ubale wapakati pa genotype ndi phenotype mwa odwala omwe ali ndi masinthidwe amtundu uwu, ndipo ndithudi lingaliroli likugwiritsidwa ntchito ku mapuloteni ena a DSC.Chifukwa chiyani odwala ena omwe ali ndi masinthidwe a FKRP amawonetsa matenda a phenotype ofanana ndi WWS pomwe ena ali ndi LGMD2I?Yankho la funsoli likhoza kukhala mu i) ndi sitepe iti ya glycosylation pathway yomwe imakhudzidwa ndi masinthidwe, kapena ii) kuchuluka kwa hypoglycosylation pa sitepe iliyonse.Hypoglycosylation ya α-DG ikhoza kuloleza kuyanjana kwina ndi ECM zomwe zimapangitsa kuti pakhale phenotype yofatsa, pamene kupatukana ndi membrane yapansi kumawonjezera kuopsa kwa phenotype ya matenda.Odwala omwe ali ndi LGMD2I amakhalanso ndi DCM, ngakhale kuti izi ndizochepa kwambiri kuposa DMD, zomwe zimalimbikitsa kufulumira kumvetsetsa kusintha kumeneku pazochitika za cardiomyocytes.
Sarcospan-sarcoglycan subcomplex imalimbikitsa kupanga DHA ndipo imagwirizana mwachindunji ndi β-DH.Pali anayi unidirectional sarcoglycans mu mtima minofu: α, β, γ, ndi δ91.Posachedwapa zafotokozedwa kuti kusintha kwa c.218C>T missense mu exon 3 ya jini ya SGCA ndi kuchotsedwa kwapang'ono kwa heterozygous mu exons 7-8 kumayambitsa LGMD2D92.Komabe, mu nkhaniyi, olembawo sanayesetse phenotype ya mtima.
Magulu ena apeza kuti SGCD mumitundu ya porcine93 ndi mouse94 imabweretsa kuchepa kwa mapuloteni mu sarcoglycan subcomplex, kusokoneza dongosolo lonse la DGCs ndikupangitsa DCM.Kuonjezera apo, 19% mwa odwala onse omwe ali ndi kusintha kwa SGCA, SGCB, kapena SGCG adanena kuti ali ndi matenda a mtima, ndipo 25% mwa odwala onse amafunanso chithandizo cha kupuma95.
Kusintha kochulukira mu sarcoglycan (SG) δ kumabweretsa kuchepa kapena kusapezeka kwathunthu kwa ma sarcoglycan complexes motero DGC mu minofu yamtima ndipo amayang'anira LGMD ndi DCM96 yake.Chochititsa chidwi n'chakuti, kusintha kwakukulu-koipa mu SG-δ kumakhudza kwambiri mtima wamtima ndipo ndizomwe zimayambitsa matenda a mtima wamtima97.SG-δ R97Q ndi R71T zosintha zoyipa kwambiri zawonetsedwa mokhazikika mu makoswe a cardiomyocyte popanda kuwonongeka kwakukulu kwa DGC98 yonse.Komabe, maselo amtima omwe amanyamula masinthidwewa amatha kuwonongeka kwambiri ndi sarcolemma, permeability, ndi kusokonezeka kwa makina pansi pa zovuta zamakina, zogwirizana ndi DCM98 phenotype.
Sarcospan (SSPN) ndi 25 kDa tetraspanin yomwe imapezeka mu sarcoglycan subcomplex ndipo imakhulupirira kuti imakhala ngati scaffold ya mapuloteni99,100.Monga scaffold ya mapuloteni, SSPN imakhazikitsa malo ndi glycosylation ya α-DG99,101.Kufotokozera kwakukulu kwa SSPN mu zitsanzo za mbewa zapezeka kuti zikuwonjezera kumanga pakati pa minofu ndi laminin 102.Kuphatikiza apo, SSPN yawonetsedwa kuti ilumikizana ndi ma integrins, kutanthauza kuchuluka kwa crosstalk pakati pa nthiti ziwiri commissures, DGC, ndi integrin-talin-vinculin glycoprotein structure100,101,102.Kugogoda kwa SSPN kunapangitsanso kuwonjezeka kwa α7β1 mu minofu ya chigoba cha mbewa.
Kafukufuku waposachedwapa anasonyeza kuti sarcospan overexpression imapangitsa kusasitsa ndi glycosylation ya α-DG mu minofu ya mtima popanda galactosylaminotransferase 2 (Galgt2) knockdown mu mdx mbewa chitsanzo cha DMD, potero kuchepetsa matenda phenotype 101. Kuwonjezeka kwa glycosylation ya kuyanjana kwa dystroglycan kungapangitse kuyanjana ndi dystroglycan complex. ECM, potero kuchepetsa matendawa.Komanso, awonetsa kuti sarcospan overexpression imachepetsa kuyanjana kwa β1D integrin ndi DGCs, kuwonetsa gawo lomwe lingakhalepo la sarcospan pakuwongolera kwa integrin complexes101.
Ma Syntrophins ndi banja la mapuloteni ang'onoang'ono (58 kDa) omwe amapezeka ku DGCs, alibe zochita za enzymatic, ndipo amagwira ntchito ngati ma adapter molecular103,104.Ma isoforms asanu (α-1, β-1, β-2, γ-1 ndi γ-2) adadziwika kuti akuwonetsa mawonekedwe enieni a minofu, ndi α-1 isoform yomwe imasonyezedwa kwambiri mu minofu yowonongeka 105.Ma Syntrophins ndi mapuloteni ofunikira omwe amathandizira kulumikizana pakati pa dystrophin ndi mamolekyu owonetsa, kuphatikiza neuronal nitric oxide synthase (nNOS) mu skeletal muscle106.α-syntrophin imalumikizana mwachindunji ndi dystrophin 16-17 spectrin yobwereza domain, yomwe imamangiriza ku nNOS106,107 PDZ-binding motif.
Ma Syntrophins amalumikizananso ndi dystrobrevin kudzera pa PH2 ndi SU zomangira madera, komanso amalumikizana ndi actin cytoskeleton 108.Zowonadi, ma syntrophins akuwoneka kuti amathandizira kwambiri pakuwongolera mphamvu za cytoskeletal, ndipo α ndi β isoforms amatha kulumikizana mwachindunji ndi F-actin 108 ndipo motero amathandizira pakuwongolera kulimba mtima ndi biomechanics yama cell. zotsatira.Kuphatikiza apo, ma syntrophins awonetsedwa kuti amawongolera cytoskeleton kudzera mu Rac1109.
Kuwongolera ma syntrophin kungabwezeretse ntchito, ndipo kafukufuku waposachedwapa pogwiritsa ntchito mini-dystrophin anasonyeza kuti ΔR4-R23 / ΔCT yomanga inatha kubwezeretsa α-syntrophin komanso mapuloteni ena a DGC kumagulu ofanana ndi WT mdx cardiomyocytes.
Kuphatikiza pa ntchito yawo pakuwongolera cytoskeleton, ma syntrophins amalembedwanso bwino pakuwongolera njira za ion 111,112,113.PDZ-binding motif of syntrophins imayang'anira mayendedwe a mtima wamagetsi a Nav1.5111, omwe amathandizira kwambiri pakukhazikitsa chisangalalo cha mtima ndi kuwongolera.Chochititsa chidwi n'chakuti mu mdx mouse model, njira za Nav1.5 zinapezeka kuti ndizochepa ndipo ma arrhythmias a mtima anapezeka mu zinyama 111.Kuonjezera apo, banja la makina a ion mechanosensitive, transient receptor potential channel (TRPC), yasonyezedwa kuti ikuyendetsedwa ndi α1-syntrophin mu minofu ya mtima 113 ndi TRPC6 inhibition yasonyezedwa kuti ipititse patsogolo arrhythmias mu DMD112 chitsanzo cha mouse.Kuwonjezeka kwa ntchito ya TRPC6 ku DMD kwanenedwa kuti kumayambitsa matenda a mtima, omwe amamasulidwa akaphatikizidwa ndi PKG 112.Mwachidziwitso, kuchepa kwa dystrophin kumalimbikitsa kuwonjezereka kwa [Ca2 +] i yomwe imagwira pamwamba pa TRPC6 kuti iyambe, monga momwe tawonetsera mu cardiomyocytes ndi vascular smooth muscle cells112,114.Hyperactivation ya TRPC6 kutambasula kumapangitsa kuti ikhale mechanosensor yayikulu komanso chandamale chochizira mu DMD112,114.
Kutayika kwa dystrophin kumayambitsa lysis kapena kuponderezedwa kwa DGC yonse yovuta, ndi kutayika kotsatira kwa ntchito zambiri za mechanoprotective ndi mechanotransduction, zomwe zimapangitsa kuti pakhale ngozi yowonongeka yomwe imapezeka mu minofu yowonongeka mu DMD.Choncho, zingakhale zomveka kulingalira kuti ma RSK amagwira ntchito mogwirizana komanso kuti zigawo zake zimadalira kukhalapo ndi kugwira ntchito kwa zigawo zina.Izi ndizowona makamaka kwa dystrophin, yomwe ikuwoneka kuti ikufunika kusonkhanitsa ndi kumasulira kwa sarcolemma complex mu cardiomyocytes.Chigawo chilichonse chimakhala ndi gawo lapadera pothandizira kukhazikika kwa sarcolemma, kukhazikitsidwa kwa mapuloteni ofunikira, kuwongolera njira za ion ndi ma jini, komanso kutayika kwa puloteni imodzi mu DGC kumabweretsa kusokoneza kwa myocardium yonse.
Monga momwe tawonetsera pamwambapa, mapuloteni ambiri a DGC akuphatikizidwa mu mechanotransduction ndi chizindikiro, ndipo dystrophin imagwirizana kwambiri ndi ntchitoyi.Ngati DGC ili mu nthiti, izi zimatsimikizira lingaliro lakuti imatenga nawo mbali mu mechanotransduction pamodzi ndi integrins.Chifukwa chake, ma DGC amatha kusintha mphamvu ya anisotropic ndikuchita nawo ma mechanosensory ndi cytoskeletal rearrangement ya intracellular microenvironment, mogwirizana ndi chitsanzo cha tensegrity.Kuphatikiza apo, Dp427m imatchingira mphamvu zomwe zikubwera za biomechanical mwa kukulitsa kubwereza kwa ma spectrin mkati mwa chigawo chake chapakati, potero kumakhala ngati mechanoprotector posunga mphamvu ya 25 pN yosasunthika pamtunda wotalikirapo wa 800 nm.Mwa kupatukana, dystrophin imatha "kubisa" mphamvu yopumula yopangidwa ndi cardiomyocytes10.Chifukwa cha kusiyanasiyana kwa mapuloteni ndi ma phospholipids omwe amalumikizana ndi madera obwereza a spectrin, ndizosangalatsa kulingalira ngati spectrin kubwereza kubwereza kumasintha ma kinetics omangira mapuloteni a mechanosensitive mofanana ndi talin116,117,118.Komabe, izi sizinatsimikizidwebe ndipo kufufuza kwina kumafunika.