310 igwe anaghị agba nchara capillary eriri igwe tubing kemịkalụ kemịkalụ, ọrụ nke dystrophin glycoprotein complexes na mechanotransduction nke mkpụrụ ndụ akwara.

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310 igwe anaghị agba nchara capillary eriri igwe tubing tubing

Dystrophin bụ isi protein nke dystrophin-glycoprotein complex (DGC) na akwara skeletal na cardiomyocytes.Dystrophin na-ejikọta cytoskeleton actin na matrix extracellular (ECM).Nkwụsị nke njikọ dị n'etiti matrix extracellular na cytoskeleton intracellular nwere ike nweta nsonaazụ na-agbawa obi maka homeostasis nke sel anụ ahụ skeletal, na-eduga n'ọtụtụ dystrophy muscular.Na mgbakwunye, ọnwụ nke DGC ndị na-arụ ọrụ na-eduga na cardiomyopathy na-aga n'ihu na ọnwụ akaghi aka.Dystrophin na-arụ ọrụ dị ka mmiri molekụla na DHA na-arụkwa ọrụ dị mkpa n'ịkwado iguzosi ike n'ezi ihe nke sarcolemma.Ọzọkwa, ihe akaebe na-achịkọta ijikọ DGC na nrịbama igwe, n'agbanyeghị na a ghọtara ọrụ a nke ọma.Edemede nlegharị anya a na-achọ ịnye echiche ọgbara ọhụrụ nke DGC na ọrụ ha na mechanotransduction.Anyị na-ebu ụzọ kwurịta njikọ dị mgbagwoju anya n'etiti sistemu mkpụrụ ndụ akwara na arụ ọrụ, wee nyochaa nyocha na nso nso a gbasara ọrụ dystrophin glycoprotein complex na mechanotransduction na mmezi nke iguzosi ike n'ezi ihe nke mkpụrụ ndụ akwara.N'ikpeazụ, anyị na-enyocha akwụkwọ ndị dị ugbu a iji ghọta otú mgbaàmà DGC si ejikọta na ụzọ nhazi iji gosipụta ihe ntinye aka nwere ike ime n'ọdịnihu, na-elekwasị anya na cardiomyopathy.
Selụ na-enwe mkparịta ụka mgbe niile na microenvironment ha, na mkparịta ụka ụzọ abụọ n'etiti ha dị mkpa maka nkọwa na ntinye nke ozi biomechanical.Biomechanics na-achịkwa isi ihe ndị na-esote (dịka ọmụmaatụ, nhazigharị cytoskeletal) site na ịchịkwa phenotype cell n'ozuzu ya na oghere na oge.Central na usoro a na cardiomyocytes bụ mpaghara ọnụ ahịa, mpaghara ebe sarcolemma na-ejikọta na sarcomere nke mejupụtara integrin-talin-vinculin na dystrophin-glycoprotein (DGC).Ejikọtara ya na cytoskeleton intracellular, adhesions ndị a pụrụ iche (FAs) na-agbasa mgbanwe mgbanwe cellular biomechanical na biochemical nke na-achịkwa ọdịiche, mmụba, organogenesis, mbugharị, ọganihu ọrịa, na ndị ọzọ.Ntughari nke ike biomechanical ka ọ bụrụ biochemical na/ma ọ bụ (epi) mgbanwe mkpụrụ ndụ ihe nketa ka amara dị ka mechanotransduction1.
Ọ dịla anya a mara onye nnabata integrin transmembrane 2 ka ọ na-ejikọ matrix extracellular n'ime sel ma na-agbazi mgbama n'ime na nke mpụga.N'otu aka ahụ na integrins, ndị DGC na-ekekọta ECM na cytoskeleton, na-ewepụta njikọ dị egwu n'etiti mpụta na n'ime cell3.Dytrophin zuru oke (Dp427) bụ isi egosipụtara na akwara obi na skeletal, mana a na-ahụkwa ya na anụ ahụ nke sistemu ụjọ etiti, gụnyere retina na Purkinje tissue4.A na-eche na mmụgharị na integrins na DGC bụ ihe na-akpata dystrophy muscular na cardiomyopathy na-aga n'ihu (DCM) (Table 1) 5,6.Karịsịa, mmụgharị DMD na-edobe protein dystrophin etiti DGC na-akpata Duchenne muscular dystrophy (DMD)7.DGC nwere ọtụtụ subcomplexes gụnyere α- na β-dystroglycan (α/β-DG), sarcoglycan-sarcospan, syntrophin, na dystrophin8.
Dystrophin bụ protein cytoskeletal nke DMD (Xp21.1-Xp22) na-arụ ọrụ bụ isi n'idebe DGC.DGC na-edobe iguzosi ike n'ezi ihe nke sarcolemma, akpụkpọ ahụ plasma nke anụ ahụ striated.Dystrophin na-eme ka mmebi ahụ na-emebi site n'ịrụ ọrụ dịka mmiri mmiri na molecular scaffold9,10.Dystrophin nke ogologo zuru oke nwere ihe dị arọ nke 427 kDa, Otú ọ dị, n'ihi ọtụtụ ndị na-akwalite ime na DMD, e nwere ọtụtụ ihe ndị na-emepụta ihe na-emekarị, gụnyere Dp7111.
Egosiputara protein ngwa ngwa ka etinyere ya na dystrophin, gụnyere ezi mechanotransducers dị ka neuronal nitric oxide synthase (nNOS), protein jikọrọ Ee (YAP), na caveolin-3, si otú a na-anọchi anya akụkụ dị mkpa nke akara ekwentị.Ngwakọta 12, 13, 14. Na mgbakwunye na adhesion, usoro cellular jikọtara ya na mmekọrịta dị n'etiti sel na matrix, nke e guzobere site na integrins na ihe mgbaru ọsọ ha dị n'okpuru ala, mgbagwoju abụọ a na-anọchite anya interface n'etiti "n'ime" na "n'èzí" nke cell. .Ichekwa ebe mgbakwasị ụkwụ ndị a site na mbibi na-adịghị mma dị mkpa maka omume cell na ndụ.Na mgbakwunye, nkwado data na dystrophin bụ modulator nke mechanosensitive ion channels, gụnyere ọwa ịgbatị-arụ ọrụ, karịsịa L-ụdị Ca2 + ọwa na TRPC 15 ọwa.
Ọ bụ ezie na dystrophin dị mkpa maka ọrụ homeostatic nke mkpụrụ ndụ akwara dị warara, usoro nkwado ziri ezi adịchaghị nke ọma, ọkachasị ọrụ dystrophin na ikike ya ịrụ ọrụ dị ka onye na-ahụ maka igwe na ihe nchekwa igwe.N'ihi nkwụsị nke dystrophin, ọtụtụ ajụjụ a na-azaghị ebiliwo, gụnyere: bụ protein ndị na-emepụta ihe dị ka YAP na AMPK na-eduhie na sarcolemma;Enwere crosstalk nwere integrins, ọnọdụ ndị nwere ike iduga n'ụzọ na-adịghị mma?Atụmatụ ndị a niile nwere ike itinye aka na ụdị ụdị DCM siri ike a na-ahụ na ndị ọrịa nwere DMD.
Na mgbakwunye, njikọ nke mgbanwe na biomechanics cellular na mkpokọta DMD phenotype nwere mmetụta ahụike dị mkpa.DMD bụ dystrophy muscular jikọtara X na-emetụta 1: 3500-5000 ndị ikom, nke e ji n'oge mfu nke mmegharị (<5 afọ) na DCM na-aga n'ihu na prognosis dị njọ karịa DCM nke etiologies ndị ọzọ16,17,18.
A kọwabeghị ihe ndị biomechanics nke ọnwụ dystrophin n'ụzọ zuru ezu, ebe a, anyị na-enyocha ihe akaebe na-akwado echiche ahụ na dystrophin na-arụ ọrụ nke mechanoprotective n'ezie, ya bụ na-edobe iguzosi ike n'ezi ihe nke sarcolemma, ma dị oke egwu na ntụgharị ntụgharị.Na mgbakwunye, anyị nyochara ihe akaebe na-atụ aro crosstalk dị mkpa na integrins, kpọmkwem na-ejikọta laminin α7β1D n'ime sel anụ ahụ dị iche iche.
Ntinye na nhichapụ bụ maka ọnụ ọgụgụ dị ukwuu nke mmụgharị na DMD, yana 72% nke mmụgharị na-ebute site na ngbanwe dị otú ahụ19.N'ụlọ ọgwụ, DMD na-egosi n'oge ọ bụ nwata (≤5 afọ) na hypotension, akara Gower dị mma, oge na-aga n'ihu nke mgbanwe ndị metụtara afọ, nkwụsị uche, na atrophy skeletal muscle atrophy.Nsogbu iku ume bụ akụkọ ihe mere eme na-akpata ọnwụ na ndị ọrịa DMD, ma nlekọta nkwado dị mma (corticosteroids, nrụgide ikuku na-aga n'ihu) emeela ka ndụ dịkwuo ogologo ndụ na ndị ọrịa a, na etiti afọ nke ndị ọrịa DMD a mụrụ mgbe 1990 gasịrị bụ 28.1 afọ 20,21. ..Otú ọ dị, ka ịdị ndụ nke onye ọrịa na-abawanye, nchọpụta nke DCM na-aga n'ihu na-akawanye njọ ma e jiri ya tụnyere ndị ọzọ cardiomyopathies16, na-eduga na njedebe njedebe obi, nke bụ isi ihe kpatara ọnwụ ugbu a, na-aza ihe dịka 50% nke ọnwụ DMD17,18.
A na-eji DCM na-aga n'ihu site na mmụba ventricular aka ekpe na nrube isi, nhịahụ ventricular, ịba ụba fibrofatty infiltration, mbelata ọrụ systolic, yana ịba ụba nke arrhythmias.Ogo nke DCM na ndị ọrịa nwere DMD fọrọ nke nta ka ọ bụrụ ụwa niile n'oge uto (90% ruo 18 afọ), mana ọ dị na ihe dịka 59% nke ndị ọrịa site na afọ 10 dị afọ8,22.Ịkwado okwu a dị oke mkpa n'ihi na akụkụ dị nta nke ejection ventricular ekpe na-agbadata nke nta nke nta nke 1.6% kwa afọ23.
Obi arrhythmias nke obi na-adịkarị na ndị ọrịa nwere DMD, ọkachasị sinus tachycardia na tachycardia ventricular, ma bụrụ ihe kpatara ọnwụ obi mberede22.Arrhythmias bụ nsonaazụ fibrofatty infiltration, karịsịa na subbasal ekpe ventricle, nke na-emebi sekit nloghachi yana [Ca2 +] i nhazi dysfunction na ion channel dysfunction24,25.Nghọta nke ngosipụta obi obi ụlọ ọgwụ dị oke mkpa, dịka usoro ọgwụgwọ mmalite nwere ike igbu oge mmalite nke DCM siri ike.
A na-egosi mkpa ọ dị n'ịgwọ ọrịa obi na-arịa ọrịa obi na ọkpụkpụ ọkpụkpụ n'ime nchọpụta na-adọrọ mmasị nke na-eji ụdị òké nke DMD a na-akpọ mdx26 iji mụọ mmetụta nke imeziwanye anụ ahụ ọkpụkpụ n'emeghị ka nsogbu obi obi dị na DMD pụta.N'ebe a, ndị edemede gosipụtara mmụba nke okpukpu 5 na-emegiderịta onwe ya na arụrụ ọrụ obi mgbe emechara nke ọma na akwara skeletal, na ụmụ oke nwere mbelata dị ukwuu na ejection fraction26.Ịrụ ọrụ akwara ọkpụkpụ dị mma na-enye ohere ka mgbatị ahụ dị elu na-etinyekwu nrụgide na myocardium, na-eme ka ọ dịkwuo mfe ịnweta nkwụsịtụ n'ozuzu ya.Nke a na-egosi mkpa ọ dị ịgwọ ndị ọrịa DMD n'ozuzu ya na ịdọ aka ná ntị megide ọgwụgwọ anụ ahụ skeletal naanị.
Ndị DGC na-arụ ọtụtụ ọrụ ndị ọzọ, ya bụ, na-enye nkwụsi ike n'usoro na sarcolemma, na-aghọ ihe na-eme ka mkpụrụ ndụ ihe nketa na-arụ ọrụ dị ka njikọ na-egosi, na-achịkwa ọwa ion mechanosensitive, isi nke mechanotransduction nke ọnụ ahịa, ma na-ekere òkè na nnyefe nke ike n'akụkụ na mpaghara mpaghara. ọgịrịga (Fig 1b)..Dystrophin na-arụ ọrụ dị mkpa na ikike a, na n'ihi ọnụnọ nke ọtụtụ ndị na-akwalite ime ime, e nwere ọtụtụ isoforms dị iche iche, nke ọ bụla na-arụ ọrụ dị iche iche na anụ ahụ dị iche iche.Okwu dị iche iche nke anụ ahụ dị iche iche nke isoforms dystrophin dị iche iche na-akwado echiche na isoform ọ bụla na-arụ ọrụ dị iche iche.Dịka ọmụmaatụ, anụ ahụ obi na-egosipụta ogologo ogologo (Dp427m) yana mkpụmkpụ Dp71m isoform nke dystrophin, ebe ọkpụkpụ ọkpụkpụ na-egosipụta naanị nke mbụ n'ime ha abụọ.Nleba anya na ọrụ nke subtype ọ bụla nwere ike ikpughe ọ bụghị naanị ọrụ physiological ya, kamakwa pathogenesis nke dystrophy muscular.
Nnọchite anya nhazi nke dystrophin zuru oke (Dp427m) yana nke pere mpe, dọkpụ Dp71 isoform.Dystrophin nwere 24 spectrin spectrin nkewapụrụ site na loops anọ, yana ngalaba actin-binding (ABD), ngalaba cysteine-rich (CR), na C-terminus (CT).Achọpụtala ndị mmekọ isi ihe, gụnyere microtubules (MTs) na sarcolemma.Enwere ọtụtụ isoforms nke Dp71, Dp71m na-ezo aka na anụ ahụ anụ ahụ na Dp71b na-ezo aka na isoform anụ ahụ ụjọ.Karịsịa, Dp71f na-ezo aka na cytoplasmic isoform nke neurons.b Ihe mgbagwoju anya dystrophin-glycoprotein (DHA) dị na sarcolemma n'ozuzu ya.Ndị agha biomechanical na-agbanwe n'etiti ECM na F-actin.Rịba ama mkparịta ụka nwere ike n'etiti DGCs na integrin adhesion, Dp71 nwere ike ịrụ ọrụ na nrapagidesi ike.Emepụtara ya na Biorender.com.
DMD bụ dystrophy muscular a na-ahụkarị ma na-ebute mmụgharị na DMD.Agbanyeghị, iji ghọta nke ọma nghọta anyị ugbu a banyere ọrụ mgbochi dystrophin, ọ dị mkpa itinye ya na ọnọdụ DGC n'ozuzu ya.Ya mere, a ga-akọwapụta protein ndị ọzọ mejupụtara.A malitere ịmụ ihe mejupụtara protein nke DGC na ngwụcha afọ 1980, na-elebara anya dystrophin.Koenig27,28, Hoffman29 na Ervasti30 mere nchọpụta dị mkpa site n'ịchọpụta dystrophin, protein 427 kDa na muscle striated31.
Mgbe nke ahụ gasịrị, egosiri na ihe mgbagwoju anya ndị ọzọ na-ejikọta ya na dystrophin, gụnyere sarcoglycan, transsyn, dystrophin subcomplex, dysbrevin, na syntrophins8, nke jikọtara ọnụ na ụdị DGC dị ugbu a.Akụkụ a ga-ebu ụzọ kesaa ihe akaebe maka ọrụ DGC na nhụta nke igwe mgbe ị na-enyocha ihe ndị dị n'otu n'otu n'ụzọ zuru ezu.
Dystrophin isoform zuru oke dị ugbu a na anụ ahụ dị mgbagwoju anya bụ Dp427m (dịka "m" maka akwara iji mata ọdịiche dị na ụbụrụ) yana protein buru ibu nke nwere akụkụ anọ na-arụ ọrụ nke dị n'okpuru cardiomyocyte sarcolemma, karịsịa na mpaghara ọnụ ala. 29, 32. Dp427m, nke DMD gene coded na Xp21.1, nwere exons 79 emepụtara na megabases 2.2 ma bụrụkwa mkpụrụ ndụ kachasị na genome8 anyị.
Ọtụtụ ndị na-akwalite ime ime na DMD na-emepụta ọtụtụ isoforms dystrophin truncated, ụfọdụ n'ime anụ ahụ akọwapụtara.Tụnyere Dp427m, Dp71m na-agbaji nke ọma na enweghị ngalaba ikwugharị spectrin ma ọ bụ ngalaba N-terminal ABD.Agbanyeghị, Dp71m na-ejigide usoro njikọ C-terminal.Na cardiomyocytes, ọrụ nke Dp71m edoghị anya, mana egosila na ọ ga-edobe ya na T tubules, na-atụ aro na ọ nwere ike inye aka ịhazi njikọ mkpali-mmekọrịta 33,34,35.N'ihe ọmụma anyị, nchọpụta Dp71m n'oge na-adịbeghị anya na anụ ahụ obi anataghị nlezianya anya, ma ụfọdụ nchọpụta na-egosi na ọ na-ejikọta ya na channels ion na-agbatị agbatị, na Masubuchi tụrụ aro na ọ nwere ike itinye aka na nhazi nke nNOS33., 36. N'ime nke a, Dp71 enwetawo nlebara anya dị ukwuu na neurophysiology na nchọpụta platelet, ebe ndị nwere ike inye nghọta banyere ọrụ na cardiomyocytes37,38,39.
N'ime anụ ahụ ụjọ, a na-egosipụtakarị isoform Dp71b, yana 14 isoforms kọrọ38.Nhichapụ nke Dp71b, ihe dị mkpa na-achịkwa aquaporin 4 na Kir4.1 potassium channels na etiti ahụ ụjọ usoro, ka egosiri na-agbanwe ọbara-ụbụrụ mgbochi permeability40.Nyere ọrụ Dp71b na nhazi ọwa ion, Dp71m nwere ike rụọ ọrụ yiri nke ahụ na cardiomyocytes.
Ọnụnọ nke DGC na ganglia costal na-egosi ozugbo ọrụ na mechanotransduction, na n'ezie egosila na ọ na-ejikọta ya na integrin-talin-vinculin complexes 41.Ọzọkwa, nyere na akụkụ ọnụ ahịa bụ ihe a na-elekwasị anya maka transverse mechanotransduction, nhazi nke Dp427m ebe a na-egosipụta ọrụ ya n'ichebe mkpụrụ ndụ site na mmebi nke nkwekọrịta kpatara.Ọzọkwa, Dp427m na-emekọ ihe na actin na microtubule cytoskeleton, si otú a na-emecha njikọ dị n'etiti gburugburu intracellular na matrix extracellular.
N-terminus nwere ngalaba actin-binding 1 (ABD1) nwere ngalaba calmodulin homology abụọ (CH) nke achọrọ maka mmekọrịta ya na F-actin yana itinye γ-actin isoform na sarcolemma42,43.Dystrophin nwere ike itinye aka na viscoelasticity nke cardiomyocytes n'ozuzu ya site na itinye aka na cytoskeleton subsarcolemmal, na nhazi ya na ganglia costal na-akwado itinye aka na mechanotransduction yana mechanoprotection44,45.
Ngalaba etiti etiti nwere protein 24 spectrin dị ka ikwugharị, nke ọ bụla n'ime ha dị ihe dị ka 100 fọdụrụ amino acid n'ogologo.A na-ejikọta spectrin na-emegharị ya na ngalaba hinge anọ, na-enye protein mgbanwe na oke nke extensibility.Dystrophin spectrin ikwugharị nwere ike gbasaa n'ime oke ike nke physiological (15-30 pN) na-agbatị site na 21 nm ruo 84 nm, ike a ga-enweta maka myosin contraction 46.Akụkụ ndị a nke spectrin na-emegharị ngalaba na-enye ohere dystrophin ka ọ rụọ ọrụ dị ka ihe na-ekpo ọkụ molekụla.
Mkpanaka etiti nke Dp427m na-eme ka ebe obibi ya dị na sarcolemma, karịsịa, site na mmekọrịta hydrophobic na electrostatic na phosphatidylserine 47,48.N'ụzọ na-akpali mmasị, isi isi nke dystrophin na-emekọrịta ihe dị iche iche na sarcolemma phospholipids na skeletal na obi anụ ahụ, ikekwe na-egosipụta usoro mmiri dị iche iche.dị oke egwu, ebe akwara skeletal jikọtara ya na R10-R1249.
Njide na cytoskeleton γ-actin chọrọ ka ABD2 spectrin megharịa mpaghara 11–17, nke nwere ihe fọdụrụ na amino acid bụ isi ma dị iche na ngalaba F-actin-binding CH.Microtubules na-emekọrịta ozugbo na ngalaba isi nke dystrophin, mmekọrịta a na-achọ ihe fọdụrụnụ nke spectrin na-emegharị 4-15 na 20-23, na ọnụnọ ankyrin B dị mkpa iji gbochie ịmepụta microtubules na saịtị a.Tubes adịghị 50,51,52.E gosipụtara ọdịiche dị n'etiti microtubules na dystrophin na-eme ka ọrịa DMD dịkwuo njọ site n'ịbawanye ụdị oxygen na-emeghachi omume (X-ROS).
Ngalaba CR site na ankyrin B bụ arịlịka ọzọ maka sarcolemmal phospholipids52.Achọrọ Ankyrin-B na ankyrin-G maka nhazi ọgịrịga nke dystrophin/DGC, na enweghị ha na-ebute ụdị sarcolemmal na-agbasa nke DGC52.
Ngalaba CR nwere ngalaba njikọ WW nke na-emekọrịta ihe ozugbo na ebumnuche njikọ PPxY nke β-DG.Site na ijikọ na mgbagwoju anya dystrophin-glycan, dystrophin na-emecha njikọ dị n'etiti ime na n'èzí nke cell54.Njikọ a dị oké mkpa maka ahụ ike gbawara agbawa, dị ka ọ na-egosi site n'eziokwu ahụ na nkwụsị nke njikọ dị n'etiti ECM na ime cell na-eduga ná nkwụsị nke muscular dystrophy na-egbochi ndụ.
N'ikpeazụ, ngalaba CT bụ mpaghara echekwara nke ukwuu nke na-etolite helix gbakọtara ma dị oke mkpa maka ijikọ α-dystrobrevin na α1-,β1-syntrophins55,56.α-dystrobrevin na-ejikọta na ngalaba CT nke dystrophin ma na-enyekwu iguzogide dystrophin na sarcolemma57.
N'oge mmepe nwa ebu n'afọ na nwa ebu n'afọ, a na-egosipụta Utrophin n'ọtụtụ ebe n'anụ ahụ dị iche iche, gụnyere sel endothelial, anụ ahụ ụjọ, na muscle anụ ahụ dị nro58.Utrophin bụ nke UTRN gosipụtara na chromosome 6q ma bụrụ autolog dystrophin nwere protein homology 80%.N'oge mmepe, utrophin na-adị na sarcolemma mana ọ na-ebelata nke ọma n'ime anụ ahụ nwere ike ime nwa, ebe dystrophin dochie ya.Mgbe amuchara nwa, nhazi nke utrophin na-ejedebe na akwara na akwara neuromuscular nke akwara skeletal58,59.
Ndị mmekọ njikọ Utrophin yiri nke dystrophins, n'agbanyeghị na akọwara ụfọdụ isi dị iche iche.Dịka ọmụmaatụ, dystrophin na-emekọ ihe na β-DG site na ngalaba WW ya, nke na-eme ka mpaghara ZZ guzosie ike (aha ya maka ike ya iji jikọta ion zinc abụọ) n'ime mpaghara CT ya, ebe cysteic acid residues 3307-3354 dị mkpa karịsịa maka mmekọrịta a60. ., 61. Utrophin na-ejikọta ya na β-DG site na ngalaba WW / ZZ, ma kpọmkwem ihe fọdụrụ na-akwado mmekọrịta a dị iche na residues dystrophin (3307-3345 na dystrophin na 3064-3102 na utrophin) 60,61.N'ụzọ dị mkpa, njikọ nke utrophin na β-DG dị ihe dị ka okpukpu abụọ dị ala ma e jiri ya tụnyere dystrophin 61. A kọwo Dystrophin na-ejikọta F-actin site na spectrin na-emegharị 11-17, ebe saịtị ndị yiri ya na utrophin enweghị ike ijikọta na F-actin, ọbụna na nnukwu mkpokọta, mana enwere ike ịmekọrịta site na ngalaba CH ha.Ihe omume 62,63,64.N'ikpeazụ, n'adịghị ka dystrophin, utrophin enweghị ike ijikọ na microtubules51.
N'ụzọ dị iche iche, utrophin spectrin na-emegharị nwere usoro mkpughe dị iche ma e jiri ya tụnyere dystrophin65.Utrophin-spectrin na-emegharị mbugharị na ndị agha dị elu, dị ka titin mana ọ bụghị dystrophin65.Nke a dabara na nhazi ya na ọrụ ya na nnyefe nke ike na-agbanwe ike siri ike na nkwonkwo akwara, mana ọ nwere ike mee ka utrophin ghara ịdị mma iji rụọ ọrụ dị ka mmiri mmiri molekụla n'ime ihe ndị na-emepụta ihe na-akpata site na nkwekọrịta 65.N'ịchịkọta ọnụ, data ndị a na-atụ aro na enwere ike gbanwee ike ntụgharị na mechanobuffering na ọnụnọ nke utrophin overexpression, karịsịa nyere ndị mmekọ / usoro dị iche iche na-ejikọta, agbanyeghị nke a chọrọ nyocha nyocha ọzọ.
Site n'echiche ọrụ, eziokwu ahụ bụ na a kwenyere na utrophin nwere mmetụta yiri nke ahụ na dystrophin na-eme ka ọ bụrụ ihe mgbaru ọsọ ọgwụgwọ maka DMD66,67.N'ezie, ụfọdụ ndị ọrịa DMD egosila na ha na-emebiga ihe ókè na utrophin, ikekwe dị ka usoro nkwụghachi ụgwọ, na phenotype ka eweghachiri nke ọma na ụdị òké na utrophin overexpression 68.Ọ bụ ezie na nchikota utrophin nwere ike ịbụ usoro ọgwụgwọ ọgwụgwọ, nleba anya na ọdịiche dị n'ụdị na arụ ọrụ dị n'etiti utrophin na dystrophin na ịba uru nke ịmebiga ihe ókè a na-eme ka ọ bụrụ ebe kwesịrị ekwesị na mpaghara sarcolemma na-eme ka atụmatụ ogologo oge nke utrophin ka edoghị anya.N'ụzọ doro anya, ndị na-ebu nwanyị na-egosi usoro mosaic nke okwu utrophin, na oke dị n'etiti dystrophin na utrophin nwere ike imetụta ogo nke cardiomyopathy dilated na ndị ọrịa a, 69 ọ bụ ezie na ụdị murine nke ndị na-ebu ya egosila..
Dystroglycan subcomplex nwere protein abụọ, α- na β-dystroglycan (α-, β-DG), ha abụọ depụtara site na DAG1 gene na mgbe ahụ post-translationally kewara n'ime protein akụkụ abụọ 71.α-DG bụ nke ukwuu glycosylated na extracellular akụkụ nke DGCs na-emekọ ihe ozugbo na proline residues na laminin α2 yana agrin72 na picaculin73 na CT / CR mpaghara nke dystrophin73,74,75,76.O-njikọ glycosylation, karịsịa nke serine residues, ka achọrọ maka mmekọrịta ya na ECM.Ụzọ glycosylation gụnyere ọtụtụ enzymes nke mmụgharị ha na-eduga na muscular dystrophy (leekwa Tebụl 1).Ndị a gụnyere O-mannosyltransferase POMT2, fucutin na protein metụtara fucutin (FKRP), ribitol phosphotransferases abụọ na-agbakwunye tandem ribitol phosphates na glycan bụ isi, na protein LARGE1 nke na-agbakwunye xylose na glucose.Linear uronic acid polysaccharide, makwaara dị ka matrix glycan na njedebe nke glycan77.FKRP na-etinyekwa aka na mmepe na mmezi nke ECM, na mmụgharị dị na ya na-eduga n'ibelata okwu nke laminin α2 na α-DG77,78,79.Na mgbakwunye, FKRP nwekwara ike iduzi nguzobe nke basal lamina na matrix extracellular obi site na glycosylated fibronectin 80.
β-DG nwere motif njikọ PPxY nke na-akọwapụta ozugbo yana ndị sequesters YAP12.Nke a bụ nchoputa na-adọrọ mmasị dịka ọ na-egosi na DGC na-achịkwa okirikiri sel cardiomyocyte.α-DH na neonatal cardiomyocytes na-emekọrịta ihe na agrin, nke na-akwalite mmeghari obi na DGC76 lysis n'ihi mmụba cell.Ka cardiomyocytes na-etolite, okwu aggrin na-ebelata na ihu ọma nke laminin, nke a na-eche na ọ na-enye aka na njide okirikiri cell76.Morikawa12 gosiri na okpukpu abụọ nke dystrophin na salvador, onye na-achịkwa YAP na-adịghị mma, na-eduga na hyperproliferation nke cardiomyocytes na rumen na-akpata infarct.Nke a butere echiche na-akpali akpali na njikwa YAP nwere ike ịba uru n'ụlọ ọgwụ iji gbochie mfu anụ ahụ mgbe infarction myocardial gasịrị.Ya mere, agrin-induced DGC lysis nwere ike ịnọchite anya axis nke na-enye ohere maka ịgbalite YAP ma bụrụ ụzọ nwere ike isi nwetaghachi obi.
Mechanically, α- na β-DG chọrọ ịnọgide na-enwe mmekọrịta n'etiti sarcolemma na basal oyi akwa 81.Ma α-DG na α7 integrins na-enye aka na-amanye ọgbọ na ganglion na-eri ego, na ọnwụ nke α-DG na-akpata nkewa nke sarcolemma na basal lamina, na-ahapụ anụ ahụ skeletal na-adịghị ike na mmebi-akpata mmebi.Dị ka akọwara na mbụ, mgbagwoju anya dystroglycan na-achịkwa ntụgharị nke DGC n'ozuzu ya, ebe njide na cognate ligand laminin na-ebute tyrosine phosphorylation nke PPPY-binding motif nke β-DG892.Tyrosine phosphorylation ebe a na-akwalite dissembly dystrophin, nke na-atụgharị mgbagwoju DGC.N'ihe gbasara anụ ahụ, a na-ahazi usoro a nke ọma, nke na-adịghị na muscular dystrophy82, ọ bụ ezie na aghọtachaghị usoro ndị dị n'okpuru na-achịkwa usoro a.
E gosiputara mgbatị cyclic ka ọ rụọ ọrụ ụzọ ERK1/2 na AMPK site na mgbagwoju anya dystrophin na protein plectin83 metụtara ya.Ọnụ, a na-achọrọ plectin na dystroglycan ọ bụghị naanị ka ha rụọ ọrụ dị ka scaffold, kamakwa isonye na mechanotransduction, na knockdown nke plectin na-eduga na mbelata ọrụ nke ERK1/2 na AMPK83.Plectin na-ejikọta na cytoskeletal intermediate filament desmin, na desmin overexpression egosiwo na ọ na-eme ka ọrịa phenotype dị na mdx: desmin na mdx ụmụ oke, ụdị DMD84 okpukpu abụọ knockout òké.Site na mmekọrịta ya na β-DG, plectin na-ejikọta DGC na mpaghara cytoskeleton na-apụtaghị ìhè.Na mgbakwunye, dystroglycan na-emekọrịta ihe na protein protein 2 (Grb2) na-anabata ihe uto, nke amara na ọ na-etinye aka na nhazigharị cytoskeletal85.Egosiputara ịgbalite Ras site na integrin ka a ga-emezi ya site na Grb2, nke nwere ike inye ụzọ enwere ike maka mkparịta ụka n'etiti integrins na DGC86.
Mgbanwe dị na mkpụrụ ndụ ihe nketa na-etinye aka na α-DH glycosylation na-eduga na ihe a na-akpọ dystrophy muscular.Dystroglycanopathies na-egosi ụdị dị iche iche nke ụlọ ọgwụ mana ọ na-ebutekarị ya site na nkwụsịtụ na mmekọrịta dị n'etiti α-DG na laminin α277.Dystrophiglicanoses kpatara site na mmụgharị ndị bụ isi na DAG1 na-adịkarị ụkọ, ikekwe n'ihi na ha na-egbu egbu embrayo87, si otú a na-egosi mkpa ọ dị maka mkpakọrịta cellular na ECM.Nke a pụtara na ọtụtụ ọrịa dystrophic glycan na-ebute site na mmụgharị protein nke abụọ jikọtara ya na glycosylation.Dịka ọmụmaatụ, ngbanwe dị na POMT1 na-ebute ọrịa Walker-Warburg siri ike, nke a na-eji anencephaly mara ma dị mkpụmkpụ ogologo ndụ (ihe na-erughị afọ 3)88.Agbanyeghị, ngbanwe FKRP na-egosipụtakarị dị ka dystrophy muscular dystrophy (LGMD), nke na-abụkarị (ma ọ bụghị mgbe niile) dị obere.Agbanyeghị, ngbanwe na FKRP bụ ihe na-adịghị ahụkebe maka WWS89.Achọpụtala ọtụtụ mmụgharị n'ime FKRP, nke onye ntọhapụ nke onye malitere (c.826>A) na-ebutekarị LGMD2I90.
LGMD2I bụ dystrophy muscular dị nro nke pathogenesis ya dabere na nbibi njikọ dị n'etiti matrix extracellular na cytoskeleton intracellular.Ihe doro anya bụ mmekọrịta dị n'etiti genotype na phenotype na ndị ọrịa nwere mmụgharị na mkpụrụ ndụ ihe nketa ndị a, na n'ezie echiche a na-emetụta protein DSC ndị ọzọ.Kedu ihe kpatara ụfọdụ ndị ọrịa nwere mmụkọ FKRP ji egosi ụdị ọrịa phenotype kwekọrọ na WWS ebe ndị ọzọ nwere LGMD2I?Azịza nye ajụjụ a nwere ike ịdabere na i) Kedu nzọụkwụ nke ụzọ glycosylation nke mgbanwe mgbanwe na-emetụta, ma ọ bụ ii) ogo hypoglycosylation n'oge ọ bụla.Hypoglycosylation nke α-DG ka nwere ike ikwe ka mmekọrịta dị n'etiti ya na ECM na-ebute ọdịdị dị nro n'ozuzu ya, ebe ikewapụ site na akpụkpọ ahụ okpuru ulo na-abawanye ogo nke ọrịa phenotype.Ndị ọrịa nwere LGMD2I na-etolitekwa DCM, ọ bụ ezie na nke a dị ntakịrị karịa DMD, na-akpali ngwa ngwa nke ịghọta mgbanwe ndị a na ọnọdụ nke cardiomyocytes.
Ihe mgbagwoju anya sarcospan-sarcoglycan na-akwalite nguzobe DHA ma na-emekọrịta ihe ozugbo na β-DH.Enwere sarcoglycans anọ unidirectional na anụ ahụ obi: α, β, γ, na δ91.A kọwapụtara ya n'oge na-adịbeghị anya na c.218C>T missense mutation na exon 3 nke gene SGCA na mkpochapụ heterozygous na exons 7-8 na-akpata LGMD2D92.Otú ọ dị, na nke a, ndị edemede atụleghị phenotype obi obi.
Ndị otu ndị ọzọ achọpụtala na SGCD na ụdị porcine93 na mouse94 na-ebute okwu protein belata na sarcoglycan subcomplex, na-akpaghasị usoro nhazi nke DGC na-eduga na DCM.Na mgbakwunye, 19% nke ndị ọrịa niile nwere mgbanwe SGCA, SGCB, ma ọ bụ SGCG ka akọọrọ na ha nwere ọrịa cardiomyopathy, na 25% nke ndị ọrịa niile chọkwara nkwado iku ume95.
Mmụba nkwụghachi azụ na sarcoglycan (SG) δ na-ebute mbelata ma ọ bụ enweghị zuru oke nke ogige sarcoglycan na ya mere DGC na anụ ahụ obi ma na-ahụ maka LGMD na DCM96 metụtara ya.N'ụzọ na-akpali mmasị, mmụgharị na-adịghị mma na SG-δ bụ kpọmkwem maka usoro obi na ọ bụ ihe kpatara ezinụlọ dilated cardiomyopathy97.SG-δ R97Q na R71T mmụgharị ndị na-adịghị mma egosipụtara ka egosipụtara nke ọma na cardiomyocytes oke na-enweghị nnukwu mmebi nke mkpokọta DGC98.Otú ọ dị, mkpụrụ ndụ obi na-ebu mmụgharị ndị a na-enwekarị ike ịdaba na mmebi sarcolemma, nkwụsịtụ, na arụrụ arụ ọrụ n'okpuru nrụgide ígwè ọrụ, kwekọrọ na DCM98 phenotype.
Sarcospan (SSPN) bụ 25 kDa tetraspanin nke etinyere na sarcoglycan subcomplex ma kwenyere na ọ na-eje ozi dị ka protein scaffold99,100.Dị ka ihe mkpofu protein, SSPN na-eme ka nhazi na glycosylation nke α-DG99,101 guzosie ike.Ngosipụta nke SSPN na ụdị òké ka achọpụtara na-eme ka njikọ dị n'etiti muscle na laminin 102.Na mgbakwunye, egosiri SSPN ka ya na integrins na-emekọrịta ihe, na-atụ aro ogo nke crosstalk n'etiti rib commissures abụọ, DGC, na integrin-talin-vinculin glycoprotein Ọdịdị100,101,102.Knockdown nke SSPN mekwara ka mmụba na α7β1 na akwara skeletal òké.
Nnyocha e mere n'oge na-adịbeghị anya gosiri na sarcospan overexpression na-eme ka maturation na glycosylation nke α-DG na anụ ahụ obi n'adabereghị na galactosylaminotransferase 2 (Galgt2) knockdown na ụdị mdx òké nke DMD, si otú ahụ na-ebelata ọrịa phenotype 101. Ịbawanye glycosylation nke mgbagwoju anya dystroglycan. ECM, si otú a na-ebelata ọrịa ahụ.Ọzọkwa, ha egosila na sarcospan overexpression na-ebelata mmekọrịta nke β1D integrin na DGCs, na-egosipụta ọrụ ga-ekwe omume maka sarcospan na nhazi nke integrin complexes101.
Syntrophins bụ ezinụlọ nke obere protein (58 kDa) nke na-abanye na DGCs, na-enweghị n'onwe ha nwere ọrụ enzymatic intrinsic, ma na-eje ozi dị ka ihe nkwụnye ọkụ molecular103,104.Achọpụtala isoforms ise (α-1, β-1, β-2, γ-1 na γ-2) na-egosi ngosipụta nke anụ ahụ, ya na α-1 isoform nke a na-egosipụtakarị na anụ ahụ striated 105.Syntrophins bụ protein nkwụnye ihe dị mkpa nke na-eme ka nkwurịta okwu dị n'etiti dystrophin na akara akara, gụnyere neuronal nitric oxide synthase (nNOS) na skeletal muscle106.α-syntrophin na-emekọrịta ihe ozugbo na ngalaba dystrophin 16-17 spectrin spectrin, nke n'aka nke ya jikọtara ya na nNOS106,107 PDZ-binding motif.
Syntrophins na-emekọrịtakwa na dystrobrevin site na ngalaba PH2 na SU, ha na-emekọkwa ihe na actin cytoskeleton 108.N'ezie, syntrophins yiri ka ọ na-arụ ọrụ dị mkpa na nhazi nke usoro cytoskeletal, na α na β isoforms nwere ike ịmekọrịta F-actin 108 ozugbo ma si otú a na-ekere òkè na nhazi nke tensegrity na biomechanics nke cellular. mmetụta.Na mgbakwunye, egosila syntrophins na-achịkwa cytoskeleton site na Rac1109.
Ịgbanwe ọkwa syntrophin nwere ike iweghachi ọrụ, na nnyocha e mere n'oge na-adịbeghị anya site na iji mini-dystrophin gosipụtara na ΔR4-R23 / ΔCT arụ ọrụ nwere ike iweghachi α-syntrophin yana protein DGC ndị ọzọ na ọkwa dị ka WT mdx cardiomyocytes.
Na mgbakwunye na ọrụ ha na nhazi nke cytoskeleton, a na-edekwa syntrophins nke ọma na nhazi nke ọwa ion 111,112,113.Ihe PDZ-binding motif nke syntrophins na-achịkwa ọwa Nav1.5111 na-adabere na voltaji obi, nke na-arụ ọrụ dị mkpa n'ịmepụta mkpali obi na nduzi.N'ụzọ na-akpali mmasị, na ụdị mdx mouse, a chọpụtara na ọwa Nav1.5 na-agbadata na ahụrụ arrhythmias obi obi na ụmụ anụmanụ 111.Tụkwasị na nke ahụ, ezinụlọ nke mechanosensitive ion channels, transient receptor potential channel (TRPC), egosila na a na-achịkwa ya site na α1-syntrophin na anụ ahụ obi 113 na mgbochi TRPC6 iji meziwanye arrhythmias na ụdị òké DMD112.Mmụba TRPC6 na-arụ ọrụ na DMD ka akọọrọ na ọ na-ebute ọrịa obi arrhythmias, bụ nke a na-ebelata mgbe ejikọtara ya na PKG 112.Mechanically, dystrophin depletion na-akwalite ntinye nke na-agbatị [Ca2 +] i nke na-eme elu nke TRPC6 iji mee ka ọ rụọ ọrụ, dị ka egosiri na cardiomyocytes na vaskụla sel muscle dị nro112,114.Hyperactivation nke TRPC6 iji gbatịa na-eme ka ọ bụrụ isi mechanosensor na ebumnuche ọgwụgwọ nwere ike na DMD112,114.
Ọnwụ nke dystrophin na-eduga na lysis ma ọ bụ nkwụsị akara nke mgbagwoju anya DGC dum, yana mfu nke ọtụtụ ọrụ nchebe na mechanotransduction, na-ebute ọdachi phenotype hụrụ na anụ ahụ dị nro na DMD.Ya mere, ọ nwere ike ịbụ ihe ezi uche dị na ya ịtụle na RSK na-arụ ọrụ na egwu yana na akụkụ nke ọ bụla dabere na ọnụnọ na ịrụ ọrụ nke ihe ndị ọzọ.Nke a bụ eziokwu karịsịa maka dystrophin, nke yiri ka achọrọ maka mgbakọ na nhazi nke sarcolemma complex na cardiomyocytes.Akụkụ ọ bụla na-arụ ọrụ pụrụ iche n'ịtụnye aka na nkwụsi ike nke sarcolemma n'ozuzu, nhazi nke protein ngwa ngwa, nhazi nke ọwa ion na okwu mkpụrụ ndụ ihe nketa, na mfu nke otu protein na DGC na-eduga na dysregulation nke myocardium dum.
Dịka egosiri n'elu, ọtụtụ protein DGC na-etinye aka na mechanotransduction na nrịbama, na dystrophin dabara adaba maka ọrụ a.Ọ bụrụ na DGC dị na ọgịrịga, nke a na-akwado echiche na ọ na-ekere òkè na mechanotransduction tinyere integrins.Ya mere, DGC n'anụ ahụ na-enweta nnyefe ike anisotropic ma sonye na nhazi usoro na nhazi cytoskeletal nke microenvironment intracellular, kwekọrọ n'ụdị tensegrity.Na mgbakwunye, Dp427m na-echekwa ndị agha biomechanical na-abata site n'ịgbasa spectrin ugboro ugboro n'ime mpaghara etiti ya, si otú a na-eme ihe dị ka mechanoprotector site na idowe ike na-eweghara 25 pN n'ogo ogologo 800 nm.Site na nkewa, dystrophin na-enwe ike "ichekwa" ike nke nkwụsịtụ-ezumike nke cardiomyocytes10 na-emepụta.Nyere ụdịdị protein dị iche iche na phospholipids ndị na-emekọrịta ihe na ngalaba spectrin ikwugharị, ọ bụ ihe na-atọ ụtọ ịkọ nkọ ma spectrin na-emegharị emegharị na-agbanwe njikọ njikọ nke protein mechanosensitive n'ụzọ yiri nke 116,117,118.Agbanyeghị, ekpebibeghị nke a ma achọrọ nyocha ọzọ.