I-Stainless Steel 347 / 347H I-coil ene-Welded coil Tubes zhemical component, Indima ye-dystrophin glycoprotein complexes kwi-mechanotransduction yeeseli zemisipha.

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I-Dystrophin yiprotheni ephambili ye-dystrophin-glycoprotein complex (DGC) kwi-skeletal muscle kunye ne-cardiomyocytes.I-Dystrophin ibophelela i-actin cytoskeleton kwi-matrix ye-extracellular (ECM).Ukuqhawulwa koxhulumaniso phakathi kwe-matrix ye-extracellular kunye ne-intracellular cytoskeleton ingaba nemiphumo emibi kwi-homeostasis yeeseli ze-muscle skeletal, ezikhokelela kwinani le-muscular dystrophies.Ukongeza, ukulahleka kwe-DGCs esebenzayo kukhokelela kwi-cardiomyopathy eqhubekayo kunye nokufa kwangaphambi kwexesha.I-Dystrophin isebenza njengentwasahlobo ye-molecular kwaye i-DHA idlala indima ebalulekileyo ekugcineni ingqibelelo ye-sarcolemma.Ngaphezu koko, ubungqina buqokelelana ngokunxibelelanisa i-DGC nokusayinwa koomatshini, nangona le ndima ihlala ingaqondwa kakuhle.Eli nqaku lokuphonononga lijolise ekunikeni umbono wanamhlanje we-DGCs kunye nendima yabo kwi-mechanotransduction.Siqala sixoxe ngobudlelwane obunzima phakathi kwe-muscle cell mechanics kunye nomsebenzi, kwaye emva koko sihlolisise uphando olutshanje malunga nendima ye-dystrophin glycoprotein eyinkimbinkimbi kwi-mechanotransduction kunye nokugcinwa kwe-muscle cell biomechanical integrity.Ekugqibeleni, sihlaziya uncwadi lwangoku ukuze siqonde indlela i-DGC yokubonisa i-intersecting kunye ne-mechanosignaling pathways ukugqamisa iindawo ezinokuthi zingenelele kwixesha elizayo, ngokugxininisa ngokukodwa kwi-cardiomyopathy.
Iiseli zinxibelelana rhoqo kunye ne-microenvironment yazo, kwaye i-dialogue yeendlela ezimbini phakathi kwabo iyimfuneko ekutolikeni nasekudityanisweni kolwazi lwe-biomechanical.I-Biomechanics ilawula iziganeko eziphambili ezilandelayo (umzekelo, ukulungiswa kwakhona kwe-cytoskeletal) ngokulawula i-phenotype yeselula ngokubanzi kwindawo kunye nexesha.Eyona nto iphambili kule nkqubo kwi-cardiomyocytes yindawo yeendleko, ummandla apho i-sarcolemma idibanisa kwi-sarcomere ehlanganiswe ne-integrin-talin-vinculin kunye ne-dystrophin-glycoprotein (DGC) complexes.Incanyathiselwe kwi-cytoskeleton ye-intracellular, ezi zi-discrete focal adhesions (FAs) zisasaza i-cascade ye-biomechanical kunye neenguqu ze-biochemical zeselula ezilawula ukuhlukana, ukwanda, i-organogenesis, ukufuduka, ukuqhubela phambili kwesifo, kunye nokunye.Ukuguqulwa kwamandla e-biomechanical kwi-biochemical kunye / okanye (epi) utshintsho lwezofuzo luyaziwa ngokuba yi-mechanotransduction1.
I-integrin transmembrane receptor 2 sele iyaziwa ngokuba yi-anchor i-matrix ye-extracellular kwiiseli kunye nokudibanisa kokubili ukubonakaliswa kwangaphakathi nangaphandle.Ngokuhambelana nee-interins, ii-DGCs zibophelela i-ECM kwi-cytoskeleton, ukuseka ikhonkco elibalulekileyo phakathi kwangaphandle nangaphakathi kweseli3.I-dystrophin yobude obupheleleyo (i-Dp427) ibonakaliswe ngokuyinhloko kwi-cardiac kunye ne-skeletal muscle, kodwa iphinda ibonwe kwizicubu zenkqubo ye-nervous central, kuquka i-retina kunye ne-Purkinje tissue4.Ukuguqulwa kwee-interins kunye ne-DGC kucingelwa ukuba yimbangela ye-muscular dystrophy kunye ne-progressive dilated cardiomyopathy (DCM) (Itheyibhile 1) 5,6.Ngokukodwa, iinguqu ze-DMD ezifaka i-protein ye-dystrophin ephakathi kwee-DGCs zibangela i-Duchenne muscular dystrophy (DMD)7.I-DGC yenziwe ngee-subcomplexes ezininzi eziquka i-α- kunye ne-β-dystroglycan (α/β-DG), i-sarcoglycan-spanin, i-dystrophin, kunye ne-dystrophin 8.
I-Dystrophin yiprotheni ye-cytoskeletal encoded yi-DMD (Xp21.1-Xp22) edlala indima ebalulekileyo ekugcineni i-DGC.I-DGC igcina ingqibelelo ye-sarcolemma, i-membrane ye-plasma ye-striated muscle tissue.I-Dystrophin iphinda inciphise umonakalo obangelwa kukunqanda ngokusebenza njenge-molecular spring kunye ne-molecular scaffold9,10.I-dystrophin yobude obugcweleyo inobunzima be-molecular ye-427 kDa, nangona kunjalo, ngenxa yabaninzi abagqugquzeli bangaphakathi kwi-DMD, kukho ii-isoforms ze-truncated zendalo ezininzi, kuquka i-Dp7111.
Iiprotheyini ze-accessory ziye zaboniswa ukuba zenzeke kwi-dystrophin, kubandakanywa i-mechanotransducers yokwenene njenge-neuronal nitric oxide synthase (nNOS), iprotheyini edibeneyo ye-Yes (YAP), kunye ne-caveolin-3, ngaloo ndlela imele amacandelo abalulekileyo okubonakaliswa kweselula.I-Compounds 12, 13, 14. Ukongeza kwi-adhesion, indlela yeselula ehambelana nokusebenzisana phakathi kweeseli kunye ne-matrix, eyenziwe ngama-integrin kunye neethagethi zabo ezisezantsi, ezi zimbini zimbini zimela ukudibanisa phakathi "ngaphakathi" kunye "ngaphandle" kweseli. .Ukukhusela oku kuncamathele kwintshabalalo engaqhelekanga kubalulekile ekuziphatheni kweeseli nasekuphileni.Ukongezelela, inkxaso yedatha yokuba i-dystrophin i-modulator ye-ion ye-mechanosensitive channels, kubandakanywa iziteshi ezisetyenzisiweyo ezilula, ngakumbi i-L-type Ca2 + iziteshi kunye ne-TRPC 15 iziteshi.
Nangona i-dystrophin ibalulekile kumsebenzi we-homeostatic we-striated muscle cells, iindlela ezichanekileyo ezixhasayo azicaci kakuhle, ngokukodwa indima ye-dystrophin kunye nokukwazi kwayo ukusebenza njenge-mechanosensor kunye nomkhuseli womatshini.Ngenxa yokulahleka kwe-dystrophin, kuye kwavela imibuzo emininzi engaphendulwanga, kubandakanywa: ngaba iiprotheyini ze-mechanosensitive ezifana ne-YAP kunye ne-AMPK ephosakeleyo kwi-sarcolemma;Ngaba kukho i-crosstalk ene-interins, iimeko ezinokukhokelela kwi-mechanotransduction engaqhelekanga?Zonke ezi mpawu zinokuba negalelo kwi-phenotype ye-DCM enzima ebonwa kwizigulane ezine-DMD.
Ukongezelela, umbutho weenguqu kwi-biomechanics yeselula kunye ne-DMD yonke phenotype ineempembelelo ezibalulekileyo zeklinikhi.I-DMD i-X-linked muscular dystrophy echaphazela amadoda e-1: 3500-5000, ebonakaliswe ngokulahleka kwangaphambili kokuhamba (I-biomechanics yokulahlekelwa kwe-dystrophin ayizange ichazwe ngokupheleleyo, kwaye apha sihlaziya ubungqina obuxhasa ingcamango yokuba i-dystrophin ngokwenene idlala indima ye-mechanoprotective, oko kukuthi, ukugcina ingqibelelo ye-sarcolemma, kwaye ibalulekile kwi-mechanotransduction.Ukongezelela, sihlolisise ubungqina obubonisa ukuba i-crosstalk ebalulekileyo kunye ne-interins, ngokukodwa i-laminin α7β1D kwiiseli ze-striated muscle.
Ukufakwa kunye nokususwa kuxanduva lwenani elikhulu lokuguqulwa kwe-DMD, kunye ne-72% yeenguqu ezibangelwa ukuguqulwa okunjalo19.Ngokonyango, i-DMD ibonisa ebuntwaneni (≤5 iminyaka) kunye ne-hypotension, uphawu oluhle lwe-Gower, ukulibaziseka ukuqhubela phambili kweenguqu ezinxulumene neminyaka yobudala, ukukhubazeka kwengqondo, kunye ne-skeletal muscle atrophy.Uxinzelelo lokuphefumula luye lwaba yimbangela ehamba phambili yokufa kwizigulane ze-DMD, kodwa ukunakekelwa kwenkxaso ephuculweyo (i-corticosteroids, uxinzelelo oluqhubekayo lwe-airway) luye lwandisa ixesha lokuphila kwezi zigulana, kwaye iminyaka ephakathi yezigulane ze-DMD ezizalwe emva kwe-1990 yi-28.1 iminyaka ye-20, i-21 ..Nangona kunjalo, njengoko ukusinda kwesigulane kunyuka, i-prognosis ye-DCM eqhubekayo imbi kakhulu xa kuthelekiswa nezinye i-cardiomyopathies16, ekhokelela ekupheleni kokuphelelwa yintliziyo, okwangoku iyona nto ibangela ukufa, kubalwa malunga ne-50% ye-DMD yokufa17,18.
I-DCM eqhubekayo ibonakala ngokunyuka kwe-ventricular dilatation kunye nokuthotyelwa, ukuncipha kwe-ventricular, ukunyuka kwe-fibrofatty infiltration, ukunciphisa umsebenzi we-systolic, kunye nokunyuka kwe-arrhythmias.Iqondo le-DCM kwizigulane ezine-DMD liphantse lifike kwindalo yonke ebusheni (90% ukuya kwi-18 yeminyaka ubudala), kodwa ikhona malunga ne-59% yezigulane nge-10 yeminyaka yobudala8,22.Ukujongana nalo mba kubalulekile njengoko iqhezu le-left ventricular ejection liye lahla ngokuthe ngcembe kwireyithi ye-1.6% ngonyaka23.
I-cardiac arrhythmias ixhaphake kwizigulane ezine-DMD, ngakumbi i-sinus tachycardia kunye ne-ventricular tachycardia, kwaye yimbangela yokufa kwentliziyo ngokukhawuleza22.I-Arrhythmias yimiphumo yokungena kwe-fibrofatty, ngokukodwa kwi-ventricle ye-subbasal ekhohlo, ephazamisa i-circuitry yokubuya kunye ne- [Ca2 +] i-process dysfunction kunye ne-ion channel dysfunction24,25.Ukuqatshelwa kokunikezelwa kwentliziyo yeklinikhi kubalulekile, njengoko izicwangciso zonyango zakwangoko zinokulibazisa ukuqala kwe-DCM enzima.
Ukubaluleka kokunyanga ukungasebenzi kwentliziyo kunye nokukhubazeka kwemisipha kuboniswe kwisifundo esinomdla esasebenzisa imodeli yemouse ye-DMD ebizwa ngokuba yi-mdx26 ukufunda imiphumo yokuphucula izicubu ze-skeletal muscle ngaphandle kokujongana neengxaki zentliziyo ezikhoyo kwi-DMD.Apha, ababhali babonise ukunyuka kwe-5-fold paradoxical kwi-cardiac dysfunction emva kokuphuculwa kwe-skeletal muscle, kwaye iigundane zibe nokunciphisa okukhulu kwi-fraction26 ye-ejection.Ukuphuculwa komsebenzi we-skeletal muscle kuvumela umsebenzi ophezulu womzimba ukubeka uxinzelelo olungakumbi kwi-myocardium, okwenza kube lula ukungasebenzi ngokubanzi.Oku kugxininisa ukubaluleka kokunyanga izigulane ze-DMD ngokubanzi kunye nokulumkisa ngonyango lwe-muscle ye-skeletal yodwa.
Ii-DGC zenza imisebenzi emininzi eyongezelelweyo, oko kukuthi, ukubonelela ngozinzo lwesakhiwo kwi-sarcolemma, ibe yi-scaffold ye-molecular esebenza njengekhonkco lokubonisa, ukulawula iziteshi ze-ion ze-mechanosensitive, i-core of costal mechanotransduction, kunye nokuthatha inxaxheba ekuhanjisweni kwamandla asecaleni kummandla we iimbambo (Umfanekiso 1b)..I-Dystrophin idlala indima ephambili kulo buchule, kwaye ngenxa yobukho babagqugquzeli abaninzi bangaphakathi, kukho ii-isoforms ezahlukeneyo, nganye idlala indima eyahlukileyo kwizicubu ezahlukeneyo.Ukubonakaliswa kwezicubu ezihlukeneyo ze-dystrophin isoforms ezahlukeneyo zixhasa ingcamango yokuba i-isoform nganye idlala indima eyahlukileyo.Ngokomzekelo, izicubu zentliziyo zivakalisa ubude obupheleleyo (i-Dp427m) kunye ne-Dp71m emfutshane ye-isoform ye-dystrophin, ngelixa i-skeletal tissue ichaza kuphela eyokuqala kwezi zimbini.Ukuqwalaselwa kwendima ye-subtype nganye kunokutyhila kuphela umsebenzi wayo we-physiological, kodwa kunye ne-pathogenesis ye-muscular dystrophy.
Ukubonakaliswa kweSchematic ye-dystrophin yobude obupheleleyo (Dp427m) kunye ne-isoform encinci, encinci ye-Dp71.I-Dystrophin ine-spectrin ye-24 iphinda ihlukaniswe ngama-loops amane, kunye nesizinda se-actin-binding (ABD), isizinda se-cysteine-rich (CR), kunye ne-C-terminus (CT).Amaqabane abalulekileyo abophekileyo achongiwe, kubandakanywa i-microtubules (MTs) kunye ne-sarcolemma.Zininzi ii-isoforms ze-Dp71, i-Dp71m ibhekisa kwizicubu zezihlunu kwaye i-Dp71b ibhekisa kwi-isoform ye-nervous tissue.Ngokukodwa, i-Dp71f ibhekisa kwi-cytoplasmic isoform ye-neurons.b I-dystrophin-glycoprotein complex (DHA) ifumaneka kwi-sarcolemma iyonke.Amandla e-Biomechanical atshintsha phakathi kwe-ECM kunye ne-F-actin.Qaphela i-crosstalk enokubakho phakathi kwe-DGCs kunye ne-integrin adhesion, i-Dp71 inokudlala indima ekugxininiseni ukunamathela.Yenziwe ngeBiorender.com.
I-DMD yeyona nto ixhaphakileyo ye-muscular dystrophy kwaye ibangelwa ziinguqu kwi-DMD.Nangona kunjalo, ukuqonda ngokupheleleyo ukuqonda kwethu kwangoku kwendima ye-anti-dystrophin, kubalulekile ukuyibeka kumxholo we-DGC yonke.Ke, ezinye iiproteni ezibandakanyekayo ziya kuchazwa ngokufutshane.Ukubunjwa kweprotheyini ye-DGC yaqala ukufundwa ngasekupheleni kweminyaka yee-1980, ngokuqwalasela ngokukodwa kwi-dystrophin.I-Koenig27,28, i-Hoffman29 kunye ne-Ervasti30 yenza ukufumanisa okubalulekileyo ngokuchonga i-dystrophin, iprotheni ye-427 kDa kwi-muscle striated31.
Emva koko, ezinye ii-subcomplexes zaboniswa ukuba zinxulunyaniswa ne-dystrophin, kubandakanya i-sarcoglycan, i-dystrophin transmembrane subcomplex, i-dysbrevin, kunye ne-sytrophins8, ezidibene zenza imodeli yangoku ye-DGC.Eli candelo liya kuqala ukusabalalisa ubungqina bendima ye-DGC kwimbono ye-mechanosensory ngelixa uhlola amacandelo ngabanye ngokubanzi.
I-isoform ye-dystrophin yobude obupheleleyo ekhoyo kwi-striated muscle tissue yi-Dp427m (umzekelo, "m" ye-muscle ukuze iyahlula kwingqondo) kwaye yiprotheni enkulu emile njengentonga eneendawo ezine ezisebenzayo eziphantsi kwe-cardiomyocyte sarcolemma, ngakumbi kwingingqi yeendleko. 29, 32. I-Dp427m, efakwe kwi-DMD gene kwi-Xp21.1, iqulethe ii-exons ze-79 ezenziwe kwii-megabases ze-2.2 kwaye ngoko ke i-gene enkulu kwi-genome8 yethu.
Abagqugquzeli abaninzi bangaphakathi kwi-DMD bavelisa i-multiple truncated dystrophin isoforms, ezinye zazo ziyizicubu ezithile.Xa kuthelekiswa ne-Dp427m, i-Dp71m icuthwe kakhulu kwaye ayinayo idomeyini ephindayo ye-spectrin okanye i-N-terminal ABD domain.Nangona kunjalo, i-Dp71m igcina ulwakhiwo olubophelelayo lwe-C-terminal.Kwi-cardiomyocytes, indima ye-Dp71m ayicacanga, kodwa ibonakaliswe ukuba ifakwe kwi-tubules ye-T, iphakamisa ukuba inokunceda ekulawuleni ukudibanisa kwe-excitation-contraction 33,34,35.Kulwazi lwethu, ukufunyanwa kwamva nje kwe-Dp71m kwizicubu zentliziyo kuye kwafumana ingqwalasela encinci, kodwa ezinye izifundo zibonisa ukuba zidibene neziteshi ze-ion ezisetyenzisiweyo, kwaye uMasubuchi ucebise ukuba unokudlala indima ekulawuleni i-nNOS33., 36. Ngokwenza njalo, i-Dp71 ifumene ingqwalasela ebalulekileyo kwi-neurophysiology kunye nophando lweplatelet, iindawo ezinokubonelela ngendima kwi-cardiomyocytes37,38,39.
Kwizicubu zovalo, i-Dp71b isoform ibonakaliswa ikakhulu, kunye ne-14 isoforms exeliweyo38.Ukususwa kwe-Dp71b, umlawuli obalulekileyo we-aquaporin 4 kunye ne-Kir4.1 iziteshi ze-potassium kwinkqubo ye-nervous central, ibonakaliswe ukuguqula umqobo we-blood-brain barrier permeability40.Ukunikezelwa kwendima ye-Dp71b kulawulo lwe-ion channel, i-Dp71m inokudlala indima efanayo kwi-cardiomyocytes.
Ubukho be-DGC kwi-costal ganglia ngokukhawuleza bubonisa indima kwi-mechanotransduction, kwaye ngokwenene ibonakaliswe ngokubambisana kunye ne-integrin-talin-vinculin complexes 41.Ngaphezu koko, kunikezelwa ukuba icandelo leendleko liyingqwalasela ye-mechanotransduction eguquguqukayo, indawo yokuhlala ye-Dp427m apha igxininisa indima yayo ekukhuseleni iiseli kumonakalo owenziwe ukunyathela.Ngaphezu koko, i-Dp427m isebenzisana ne-actin kunye ne-microtubule cytoskeleton, ngaloo ndlela igqibezela uxhulumaniso phakathi kwendawo ye-intracellular kunye ne-extracellular matrix.
I-N-terminus equkethe i-actin-binding domain 1 (ABD1) iqulethe i-domain ye-homology ye-callodulin (CH) efunekayo ekusebenzisaneni ne-F-actin kunye ne-anchoring i-γ-actin isoform kwi-sarcolemma42,43.I-Dystrophin inokufaka isandla kwi-viscoelasticity yonke ye-cardiomyocytes ngokunamathela kwi-cytoskeleton ye-subsarcolemmal, kwaye indawo yayo kwi-costal ganglia isekela ukubandakanyeka kwayo kwi-mechanotransduction kunye ne-mechanoprotection44,45.
Isizinda esisembindini sineeproteni ezingama-24 eziphinda-phinda ezifana ne-spectrin, nganye kuzo imalunga ne-100 yeentsalela ze-amino acid ubude.Ukuphindaphinda kwe-spectrin kuhlanganiswe kunye neendawo ezine zehinge, zinika ukuguquguquka kweprotheyini kunye neqondo eliphezulu lokwandiswa.Ukuphindaphinda kwe-Dystrophin spectrin kunokuvela ngaphakathi koluhlu lwe-physiological of forces (15-30 pN) ukusuka kwi-21 nm ukuya kwi-84 nm, imikhosi enokufezekiswa kwi-myosin contraction 46.Ezi mpawu zesizinda esiphindayo se-spectrin sivumela i-dystrophin ukuba isebenze njenge-molecular shock absorber.
Intonga ephakathi ye-Dp427m iqinisekisa indawo yayo kwi-sarcolemma, ngokukodwa, ngokusebenzisa i-hydrophobic kunye ne-electrostatic interactions kunye ne-phosphatidylserine 47,48.Kuyathakazelisa ukuba i-core central ye-dystrophin isebenzisana ngokuhlukileyo kunye ne-sarcolemma phospholipids kwi-skeletal and cardiac tissues, mhlawumbi ebonisa iipatheni ezahlukeneyo zasentwasahlobo.ebaluleke kakhulu, ngelixa izihlunu zamathambo nazo zihambelana ne-R10-R1249.
Ukubophelela kwi-γ-actin cytoskeleton idinga i-ABD2 spectrin iphinda i-11-17 indawo, equkethe iintsalela ze-amino acid ezisisiseko kwaye zihluke kwi-domain ye-F-actin-binding CH.I-Microtubules isebenzisana ngokuthe ngqo ne-core domain ye-dystrophin, le ntsebenziswano idinga i-residues ye-spectrin iphinda i-4-15 kunye ne-20-23, kwaye ubukho be-ankyrin B bufunekayo ukukhusela ukubunjwa kwe-microtubules kule ndawo.Imibhobho ayikho 50,51,52.I-gap phakathi kwe-microtubules kunye ne-dystrophin ibonakaliswe ukwandisa i-DMD pathology ngokunyusa iintlobo ze-oksijini ezisebenzayo (X-ROS).
Isizinda se-CR nge-ankyrin B yenye i-anchor ye-sarcolemmal phospholipids52.I-Ankyrin-B kunye ne-ankyrin-G ziyafuneka kwi-rib localization ye-dystrophin / DGC, kwaye ukungabikho kwazo kubangela i-diffuse sarcolemmal pattern ye-DGC52.
I-domain ye-CR iqulethe i-WW ebophelelayo i-domain esebenzisana ngqo ne-PPxY ebophelelayo i-motif ye-β-DG.Ngokunamathela kwi-complex ye-dystrophin-glycan, i-dystrophin igqiba ikhonkco phakathi kwangaphakathi nangaphandle kweseli54.Olu xhulumaniso lubaluleke kakhulu kwi-striated muscle, njengoko kuboniswa yinto yokuba ukuphazamiseka koqhagamshelwano phakathi kwe-ECM kunye nengaphakathi leseli kukhokelela kubomi bokunciphisa i-muscular dystrophy.
Ekugqibeleni, i-domain ye-CT yindawo egcinwe kakhulu eyenza i-helix edibeneyo kwaye ibaluleke kakhulu ekubopheni i-α-dystrobrevin kunye ne-α1-, β1-syntrophins55,56.I-α-dystrobrevin ibophelela kwi-CT domain ye-dystrophin kwaye inikezela ukuchasana okongeziweyo kwi-dystrophin kwi-sarcolemma57.
Ngexesha lophuhliso lwe-embryonic kunye ne-fetus, i-Utrophin ibonakaliswa ngokubanzi kwizicubu ezahlukeneyo, kubandakanywa iiseli ze-endothelial, izicubu ze-nervous, kunye ne-striated muscle tissue58.I-Utrophin iboniswa yi-UTRN efumaneka kwi-chromosome 6q kwaye i-dystrophin autolog ene-80% ye-protein homology.Ngexesha lophuhliso, i-utrophin ibekwe kwindawo ye-sarcolemma kodwa icinezelwe ngokubonakalayo kwizicubu ze-postnatal striated muscle, apho ithathelwa indawo yi-dystrophin.Emva kokuzalwa, indawo ye-utrophin inqunyelwe kwii-tendon kunye ne-neuromuscular junctions ye-skeletal muscles58,59.
Amaqabane abophezelayo e-Utrophin ngokubanzi afana nalawo e-dystrophins, nangona ezinye iiyantlukwano eziphambili zichazwe.Ngokomzekelo, i-dystrophin isebenzisana ne-β-DG ngokusebenzisa isizinda sayo se-WW, esizinziswe yi-domain ye-ZZ (egama layo likwazi ukubopha i-zinc ions ezimbini) ngaphakathi kwendawo ye-CT, apho i-cysteic acid i-residues 3307-3354 ibaluleke kakhulu kule ntsebenziswano60 ., 61. I-Utrophin iphinda ibophelele kwi-β-DG nge-domain ye-WW / ZZ, kodwa iintsalela ezichanekileyo ezixhasa le ntsebenziswano zihluke kwiintsalela ze-dystrophin (3307-3345 kwi-dystrophin kunye ne-3064-3102 kwi-utrophin) 60,61.Okubalulekileyo, ukubophelela kwe-utrophin kwi-β-DG kwakumalunga ne-2-fold ephantsi xa kuthelekiswa ne-dystrophin 61. I-Dystrophin iye yaxelwa ukuba ibophe kwi-F-actin nge-spectrin iphinda i-11-17, ngelixa iziza ezifanayo kwi-utrophin azikwazi ukubopha kwi-F-actin, nangona kunjalo. ugxininiso oluphezulu, kodwa banokusebenzisana nge-CH-domains zabo.Isenzo 62,63,64.Ekugqibeleni, ngokungafaniyo ne-dystrophin, i-utrophin ayikwazi ukubopha kwi-microtubules51.
I-Biomechanically, ukuphindaphinda kwe-utrophin spectrin kunepateni eyahlukileyo engabonakaliyo xa kuthelekiswa ne-dystrophin65.I-Utrophin-spectrin iphinda ukuthunyelwa kumandla aphezulu, afana ne-titin kodwa kungekhona i-dystrophin65.Oku kuhambelana nendawo yayo kunye nendima ekuhanjisweni kwamandla okuqina okuguquguqukayo kwi-tendon junctions, kodwa inokwenza i-utrophin ingafaneleki ukuba isebenze njengentwasahlobo ye-molecular in buffering forces eyenziwa yi-contraction 65.Kuthatyathwe kunye, ezi datha zibonisa ukuba i-mechanotransduction kunye ne-mechanobuffering capabilities ingatshintshwa phambi kwe-utrophin overexpression, ingakumbi inikwe amaqabane ahlukeneyo abophezelayo / iindlela, nangona kunjalo oku kufuna uphando olongezelelweyo lokulinga.
Ukususela kumbono wokusebenza, into yokuba i-utrophin ikholelwa ukuba ineempembelelo ezifanayo kwi-dystrophin yenza ukuba ibe yinto ekujoliswe kuyo yonyango ye-DMD66,67.Enyanisweni, ezinye izigulane ze-DMD ziye zaboniswa ukuba zigqithise i-utrophin, mhlawumbi njengendlela yokuhlawulela, kwaye i-phenotype ibuyiselwe ngempumelelo kwimodeli yegundane kunye ne-utrophin overexpression 68.Ngelixa ukunyuswa kwe-utrophin isicwangciso esinokwenzeka sonyango, ukuqwalaselwa kwentlukwano esemthethweni kunye nokusebenza phakathi kwe-utrophin kunye ne-dystrophin kunye nokusetyenziswa kokunyanzeliswa kwe-overexpression kunye neendawo ezifanelekileyo kunye ne-sarcolemma yenza ukuba isicwangciso sexesha elide le-utrophin lisacaca.Ngokucacileyo, abathwali besifazane babonisa umzekelo we-mosaic we-utrophin expression, kwaye umlinganiselo phakathi kwe-dystrophin kunye ne-utrophin inokuchaphazela iqondo le-cardiomyopathy ehlanjululweyo kwezi zigulana, i-69 nangona imizekelo ye-murine yabathwali ibonisiwe..
I-subcomplex ye-dystroglycan iqukethe iiprotheni ezimbini, i-α- kunye ne-β-dystroglycan (α-, β-DG), zombini ibhalwe kwi-DAG1 gene kwaye emva kokuguqulelwa kokuguqulelwa kwiiprotheni ezimbini ze-71.I-α-DG i-glycosylated kakhulu kwi-extracellular aspect ye-DGCs kwaye isebenzisana ngokuthe ngqo kunye neentsalela zeproline kwi-lamin α2 kunye ne-agrin72 kunye ne-picaculin73 kunye nommandla we-CT / CR we-dystrophin73,74,75,76.I-O-linked glycosylation, ngokukodwa i-serine residues, iyadingeka ekusebenzisaneni kwayo ne-ECM.Indlela ye-glycosylation ibandakanya ezininzi ii-enzyme eziguqulwayo zikhokelela kwi-muscular dystrophy (jonga kwakhona iThebhile 1).Ezi ziquka i-O-mannosyltransferase POMT2, i-fucutin kunye neprotheni ehlobene ne-fucutin (FKRP), i-ribitol phosphotransferases ezimbini ezongeza i-tandem ribitol phosphates kwi-core glycan, kunye ne-LARGE1 iprotheni eyongeza i-xylose kunye ne-glucose.Linear uronic acid polysaccharide, eyaziwa ngokuba matrix glycan ekupheleni glycan77.I-FKRP ibandakanyeka ekuphuhliseni nasekugcinweni kwe-ECM, kwaye ukuguqulwa kwayo kukhokelela ekunciphiseni ukubonakaliswa kwe-laminin α2 kunye ne-α-DG77,78,79.Ukongeza, i-FKRP inokwalathisa ukubunjwa kwe-basal lamina kunye ne-cardiac extracellular matrix nge-glycosylated fibronectin 80.
I-β-DG iqulethe i-PPxY ebophelelayo i-motif eyenza indawo ngqo kwaye ilandelelanisa i-YAP12.Oku kukufumanisa okunomdla njengoko kuthetha ukuba i-DGC ilawula umjikelo weseli ye-cardiomyocyte.I-α-DH kwi-cardiomyocytes ye-neonatal isebenzisana ne-agrin, ekhuthaza ukuvuselelwa kwentliziyo kunye ne-DGC76 lysis ngenxa yokuvuthwa kweeseli.Njengoko i-cardiomyocytes ikhula, intetho ye-aggrin iyancipha ngokuthanda i-lamin, ekucingelwa ukuba inegalelo ekubanjweni komjikelo weseli76.I-Morikawa12 ibonise ukuba i-double knockdown ye-dystrophin kunye ne-salvador, isilawuli esibi se-YAP, sikhokelela kwi-hyperproliferation ye-cardiomyocytes kwi-rumen ebangela i-infarct.Oku kukhokelele kumbono ochulumancisayo wokuba ukwenziwa kwe-YAP kunokuba nexabiso leklinikhi ekuthinteleni ukulahleka kwezicubu emva kwe-myocardial infarction.Ngaloo ndlela, i-agrin-induced DGC lysis inokumela i-axis evumela ukuba i-YAP isebenze kwaye iyindlela enokwenzeka yokuvuselelwa kwentliziyo.
Ngomatshini, i-α- kunye ne-β-DG iyadingeka ukugcina ukusebenzisana phakathi kwe-sarcolemma kunye ne-basal layer 81.Zomibini i-α-DG kunye ne-α7 integrins zinegalelo ekunyanzeliseni ukuveliswa kwi-ganglion ye-costal, kunye nokulahlekelwa kwe-α-DG kubangela ukuhlukana kwe-sarcolemma kwi-basal lamina, eshiya izicubu ze-skeletal muscle zisengozini kumonakalo owenziwe ukunqanda.Njengoko kuchazwe ngaphambili, i-complex ye-dystroglycan ilawula i-turnover yonke ye-DGCs, apho ukubopha kwi-cognate ligand laminin kubangela ukuba i-tyrosine phosphorylation ye-PPPY-binding motif ye-β-DG892.I-Tyrosine phosphorylation apha ikhuthaza i-dystrophin disassembly, eguqula i-DGC complex.I-Physiologically, le nkqubo ilawulwa kakhulu, engekhoyo kwi-muscular dystrophy82, nangona iindlela ezisisiseko ezilawula le nkqubo aziqondwa ngokupheleleyo.
I-Cyclic stretch ibonakaliswe ukuba isebenze i-ERK1 / 2 kunye neendlela ze-AMPK ngokusebenzisa i-dystrophin complex kunye ne-protein plectin83 ehambelana nayo.Ngokudibeneyo, i-plectin kunye ne-dystroglycan ayifunwa nje kuphela ukuba isebenze njenge-scaffold, kodwa kunye nokuthatha inxaxheba kwi-mechanotransduction, kunye ne-knockdown ye-plectin ikhokelela ekunciphiseni komsebenzi we-ERK1 / 2 kunye ne-AMPK83.I-Plectin iphinda ibophelele kwi-cytoskeletal intermediate filament desmin, kwaye i-desmin overexpression ibonakaliswe ukuphucula isifo se-phenotype kwi-mdx: i-desmin kunye ne-mdx iigundane, imodeli ye-DMD84 ephindwe kabini ye-mouse.Ngokusebenzisana ne-β-DG, i-plectin ibopha ngokungathanga ngqo i-DGC kule nxalenye ye-cytoskeleton.Ukongezelela, i-dystroglycan isebenzisana ne-protein-binding factor receptor-binding protein 2 (Grb2), eyaziwayo ukuba ibandakanyeka kwi-rearrangements ye-cytoskeletal85.Ukusebenza kweRas nge-integrin kubonakaliswe ukuba kulamlwa nge-Grb2, enokuthi ibonelele ngendlela enokubakho ye-crosstalk phakathi kwe-interins kunye ne-DGC86.
Ukuguqulwa kwezakhi zofuzo ezibandakanyekayo kwi-α-DH glycosylation kukhokelela kwinto ebizwa ngokuba yi-muscular dystrophy.I-Dystroglycanopathies ibonisa i-heterogeneity yeklinikhi kodwa ikakhulu ibangelwa ukuphazamiseka kwintsebenziswano phakathi kwe-α-DG kunye ne-lamin α277.I-Dystrophiglicanoses ebangelwa kukuguqulwa kweprayimari kwi-DAG1 inqabile kakhulu, mhlawumbi ngenxa yokuba i-embryonic lethal87, ngaloo ndlela iqinisekisa imfuno yobudlelwane beselula kunye ne-ECM.Oku kuthetha ukuba izifo ezininzi ze-dystrophic glycan zibangelwa ukuguqulwa kweprotheni yesibini ehambelana ne-glycosylation.Ngokomzekelo, ukuguqulwa kweenguqu kwi-POMT1 kubangela i-Walker-Warburg syndrome enzima kakhulu, ebonakaliswe yi-anencephaly kwaye iyancipha ngokuphawulekayo ixesha lokuphila (ngaphantsi kweminyaka eyi-3)88.Nangona kunjalo, iinguqu ze-FKRP zibonakaliswa kakhulu njenge-limb-girdle muscular dystrophy (LGMD), edla ngokuba (kodwa ingasoloko) incinci.Nangona kunjalo, utshintsho kwi-FKRP lubonakaliswe njengonobangela onqabileyo we-WWS89.Utshintsho oluninzi luye lwachongwa kwi-FKRP, apho umsunguli wenguquko (c.826> A) udla ngokubangela i-LGMD2I90.
I-LGMD2I yi-mild muscular dystrophy apho i-pathogenesis yayo isekelwe ekuphazamisekeni koqhagamshelwano phakathi kwe-matrix engaphandle kunye ne-intracellular cytoskeleton.Okungacacanga kakhulu ubudlelwane phakathi kwe-genotype kunye ne-phenotype kwizigulane ezinokuguqulwa kwezi zakhi zofuzo, kwaye ngokwenene le ngcamango iyasebenza kwezinye iiprotheni ze-DSC.Kutheni ezinye izigulana ezinotshintsho lwe-FKRP zibonisa isifo sephenotype esihambelana ne-WWS ngelixa ezinye zine-LGMD2I?Impendulo yalo mbuzo inokulala kwi-i) yeyiphi inyathelo lendlela ye-glycosylation echaphazelekayo kukuguqulwa, okanye ii) iqondo le-hypoglycosylation nakweliphi na inyathelo.I-Hypoglycosylation ye-α-DG isenokuthi ivumele iqondo elithile lokusebenzisana kunye ne-ECM ebangela ukuba kubekho i-phenotype epholileyo, ngelixa ukuhlukana kwi-membrane yangaphantsi kwandisa ubunzima be-phenotype yesifo.Izigulane ezine-LGMD2I ziphinda ziphuhlise i-DCM, nangona le nto ingaphantsi kwe-DMD, ikhuthaza ukuphuthuma kokuqonda oku kuguqulwa kumxholo we-cardiomyocytes.
I-sarcospan-sarcoglycan subcomplex ikhuthaza ukubunjwa kwe-DHA kwaye isebenzisana ngokuthe ngqo ne-β-DH.Kukho ezine sarcoglycans ezine unidirectional kwiithishu zentliziyo: α, β, γ, kunye ne-δ91.Kutshanje kuye kwachazwa ukuba i-c.218C>T missense ukuguqulwa kwe-exon 3 ye-SGCA gene kunye nokususwa kwe-heterozygous inxalenye kwi-exons 7-8 kubangela i-LGMD2D92.Nangona kunjalo, kule meko, ababhali abazange bahlole i-phenotype yenhliziyo.
Amanye amaqela afumene ukuba i-SGCD kwi-porcine93 kunye ne-mouse94 imodeli iphumela ekunciphiseni ukubonakaliswa kweprotheyini kwi-subcomplex ye-sarcoglycan, ukuphazamisa isakhiwo esipheleleyo se-DGC kunye nokukhokelela kwi-DCM.Ukongezelela, i-19% yazo zonke izigulane ezine-SGCA, SGCB, okanye i-SGCG yokuguqulwa kweenguqu zichazwe ukuba zine-cardiomyopathy edibeneyo, kwaye i-25% yazo zonke izigulane nazo zifuna inkxaso yokuphefumula95.
Ukuguqulwa okuphindaphindiweyo kwi-sarcoglycan (SG) δ kubangela ukunciphisa okanye ukungabikho ngokupheleleyo kwe-sarcoglycan complexes kwaye ngoko i-DGC kwizicubu zentliziyo kwaye inoxanduva lwe-LGMD kunye ne-DCM96 ehambelana nayo.Okubangel 'umdla kukuba, iinguqu ezilawulayo-ezimbi kwi-SG-δ zichanekileyo kwi-cardiovascular system kwaye ziyimbangela ye-familial dilated cardiomyopathy97.I-SG-δ i-R97Q kunye ne-R71T yokuguqulwa kwe-dominant-negative ibonakaliswe ngokuzinzileyo kwi-cardiomyocytes yegundane ngaphandle komonakalo obalulekileyo we-DGC98 iyonke.Nangona kunjalo, iiseli zentliziyo ezithwele olu tshintsho zichaphazeleka ngakumbi kumonakalo we-sarcolemma, ukunyanzeliswa, kunye nokungasebenzi kakuhle komatshini phantsi koxinzelelo lomatshini, oluhambelana ne-DCM98 phenotype.
I-Sarcospan (SSPN) yi-25 kDa tetraspanin ehlala kwi-subcomplex ye-sarcoglycan kwaye ikholelwa ukuba isebenza njenge-protein scaffold99,100.Njengeprotheyini ye-scaffold, i-SSPN izinzisa indawo yokuhlala kunye ne-glycosylation ye-α-DG99,101.Ukugqithiswa kwe-SSPN kwiimodeli zemouse kufunyenwe ukwandisa ukubopha phakathi kwe-muscle kunye ne-laminin 102.Ukongezelela, i-SSPN ibonakaliswe ukusebenzisana ne-interins, iphakamisa i-degree of crosstalk phakathi kwe-rib commissures ezimbini, i-DGC, kunye ne-integrin-talin-vinculin glycoprotein structure100,101,102.I-Knockdown ye-SSPN nayo ibangele ukwanda kwe-α7β1 kwi-mouse skeletal muscle.
Uphononongo olutshanje lubonise ukuba i-sarcospan overexpression ikhulisa ukuvuthwa kunye ne-glycosylation ye-α-DG kwizicubu zentliziyo ngokuzimeleyo kwi-galactosylaminotransferase 2 (Galgt2) i-knockdown kwimodeli ye-mdx ye-mouse ye-DMD, ngaloo ndlela inciphisa isifo se-phenotype 101. Ukwanda kwe-glycosylation ye-dystroglycan complex kunokunyusa i-interactivity ye-dystroglycan I-ECM, ngaloo ndlela inciphisa kakhulu isifo.Ngaphezu koko, baye babonisa ukuba i-sarcospan overexpression iyancipha ukusebenzisana kwe-β1D integrin kunye ne-DGCs, igxininisa indima enokwenzeka ye-sarcospan kulawulo lwe-integrin complexes101.
I-Syntrophins yintsapho encinci (i-58 kDa) iiprotheyini ezihlala kwi-DGCs, azinawo ngokwazo umsebenzi we-enzymatic wangaphakathi, kwaye zisebenza njenge-adapter molecular103,104.Ii-isoforms ezintlanu (α-1, β-1, β-2, γ-1 kunye ne-γ-2) ziye zachongwa ukubonisa inkcazo ye-tissue-specific, kunye ne-α-1 isoform echazwe ngokugqithiseleyo kwizicubu ze-muscle striated 105.I-Syntrophins zibalulekile iiprotheyini ze-adapter eziququzelela unxibelelwano phakathi kwe-dystrophin kunye neemolekyuli zokubonisa, kuquka neuronal nitric oxide synthase (nNOS) kwi-skeletal muscle106.I-α-syntrophin isebenzisana ngokuthe ngqo ne-dystrophin 16-17 i-spectin repeat domain, leyo ibophelela kwi-nNOS106,107 PDZ-binding motif.
I-Syntrophins iphinda idibanise ne-dystrobrevin ngokusebenzisa i-PH2 kunye ne-SU ezibophezelayo, kwaye ziphinde zidibanise ne-actin cytoskeleton 108.Enyanisweni, i-sytrophins ibonakala idlala indima ebaluleke kakhulu kulawulo lwe-cytoskeletal dynamics, kwaye i-α kunye ne-β isoforms ziyakwazi ukusebenzisana ngokuthe ngqo ne-F-actin 108 kwaye ngaloo ndlela zidlala indima ekulawuleni ubunzima kunye ne-biomechanics yeselula. isiphumo.Ukongezelela, i-sytrophins ibonakaliswe ukulawula i-cytoskeleton nge-Rac1109.
Ukumodareyitha amanqanaba e-syntrophin kunokubuyisela umsebenzi, kwaye uphando olutshanje olusebenzisa i-mini-dystrophin lubonise ukuba i-ΔR4-R23 / ΔCT yokwakha yakwazi ukubuyisela i-α-syntrophin kunye nezinye iiprotheni ze-DGC kumanqanaba athelekiswa ne-WT mdx cardiomyocytes.
Ukongeza kwindima yabo ekulawuleni i-cytoskeleton, i-sytrophins nayo ibhalwe kakuhle kulawulo lweziteshi ze-ion 111,112,113.I-PDZ-binding motif ye-sytrophins ilawula i-cardiac voltage-dependent-dependent-Nav1.5111 channel, edlala indima ephambili ekusekeni i-cardiac excitability and conduction.Kuyathakazelisa ukuba kwimodeli ye-mouse ye-mdx, iziteshi ze-Nav1.5 zifunyenwe ziphantsi kwaye i-cardiac arrhythmias ifunyenwe kwizilwanyana ze-111.Ukongezelela, intsapho yamajelo e-ion ye-mechanosensitive, i-channel ye-receptor enokuthi ifumaneke (TRPC), ibonakaliswe ukuba ilawulwa yi-α1-syntrophin kwi-cardiac tissue 113 kunye ne-TRPC6 inhibition iboniswe ukuphucula i-arrhythmias kwimodeli ye-mouse ye-DMD112.Ukunyuka komsebenzi we-TRPC6 kwi-DMD kuye kwabikwa ukuba kubangele i-cardiac arrhythmias, ekhululekayo xa idibene ne-PKG 112.Ngomatshini, ukuchithwa kwe-dystrophin kukhuthaza ukunyuka kwe-stretch-induced influx ye- [Ca2 +] i-isebenza phezulu kwe-TRPC6 ukuze isebenze, njengoko kuboniswe kwi-cardiomyocytes kunye ne-vascular smooth muscle cells112,114.I-Hyperactivation ye-TRPC6 yokwelula yenza i-mechanosensor enkulu kunye nethagethi enokubakho yonyango kwi-DMD112,114.
Ukulahlekelwa kwe-dystrophin kukhokelela kwi-lysis okanye ukunyanzeliswa okuphawulweyo kuyo yonke i-DGC eyinkimbinkimbi, kunye nokulahlekelwa okulandelayo kwemisebenzi emininzi ye-mechanoprotective kunye ne-mechanotransduction, okubangelwa yi-phenotype eyintlekele ebonwa kwizicubu ze-muscle ze-DMD.Ke ngoko, kunokuba sengqiqweni ukucinga ukuba ii-RSKs zisebenza kwikonsathi kwaye amalungu axhomekeke kubukho kunye nokusebenza kwamanye amacandelo.Oku kuyinyani ngokukodwa kwi-dystrophin, ebonakala ifuneka kwi-assembly kunye ne-localization ye-sarcolemma eyinkimbinkimbi kwi-cardiomyocytes.Icandelo ngalinye lidlala indima ekhethekileyo ekufakeni igalelo ekuzinziseni ngokubanzi kwe-sarcolemma, ukugcinwa kweeprotheyini eziphambili ze-accessory, ukulawulwa kweziteshi ze-ion kunye ne-gene expression, kunye nokulahlekelwa kweprotheni enye kwi-DGC kukhokelela ekudakaleni kwe-myocardium yonke.
Njengoko kuboniswe ngasentla, iiprotheni ezininzi ze-DGC zibandakanyeka kwi-mechanotransduction kunye nokubonakaliswa, kwaye i-dystrophin ifaneleka ngokukodwa kule ndima.Ukuba i-DGC ifumaneka kwiimbambo, oku kuqinisekisa uluvo lokuba ithatha inxaxheba kwi-mechanotransduction kunye ne-interins.Ke, ii-DGCs zihamba ngokwasemzimbeni ukuhanjiswa kwamandla e-anisotropic kwaye zithathe inxaxheba kwi-mechanosensory kunye ne-cytoskeletal rearrangement ye-intracellular microenvironment, ehambelana nemodeli ye-tensegrity.Ukongeza, i-Dp427m ikhusela amandla angenayo e-biomechanical ngokwandisa i-spectrin ephindaphindayo ngaphakathi kwendawo yayo engundoqo, ngokwenza oko isebenze njengomatshini wokukhusela ngokugcina amandla angama-25 pN wokukhulula kuluhlu olwandisiweyo lwe-800 nm.Ngokwahlula, i-dystrophin iyakwazi "ukuphazamisa" amandla okunciphisa i-contraction-relaxation eyenziwa yi-cardiomyocytes10.Ngenxa yokwahlukana kweeprotheyini kunye ne-phospholipids ezisebenzisana neendawo eziphindaphindayo ze-spectrin, kunomdla ukucinga ukuba i-spectrin iphinda i-unwinding iguqula i-kinetics ebophezelayo yeeprotheni ze-mechanosensitive ngendlela efana ne-talin116,117,118.Nangona kunjalo, oku akukaqinisekwa kwaye uphando olongezelelweyo luyafuneka.