Stainless hlau 347 / 347H Welded coil Tubes zhemical tivthaiv, Lub luag hauj lwm ntawm dystrophin glycoprotein complexes nyob rau hauv lub mechanotransduction ntawm cov leeg hlwb

Ua tsaug rau koj tuaj xyuas Nature.com.Koj siv lub browser version nrog kev txhawb nqa CSS tsawg.Rau qhov kev paub zoo tshaj plaws, peb xav kom koj siv qhov browser tshiab (lossis lov tes taw Compatibility Hom hauv Internet Explorer).Tsis tas li ntawd, txhawm rau xyuas kom muaj kev txhawb nqa tsis tu ncua, peb qhia lub vev xaib tsis muaj qauv thiab JavaScript.
Sliders qhia peb kab lus rau ib tus swb.Siv cov nyees khawm rov qab thiab tom ntej kom txav mus los ntawm cov slides, lossis cov khawm tswj swb thaum kawg kom txav mus los ntawm txhua tus swb.

Dystrophin yog cov protein tseem ceeb ntawm dystrophin-glycoprotein complex (DGC) hauv cov leeg pob txha thiab cardiomyocytes.Dystrophin khi cov actin cytoskeleton mus rau extracellular matrix (ECM).Kev tawg ntawm kev sib txuas ntawm extracellular matrix thiab intracellular cytoskeleton tuaj yeem ua rau muaj kev puas tsuaj loj rau homeostasis ntawm cov leeg pob txha, ua rau muaj ntau cov leeg nqaij dystrophies.Tsis tas li ntawd, kev poob ntawm kev ua haujlwm DGCs ua rau muaj kev loj hlob ntawm cardiomyopathy thiab kev tuag ntxov ntxov.Dystrophin ua raws li lub caij nplooj ntoos hlav molecular thiab DHA ua lub luag haujlwm tseem ceeb hauv kev tswj hwm kev ncaj ncees ntawm sarcolemma.Ntxiv mus, cov ntaub ntawv pov thawj tau sib txuas txuas DGC rau kev teeb tsa kev siv tshuab, txawm hais tias lub luag haujlwm no tseem nkag siab tsis zoo.Tsab xov xwm tshuaj xyuas no yog txhawm rau muab kev pom niaj hnub ntawm DGCs thiab lawv lub luag haujlwm hauv kev siv tshuab hluav taws xob.Peb thawj zaug sib tham txog txoj kev sib raug zoo ntawm cov leeg ntawm tes mechanics thiab kev ua haujlwm, thiab tom qab ntawd tshuaj xyuas cov kev tshawb fawb tsis ntev los no ntawm lub luag haujlwm ntawm dystrophin glycoprotein complex hauv mechanotransduction thiab kev saib xyuas ntawm cov leeg cell biomechanical kev ncaj ncees.Thaum kawg, peb tshuaj xyuas cov ntaub ntawv tam sim no kom nkag siab tias DGC teeb liab cuam tshuam li cas nrog cov txheej txheem mechanosignaling los qhia txog cov ntsiab lus cuam tshuam yav tom ntej, nrog rau kev tsom mus rau cardiomyopathy.
Cells yog nyob rau hauv tas li kev sib txuas lus nrog lawv cov microenvironment, thiab ob txoj kev sib tham ntawm lawv yog tsim nyog rau kev txhais lus thiab kev koom ua ke ntawm biomechanical cov ntaub ntawv.Biomechanics tswj cov xwm txheej tseem ceeb tom qab (xws li, cytoskeletal rearrangements) los ntawm kev tswj tag nrho cov cellular phenotype nyob rau hauv qhov chaw thiab lub sij hawm.Lub hauv paus rau cov txheej txheem no hauv cardiomyocytes yog thaj tsam costal, thaj av uas cov sarcolemma txuas mus rau sarcomere muaj li ntawm integrin-talin-vinculin thiab dystrophin-glycoprotein (DGC) complexes.Txuas nrog rau cov cytoskeleton intracellular, cov discrete focal adhesions (FAs) propagate ib cascade ntawm biomechanical thiab biochemical cellular hloov uas tswj kev sib txawv, proliferation, organogenesis, tsiv teb tsaws, kab mob, thiab lwm yam.Kev hloov pauv ntawm biomechanical rog rau hauv biochemical thiab / lossis (epi) kev hloov pauv caj ces yog hu ua mechanotransduction1.
Lub integrin transmembrane receptor 2 tau paub ntev los thauj cov kab mob extracellular hauv cov hlwb thiab kho ob qho tib si sab hauv thiab sab nraud.Nyob rau hauv parallel nrog integrins, DGCs khi ECM rau lub cytoskeleton, tsim kom muaj kev sib txuas tseem ceeb ntawm sab nraud thiab sab hauv ntawm tes3.Tag nrho-ntev dystrophin (Dp427) feem ntau yog qhia hauv plawv thiab pob txha pob txha, tab sis kuj pom nyob rau hauv cov ntaub so ntswg ntawm lub hauv nruab nrab lub paj hlwb, nrog rau cov retina thiab Purkinje cov ntaub so ntswg4.Kev hloov pauv hauv integrins thiab DGC tau xav tias yog qhov ua rau cov leeg nqaij dystrophy thiab nce dilated cardiomyopathy (DCM) (Table 1)5,6.Tshwj xeeb, DMD kev hloov pauv encoding lub hauv paus dystrophin protein DGCs ua rau Duchenne muscular dystrophy (DMD)7.DGC yog tsim los ntawm ntau qhov sib txawv xws li α- thiab β-dystroglycan (α/β-DG), sarcoglycan-spanin, dystrophin, thiab dystrophin 8.
Dystrophin yog cytoskeletal protein encoded los ntawm DMD (Xp21.1-Xp22) uas ua lub luag haujlwm tseem ceeb hauv kev tswj hwm DGC.DGC tswj kev ncaj ncees ntawm sarcolemma, plasma membrane ntawm striated leeg nqaij.Dystrophin ntxiv rau kev puas tsuaj los ntawm kev cog lus los ntawm kev ua raws li lub caij nplooj ntoos hlav molecular thiab molecular scaffold9,10.Tag nrho-ntev dystrophin muaj qhov hnyav molecular ntawm 427 kDa, txawm li cas los xij, vim muaj ntau tus neeg txhawb nqa sab hauv hauv DMD, muaj ntau qhov tshwm sim tshwm sim truncated isoforms, suav nrog Dp7111.
Accessory proteins tau pom tias nyob rau hauv cheeb tsam rau dystrophin, nrog rau qhov tseeb mechanotransducers xws li neuronal nitric oxide synthase (nNOS), Yes-associated protein (YAP), thiab caveolin-3, yog li sawv cev rau cov khoom tseem ceeb ntawm cellular signaling.Cov tshuaj 12, 13, 14. Ntxiv rau qhov adhesion, lub cellular mechanism txuam nrog kev sib cuam tshuam ntawm cov hlwb thiab cov matrix, tsim los ntawm integrins thiab lawv cov hom phiaj nqes hav, ob lub complexes sawv cev ntawm kev sib tshuam ntawm "sab hauv" thiab "sab nraum" ntawm lub cell. .Tiv thaiv cov focal adhesions los ntawm kev puas tsuaj txawv txav yog qhov tseem ceeb rau kev coj tus cwj pwm ntawm tes thiab kev ciaj sia.Tsis tas li ntawd, cov ntaub ntawv txhawb nqa tias dystrophin yog ib qho kev hloov pauv ntawm cov channel mechanosensitive ion, suav nrog cov kab txuas txuas ntxiv, tshwj xeeb tshaj yog L-type Ca2+ channels thiab TRPC 15 channels.
Txawm hais tias dystrophin yog ib qho tseem ceeb rau kev ua haujlwm ntawm homeostatic ntawm cov leeg nqaij striated, cov txheej txheem kev txhawb nqa meej tsis tshua meej, tshwj xeeb tshaj yog lub luag haujlwm ntawm dystrophin thiab nws lub peev xwm los ua tus mechanosensor thiab mechanical protector.Vim qhov poob ntawm dystrophin, ntau cov lus nug tsis teb tau tshwm sim, suav nrog: yog cov proteins mechanosensitive xws li YAP thiab AMPK mislocated rau sarcolemma;Puas muaj crosstalk nrog integrins, qhov xwm txheej uas tuaj yeem ua rau txawv txav mechanotransduction?Tag nrho cov yam ntxwv no tuaj yeem ua rau muaj qhov hnyav DCM phenotype pom hauv cov neeg mob DMD.
Tsis tas li ntawd, kev koom tes ntawm kev hloov pauv hauv cellular biomechanics nrog tag nrho DMD phenotype muaj qhov cuam tshuam tseem ceeb hauv kev kho mob.DMD yog ib qho X-txuas cov leeg nqaij dystrophy cuam tshuam rau 1: 3500-5000 tus txiv neej, tus cwj pwm los ntawm kev ploj mus thaum ntxov (<5 xyoo) thiab kev loj hlob DCM nrog qhov kev mob tshwm sim hnyav dua li DCM ntawm lwm yam kev mob 16,17,18.
Cov biomechanics ntawm dystrophin poob tsis tau piav qhia tag nrho, thiab ntawm no peb tshuaj xyuas cov pov thawj txhawb kev xav tias dystrophin tiag tiag ua lub luag haujlwm ntawm kev tiv thaiv, piv txwv li tswj kev ncaj ncees ntawm sarcolemma, thiab tseem ceeb heev hauv kev siv tshuab.Tsis tas li ntawd, peb tau tshuaj xyuas cov pov thawj uas qhia txog kev sib tham tseem ceeb nrog cov integrins, tshwj xeeb yog khi laminin α7β1D hauv cov leeg nqaij striated.
Ntxig thiab tshem tawm yog lub luag haujlwm rau ntau qhov kev hloov pauv hauv DMD, nrog 72% ntawm kev hloov pauv tau tshwm sim los ntawm kev hloov pauv 19.Clinically, DMD nthuav tawm hauv cov menyuam mos (≤5 xyoos) nrog hypotension, Gower qhov pom zoo, ncua kev hloov pauv ntawm hnub nyoog, kev puas hlwb, thiab cov leeg pob txha atrophy.Kev nyuaj siab ua pa muaj keeb kwm ua rau muaj kev tuag hauv cov neeg mob DMD, tab sis txhim kho kev txhawb nqa (corticosteroids, kev ua pa tsis tu ncua) tau nce lub neej nyob rau hauv cov neeg mob no, thiab lub hnub nyoog nruab nrab ntawm DMD cov neeg mob yug tom qab 1990 yog 28.1 xyoo 20,21. ..Txawm li cas los xij, raws li tus neeg mob muaj sia nyob nce ntxiv, qhov kev cia siab ntawm kev loj hlob ntawm DCM yog qhov hnyav dua piv rau lwm cov cardiomyopathies16, ua rau lub plawv tsis ua hauj lwm kawg, uas tam sim no yog qhov ua rau tuag, suav txog kwv yees li 50% ntawm DMD tuag 17,18.
Progressive DCM yog tus cwj pwm los ntawm kev nce sab laug ventricular dilatation thiab ua raws, ventricular thinning, nce fibrofatty infiltration, txo systolic muaj nuj nqi, thiab nce zaus ntawm arrhythmias.Qhov degree ntawm DCM nyob rau hauv cov neeg mob nrog DMD yog yuav luag universal nyob rau hauv thaum ntxov hluas (90% mus rau 18 xyoo), tab sis tam sim no nyob rau hauv kwv yees li 59% ntawm cov neeg mob los ntawm 10 xyoo ntawm lub hnub nyoog 8,22.Hais txog qhov teeb meem no yog qhov tseem ceeb vim tias sab laug ventricular ejection feem ntau tau poob qis tsis tu ncua ntawm tus nqi ntawm 1.6% ib xyoo 23.
Lub plawv arrhythmias muaj nyob rau hauv cov neeg mob uas muaj DMD, tshwj xeeb tshaj yog sinus tachycardia thiab ventricular tachycardia, thiab yog cov ua rau lub plawv tuag sai22.Arrhythmias yog tshwm sim los ntawm fibrofatty infiltration, tshwj xeeb tshaj yog nyob rau hauv lub subbasal sab laug ventricle, uas impairs lub rov qab circuitry raws li zoo raws li [Ca2+] ua tsis ua hauj lwm thiab ion channel dysfunction24,25.Kev lees paub ntawm kev kho mob plawv yog qhov tseem ceeb, vim tias cov tswv yim kho mob thaum ntxov tuaj yeem ncua qhov pib ntawm DCM hnyav.
Qhov tseem ceeb ntawm kev kho mob plawv thiab mob pob txha pob txha yog qhia nyob rau hauv ib qho kev tshawb fawb nthuav dav uas siv tus qauv nas ntawm DMD hu ua mdx26 los kawm txog cov teebmeem ntawm kev txhim kho cov leeg pob txha yam tsis tau hais txog cov teeb meem hauv plawv tam sim no hauv DMD.Ntawm no, cov kws sau ntawv tau pom qhov tsis sib xws 5-fold nce hauv plawv tsis ua haujlwm tom qab txhim kho cov leeg pob txha, thiab cov nas muaj qhov txo qis hauv ejection fraction26.Kev txhim kho pob txha cov leeg ua haujlwm tso cai rau lub cev ua haujlwm ntau dua los ua kom muaj zog ntau dua ntawm myocardium, ua rau nws muaj kev cuam tshuam rau kev ua haujlwm tsis zoo.Qhov no qhia txog qhov tseem ceeb ntawm kev kho cov neeg mob DMD feem ntau thiab ceeb toom tawm tsam kev kho mob pob txha ib leeg.
DGCs ua ntau yam haujlwm ntxiv, uas yog, muab cov qauv kev ruaj ntseg rau lub sarcolemma, dhau los ua ib qho molecular scaffold uas ua raws li kev sib txuas, tswj cov txheej txheem mechanosensitive ion channel, lub hauv paus ntawm costal mechanotransduction, thiab koom nrog hauv kev sib kis ntawm lub zog ntawm sab hauv cheeb tsam. ribs (Fig. 1b)..Dystrophin plays lub luag haujlwm tseem ceeb hauv lub peev xwm no, thiab vim muaj ntau tus neeg txhawb nqa sab hauv, muaj ntau yam isoforms, txhua tus ua lub luag haujlwm sib txawv hauv cov ntaub so ntswg sib txawv.Cov ntaub so ntswg sib txawv ntawm cov dystrophin isoforms sib txawv txhawb qhov kev xav tias txhua isoform plays lub luag haujlwm sib txawv.Piv txwv li, cov ntaub so ntswg ntawm lub plawv qhia tag nrho ntev (Dp427m) nrog rau qhov luv luv Dp71m isoform ntawm dystrophin, thaum cov ntaub so ntswg pob txha tsuas qhia thawj ntawm ob.Kev soj ntsuam ntawm lub luag haujlwm ntawm txhua hom subtype tuaj yeem qhia tsis tau tsuas yog nws cov haujlwm physiological, tab sis kuj yog lub pathogenesis ntawm cov leeg nqaij dystrophy.
Schematic sawv cev ntawm tag nrho-ntev dystrophin (Dp427m) thiab qhov me me, truncated Dp71 isoform.Dystrophin muaj 24 spectrin rov sib cais los ntawm plaub lub voj voog, nrog rau kev sib koom ua ke (ABD), cysteine-nplua nuj (CR) domain, thiab C-terminus (CT).Cov neeg koom tes tseem ceeb tau raug txheeb xyuas, suav nrog microtubules (MTs) thiab sarcolemma.Muaj ntau cov isoforms ntawm Dp71, Dp71m hais txog cov leeg nqaij thiab Dp71b hais txog cov paj hlwb isoform.Tshwj xeeb, Dp71f yog hais txog cytoplasmic isoform ntawm neurons.b Lub dystrophin-glycoprotein complex (DHA) nyob rau hauv lub sarcolemma tag nrho.Biomechanical rog hloov ntawm ECM thiab F-actin.Nco ntsoov muaj peev xwm sib tham ntawm DGCs thiab integrin adhesion, Dp71 tuaj yeem ua lub luag haujlwm hauv focal adhesions.Tsim nrog Biorender.com.
DMD yog cov leeg nqaij dystrophy feem ntau thiab tshwm sim los ntawm kev hloov hauv DMD.Txawm li cas los xij, kom txaus siab rau peb txoj kev nkag siab tam sim no ntawm lub luag haujlwm ntawm cov tshuaj tiv thaiv dystrophin, nws yog ib qho tseem ceeb kom muab tso rau hauv cov ntsiab lus ntawm DGC tag nrho.Yog li, lwm cov khoom siv proteins yuav piav qhia luv luv.Cov protein muaj pes tsawg leeg ntawm DGC pib kawm nyob rau xyoo 1980s, nrog rau kev saib xyuas tshwj xeeb rau dystrophin.Koenig27,28, Hoffman29 thiab Ervasti30 tau ua qhov kev tshawb pom tseem ceeb los ntawm kev txheeb xyuas dystrophin, 427 kDa protein nyob rau hauv cov leeg nqaij striated31.
Tom qab ntawd, lwm cov subcomplexes tau pom tias muaj feem xyuam nrog dystrophin, suav nrog sarcoglycan, dystrophin transmembrane subcomplex, dysbrevin, thiab syntrophins8, uas ua ke ua tus qauv DGC tam sim no.Tshooj lus no yuav xub nthuav tawm cov ntaub ntawv pov thawj rau lub luag haujlwm ntawm DGC hauv kev xaav mechanosensory thaum tshuaj xyuas cov khoom ntawm tus kheej kom ntxaws.
Tag nrho ntev dystrophin isoform tam sim no nyob rau hauv cov leeg nqaij striated yog Dp427m (xws li "m" rau cov leeg kom paub qhov txawv ntawm lub hlwb) thiab yog ib tug loj pas nrig-zoo li tus protein uas muaj plaub lub luag hauj lwm nyob rau hauv lub cardiomyocyte sarcolemma, tshwj xeeb tshaj yog nyob rau hauv lub costal cheeb tsam. 29, 32. Dp427m, encoded los ntawm DMD gene ntawm Xp21.1, muaj 79 exons generated ntawm 2.2 megabases thiab yog li cov noob loj tshaj plaws hauv peb cov genome8.
Ntau tus neeg txhawb nqa sab hauv hauv DMD tsim ntau yam dystrophin isoforms, uas yog cov ntaub so ntswg tshwj xeeb.Piv nrog rau Dp427m, Dp71m yog qhov cuam tshuam loj heev thiab tsis muaj spectrin rov sau npe lossis N-terminal ABD domain.Txawm li cas los xij, Dp71m khaws cov C-terminal binding qauv.Hauv cardiomyocytes, lub luag haujlwm ntawm Dp71m yog qhov tsis meej, tab sis nws tau pom tias muaj nyob hauv T tubules, qhia tias nws yuav pab tswj tau qhov excitation-contraction coupling 33,34,35.Rau peb txoj kev paub, qhov kev tshawb pom tsis ntev los no ntawm Dp71m hauv cov ntaub so ntswg tau txais kev saib xyuas me ntsis, tab sis qee qhov kev tshawb fawb qhia tias nws muaj feem cuam tshuam nrog cov ion-activated ion channels, thiab Masubuchi tau qhia tias nws tuaj yeem ua lub luag haujlwm hauv kev tswj hwm ntawm nNOS33., 36. Hauv kev ua li ntawd, Dp71 tau txais kev saib xyuas tseem ceeb hauv kev tshawb fawb neurophysiology thiab platelet, cov cheeb tsam uas yuav muab kev pom rau lub luag haujlwm hauv cardiomyocytes37,38,39.
Hauv cov ntaub so ntswg, Dp71b isoform feem ntau qhia, nrog 14 isoforms qhia 38.Kev tshem tawm ntawm Dp71b, tus tswj hwm tseem ceeb ntawm aquaporin 4 thiab Kir4.1 potassium channels hauv nruab nrab paj hlwb, tau pom tias hloov ntshav-hlwb barrier permeability40.Muab lub luag haujlwm ntawm Dp71b hauv kev tswj hwm ion channel, Dp71m tuaj yeem ua lub luag haujlwm zoo sib xws hauv cardiomyocytes.
Lub xub ntiag ntawm DGC nyob rau hauv lub costal ganglia tam sim ntawd qhia tau hais tias lub luag hauj lwm nyob rau hauv mechanotransduction, thiab nws yog tseeb hais tias nws tau raug qhia kom co-localize nrog integrin-talin-vinculin complexes 41.Ntxiv mus, muab hais tias cov nqi qis yog qhov tseem ceeb ntawm kev hloov pauv mechanotransduction, qhov chaw ntawm Dp427m ntawm no qhia txog nws lub luag haujlwm hauv kev tiv thaiv cov hlwb los ntawm kev puas tsuaj los ntawm kev cog lus.Tsis tas li ntawd, Dp427m cuam tshuam nrog actin thiab microtubule cytoskeleton, yog li ua kom tiav kev sib txuas ntawm ib puag ncig intracellular thiab extracellular matrix.
Lub N-terminus uas muaj actin-binding domain 1 (ABD1) muaj ob lub calmodulin homology domains (CH) uas yuav tsum tau muaj kev cuam tshuam nrog F-actin thiab anchoring γ-actin isoform rau sarcolemma42,43.Dystrophin tuaj yeem pab txhawb rau tag nrho cov viscoelasticity ntawm cardiomyocytes los ntawm kev txuas mus rau subsarcolemmal cytoskeleton, thiab nws qhov chaw nyob hauv tus nqi ganglia txhawb nws txoj kev koom tes hauv mechanotransduction thiab mechanoprotection44,45.
Lub hauv paus tseem ceeb muaj xws li 24 spectrin-zoo li rov ua cov proteins, txhua tus yog kwv yees li 100 amino acid residues ntev.Lub spectrin repeats yog interspersed nrog plaub lub pob khawm, muab cov protein yooj yooj yim thiab qib siab ntawm extensibility.Dystrophin spectrin repeats tuaj yeem nthuav dav nyob rau hauv ntau yam kev xav ntawm lub cev (15-30 pN) txuas ntxiv los ntawm 21 nm txog 84 nm, lub zog ua tiav rau myosin contraction 46.Cov yam ntxwv ntawm cov spectrin rov ua dua tso cai rau dystrophin los ua ib qho molecular shock absorber.
Lub hauv paus pas nrig ntawm Dp427m ua kom nws qhov chaw nyob hauv sarcolemma, tshwj xeeb, los ntawm hydrophobic thiab electrostatic cuam tshuam nrog phosphatidylserine 47,48.Interestingly, lub hauv paus tseem ceeb ntawm dystrophin cuam tshuam sib txawv nrog sarcolemma phospholipids nyob rau hauv pob txha thiab plawv cov ntaub so ntswg, tejzaum nws xav txog txawv caij nplooj ntoos hlav qauv.tseem ceeb, thaum cov leeg pob txha kuj tseem cuam tshuam nrog R10-R1249.
Kev khi rau γ-actin cytoskeleton yuav tsum muaj ABD2 spectrin rov ua dua 11-17 cheeb tsam, uas muaj cov amino acids tseem ceeb thiab txawv ntawm F-actin-binding CH domain.Microtubules cuam tshuam ncaj qha nrog lub hauv paus tseem ceeb ntawm dystrophin, qhov kev cuam tshuam no yuav tsum muaj cov seem ntawm spectrin rov ua dua 4-15 thiab 20-23, thiab muaj ankyrin B yuav tsum tau tiv thaiv kev tsim ntawm microtubules ntawm qhov chaw no.Cov raj tsis muaj 50,51,52.Qhov sib txawv ntawm microtubules thiab dystrophin tau pom tias ua rau DMD pathology ntau dua los ntawm kev ua kom cov pa oxygen ntau ntxiv (X-ROS).
CR sau ntawm ankyrin B yog lwm lub thauj tog rau nkoj rau sarcolemmal phospholipids52.Ankyrin-B thiab ankyrin-G yog qhov yuav tsum tau ua rau cov kab mob hauv cheeb tsam ntawm dystrophin / DGC, thiab lawv qhov tsis tuaj yeem ua rau tus qauv diffuse sarcolemmal ntawm DGC52.
CR domain muaj WW binding domain uas cuam tshuam ncaj qha nrog PPxY binding motif ntawm β-DG.Los ntawm kev txuas mus rau dystrophin-glycan complex, dystrophin ua tiav qhov kev sib txuas ntawm sab hauv thiab sab nraud ntawm cell54.Qhov kev sib txuas no yog qhov tseem ceeb rau cov leeg nqaij striated, raws li muaj pov thawj los ntawm qhov tseeb tias kev cuam tshuam ntawm kev sib txuas ntawm ECM thiab sab hauv ntawm lub xov tooj ntawm tes ua rau lub neej txwv tsis pub cov leeg nqaij dystrophy.
Thaum kawg, CT domain yog ib cheeb tsam uas tau txais kev cawmdim heev uas tsim cov coiled helix thiab tseem ceeb heev rau kev khi rau α-dystrobrevin thiab α1-,β1-syntrophins55,56.α-dystrobrevin khi rau CT domain ntawm dystrophin thiab muab kev tiv thaiv ntxiv rau dystrophin hauv sarcolemma57.
Thaum lub sij hawm embryonic thiab fetal txoj kev loj hlob, Utrophin yog dav qhia nyob rau hauv ntau yam ntaub so ntswg, xws li endothelial hlwb, paj hlwb, thiab striated leeg nqaij58.Utrophin qhia los ntawm UTRN nyob rau ntawm chromosome 6q thiab yog dystrophin autolog nrog 80% protein homology.Thaum lub sij hawm txoj kev loj hlob, utrophin yog nyob rau hauv lub sarcolemma tab sis yog markedly suppressed nyob rau hauv postnatal striated leeg nqaij, qhov twg nws yog hloov los ntawm dystrophin.Tom qab yug me nyuam, qhov chaw ntawm qhov chaw ntawm utrophin yog txwv rau tendons thiab neuromuscular junctions ntawm skeletal leeg 58,59.
Utrophin binding cov neeg koom tes yog dav zoo ib yam li cov dystrophins, txawm hais tias qee qhov sib txawv tseem ceeb tau piav qhia.Piv txwv li, dystrophin cuam tshuam nrog β-DG los ntawm nws lub npe WW, uas yog ruaj khov los ntawm ZZ domain (npe rau nws lub peev xwm los khi ob zinc ions) hauv nws cheeb tsam CT, qhov twg cysteic acid residues 3307-3354 yog qhov tseem ceeb rau qhov kev sib cuam tshuam no. ., 61. Utrophin kuj khi rau β-DG ntawm WW/ZZ domain, tab sis cov seem seem uas txhawb nqa qhov kev sib tshuam no txawv ntawm dystrophin residues (3307–3345 hauv dystrophin thiab 3064–3102 hauv utrophin) 60,61.Qhov tseem ceeb, utrophin khi rau β-DG yog kwv yees li 2-fold qis dua piv rau dystrophin 61. Dystrophin tau tshaj tawm tias khi rau F-actin ntawm spectrin rov ua dua 11-17, thaum cov chaw zoo sib xws hauv utrophin tsis tuaj yeem khi rau F-actin, txawm tias nyob ntawm siab concentrations, tab sis tuaj yeem cuam tshuam los ntawm lawv cov CH-domains.Ua 62,63,64.Thaum kawg, tsis zoo li dystrophin, utrophin tsis tuaj yeem khi rau microtubules51.
Biomechanically, utrophin spectrin repeats muaj qhov txawv txav txawv piv rau dystrophin65.Utrophin-spectrin rov ua haujlwm ntawm cov rog siab dua, zoo ib yam li titin tab sis tsis yog dystrophin65.Qhov no yog ua raws li nws qhov chaw nyob thiab lub luag haujlwm hauv kev sib kis ntawm nruj elastic quab yuam ntawm cov leeg hlwv, tab sis yuav ua rau utrophin tsis tsim nyog los ua lub caij nplooj ntoos hlav molecular hauv buffering rog induced los ntawm contraction 65.Muab ua ke, cov ntaub ntawv no qhia tias mechanotransduction thiab mechanobuffering muaj peev xwm yuav hloov pauv thaum muaj cov tshuaj utrophin overexpression, tshwj xeeb tshaj yog muab cov neeg koom tes sib txawv / cov txheej txheem, tab sis qhov no yuav tsum muaj kev sim ntxiv.
Los ntawm qhov ua tau zoo ntawm qhov pom, qhov tseeb tias utrophin ntseeg tau tias muaj txiaj ntsig zoo sib xws rau dystrophin ua rau nws muaj peev xwm kho lub hom phiaj rau DMD66,67.Qhov tseeb, qee cov neeg mob DMD tau pom tias overexpress utrophin, tejzaum nws yog ib qho nyiaj them poob haujlwm, thiab cov phenotype tau ua tiav zoo hauv tus qauv nas nrog utrophin overexpression 68.Thaum upregulation ntawm utrophin yog ib txoj hauv kev kho mob zoo, kev xav txog qhov sib txawv ntawm kev ua haujlwm thiab kev ua haujlwm ntawm utrophin thiab dystrophin thiab kev siv hluav taws xob ntawm inducing no overexpression nrog rau qhov chaw zoo nyob rau hauv sarcolemma ua rau lub sij hawm ntev lub tswv yim ntawm utrophin tseem tsis meej.Qhov tshwj xeeb tshaj yog, cov poj niam cov neeg nqa khoom qhia pom cov qauv mosaic ntawm kev qhia txog utrophin, thiab qhov sib piv ntawm dystrophin thiab utrophin tuaj yeem cuam tshuam rau qib ntawm dilated cardiomyopathy hauv cov neeg mob no, 69 txawm hais tias murine qauv ntawm cov neeg nqa khoom tau qhia..
Lub dystroglycan subcomplex muaj ob lub proteins, α- thiab β-dystroglycan (α-, β-DG), ob qho tib si transcribed los ntawm DAG1 noob thiab tom qab ntawd-translationally cleaved rau hauv ob feem proteins 71 .α-DG yog glycosylated heev nyob rau hauv lub extracellular nam ntawm DGCs thiab interacts ncaj qha nrog proline residues nyob rau hauv laminin α2 nrog rau agrin72 thiab picaculin73 thiab CT / CR cheeb tsam ntawm dystrophin73,74,75,76.O-linked glycosylation, tshwj xeeb tshaj yog ntawm cov serine residues, yuav tsum muaj rau nws cov kev cuam tshuam nrog ECM.Txoj hauv kev glycosylation suav nrog ntau cov enzymes uas nws hloov mus rau cov leeg nqaij dystrophy (saib Table 1).Cov no suav nrog O-mannosyltransferase POMT2, fucutin thiab fucutin-related protein (FKRP), ob ribitol phosphotransferases uas ntxiv tandem ribitol phosphates rau cov tub ntxhais glycan, thiab LARGE1 protein uas ntxiv xylose thiab qabzib.Linear uronic acid polysaccharide, tseem hu ua matrix glycan ntawm qhov kawg ntawm glycan77.FKRP tseem koom nrog hauv kev txhim kho thiab kev saib xyuas ntawm ECM, thiab kev hloov pauv hauv nws ua rau txo qis ntawm laminin α2 thiab α-DG77,78,79.Tsis tas li ntawd, FKRP kuj tseem tuaj yeem tswj cov kev tsim ntawm basal lamina thiab lub plawv extracellular matrix los ntawm glycosylated fibronectin 80.
β-DG muaj PPxY binding motif uas ncaj qha localizes thiab sequesters YAP12.Qhov no yog qhov kev tshawb pom nthuav vim nws txhais tau hais tias DGC tswj lub voj voog cardiomyocyte cell.α-DH hauv neonatal cardiomyocytes cuam tshuam nrog agrin, uas txhawb nqa lub plawv rov tsim dua tshiab thiab DGC76 lysis vim cell maturation.Raws li cardiomyocytes paub tab, aggrin qhia txo qis hauv kev pom zoo ntawm laminin, uas xav tias yuav pab txhawb rau lub voj voog ntawm tes raug ntes76.Morikawa12 qhia tau hais tias ob lub khob ntawm dystrophin thiab salvador, tus tswj tsis zoo ntawm YAP, ua rau hyperproliferation ntawm cardiomyocytes hauv infarct-ua rau rumen.Qhov no ua rau lub tswv yim zoo siab tias YAP kev tswj hwm tuaj yeem muaj txiaj ntsig zoo hauv kev tiv thaiv cov ntaub so ntswg poob tom qab myocardial infarction.Yog li, agrin-induced DGC lysis tuaj yeem sawv cev rau ib qho axis uas tso cai rau YAP ua kom muaj zog thiab yog txoj hauv kev muaj peev xwm rau kev rov tsim kho plawv.
Mechanically, α- thiab β-DG yuav tsum muaj kev sib cuam tshuam ntawm sarcolemma thiab basal txheej 81.Ob qho tib si α-DG thiab α7 integrins pab txhawb kev tsim khoom hauv cov kab mob kim heev, thiab kev poob ntawm α-DG ua rau kev sib cais ntawm cov sarcolemma los ntawm basal lamina, ua rau cov leeg nqaij pob txha muaj kev cuam tshuam rau kev puas tsuaj.Raws li tau piav qhia dhau los, dystroglycan complex tswj tag nrho cov kev hloov pauv ntawm DGCs, qhov uas khi rau cognate ligand laminin ua rau tyrosine phosphorylation ntawm PPPY-binding motif ntawm β-DG892.Tyrosine phosphorylation ntawm no txhawb nqa dystrophin disassembly, uas tig lub DGC complex.Physiologically, tus txheej txheem no yog heev tswj, uas yog tsis muaj nyob rau hauv cov nqaij ntshiv dystrophy82, txawm hais tias lub hauv paus mechanisms tswj cov txheej txheem no tsis tau tag nrho to taub.
Cyclic stretch tau pom tias ua kom ERK1/2 thiab AMPK txoj hauv kev los ntawm dystrophin complex thiab muaj feem xyuam rau cov protein plectin83.Ua ke, plectin thiab dystroglycan yuav tsum tsis yog tsuas yog ua raws li lub luag haujlwm xwb, tab sis kuj koom nrog hauv kev siv tshuab, thiab kev poob ntawm plectin ua rau txo qis hauv kev ua haujlwm ntawm ERK1/2 thiab AMPK83.Plectin kuj khi rau cytoskeletal intermediate filament desmin, thiab desmin overexpression tau pom tias txhim kho tus kab mob phenotype hauv mdx: desmin thiab mdx nas, DMD84 ob chav knockout nas qauv.Los ntawm kev cuam tshuam nrog β-DG, plectin indirectly khi DGC rau cov khoom no ntawm cytoskeleton.Tsis tas li ntawd, dystroglycan cuam tshuam nrog kev loj hlob ntawm receptor-binding protein 2 (Grb2), uas paub tias muaj kev koom tes hauv cytoskeletal rearrangements85.Ras activation los ntawm integrin tau pom tias muaj kev sib kho los ntawm Grb2, uas tuaj yeem muab txoj hauv kev zoo rau kev sib tham ntawm integrins thiab DGC86.
Kev hloov pauv hauv cov noob koom nrog hauv α-DH glycosylation ua rau lub npe hu ua leeg nqaij dystrophy.Dystroglycanopathies qhia kev kho mob heterogeneity tab sis feem ntau tshwm sim los ntawm kev cuam tshuam ntawm kev sib cuam tshuam ntawm α-DG thiab laminin α277.Dystrophiglicanoses tshwm sim los ntawm kev hloov pauv hauv DAG1 feem ntau tsis tshua muaj tshwm sim, tej zaum vim tias lawv yog embryonic lethal87, yog li lees paub qhov xav tau ntawm cellular koom nrog ECM.Qhov no txhais tau hais tias feem ntau cov kab mob dystrophic glycan yog tshwm sim los ntawm kev hloov pauv protein ntau cuam tshuam nrog glycosylation.Piv txwv li, kev hloov pauv hauv POMT1 ua rau muaj mob hnyav heev ntawm Walker-Warburg syndrome, uas yog tus cwj pwm los ntawm anencephaly thiab ua rau lub neej luv luv (tsawg dua 3 xyoos) 88.Txawm li cas los xij, FKRP kev hloov pauv feem ntau pom tau tias yog limb-girdle leeg nqaij dystrophy (LGMD), uas feem ntau (tab sis tsis tas li) kuj mob me.Txawm li cas los xij, kev hloov pauv hauv FKRP tau pom tias yog qhov tsis tshua muaj tshwm sim ntawm WWS89.Ntau qhov kev hloov pauv tau raug txheeb xyuas hauv FKRP, uas tus tsim kev hloov pauv (c.826>A) feem ntau ua rau LGMD2I90.
LGMD2I yog ib qho mob me me ntawm cov leeg nqaij dystrophy uas nws cov kab mob tshwm sim los ntawm kev cuam tshuam ntawm kev sib txuas ntawm cov kab mob extracellular matrix thiab intracellular cytoskeleton.Tsawg dua yog qhov kev sib raug zoo ntawm genotype thiab phenotype hauv cov neeg mob uas muaj kev hloov pauv hauv cov noob no, thiab qhov tseeb lub tswv yim no siv tau rau lwm cov proteins DSC.Vim li cas qee cov neeg mob uas muaj FKRP kev hloov pauv qhia pom tus kab mob phenotype zoo ib yam nrog WWS thaum lwm tus muaj LGMD2I?Cov lus teb rau lo lus nug no yuav dag nyob rau hauv i) cov kauj ruam twg ntawm txoj kev glycosylation yog cuam tshuam los ntawm kev hloov, lossis ii) qib ntawm hypoglycosylation ntawm txhua kauj ruam.Hypoglycosylation ntawm α-DG tseem tuaj yeem tso cai rau qee qhov kev cuam tshuam nrog ECM uas ua rau muaj qhov mob me me, thaum kev sib cais los ntawm cov ntaub hauv qab daus ua rau muaj qhov hnyav ntawm tus kab mob phenotype.Cov neeg mob nrog LGMD2I kuj tsim DCM, txawm hais tias qhov no yog cov ntaub ntawv tsawg dua li DMD, txhawb qhov ceev ntawm kev nkag siab cov kev hloov pauv hauv cov ntsiab lus ntawm cardiomyocytes.
Lub sarcospan-sarcoglycan subcomplex txhawb kev tsim DHA thiab cuam tshuam ncaj qha nrog β-DH.Muaj plaub unidirectional sarcoglycans hauv cov ntaub so ntswg: α, β, γ, thiab δ91.Nws tsis ntev los no tau piav qhia tias ib qho c.218C>T tsis muaj kev hloov pauv hauv exon 3 ntawm SGCA gene thiab ib feem heterozygous deletion hauv exons 7-8 ua rau LGMD2D92.Txawm li cas los xij, nyob rau hauv cov ntaub ntawv no, cov kws sau ntawv tsis tau soj ntsuam lub plawv phenotype.
Lwm pab pawg tau pom tias SGCD hauv porcine93 thiab mouse94 qauv ua rau txo qis cov protein qhia hauv sarcoglycan subcomplex, cuam tshuam tag nrho cov qauv ntawm DGCs thiab ua rau DCM.Tsis tas li ntawd, 19% ntawm tag nrho cov neeg mob uas muaj SGCA, SGCB, lossis SGCG kev hloov pauv tau qhia tias muaj kev mob plawv, thiab 25% ntawm tag nrho cov neeg mob kuj xav tau kev pab ua pa 95.
Recessive mutations nyob rau hauv sarcoglycan (SG) δ ua rau txo qis los yog ua tsis tiav ntawm sarcoglycan complexes thiab li no DGC nyob rau hauv cov ntaub so ntswg plawv thiab yog lub luag hauj lwm rau LGMD thiab nws cov txuam nrog DCM96.Interestingly, dominant-negative mutations nyob rau hauv SG-δ yog tshwj xeeb rau cov hlab plawv system thiab yog ua rau tsev neeg dilated cardiomyopathy97.SG-δ R97Q thiab R71T dominant-negative mutations tau pom tias muaj kev ruaj ntseg hauv nas cardiomyocytes yam tsis muaj kev puas tsuaj loj ntawm tag nrho DGC98.Txawm li cas los xij, lub plawv hlwb nqa cov kev hloov pauv no ntau dua rau kev puas tsuaj rau sarcolemma, permeability, thiab kev ua haujlwm tsis zoo hauv kev siv tshuab, raws li DCM98 phenotype.
Sarcospan (SSPN) yog 25 kDa tetraspanin hauv zos nyob rau hauv sarcoglycan subcomplex thiab ntseeg tau tias ua haujlwm raws li cov protein scaffold99,100.Raws li cov protein scaffold, SSPN stabilizes localization thiab glycosylation ntawm α-DG99,101.Overexpression ntawm SSPN hauv cov qauv nas tau pom los ua kom muaj kev sib txuas ntawm cov leeg thiab laminin 102.Tsis tas li ntawd, SSPN tau pom tias muaj kev cuam tshuam nrog integrins, qhia txog qib ntawm crosstalk ntawm ob txoj kab nruab nrab, DGC, thiab integrin-talin-vinculin glycoprotein structure100,101,102.Knockdown ntawm SSPN kuj ua rau muaj kev nce hauv α7β1 hauv nas pob txha pob txha.
Ib txoj kev tshawb fawb tsis ntev los no tau pom tias sarcospan overexpression txhim kho kev loj hlob thiab glycosylation ntawm α-DG nyob rau hauv cov ntaub so ntswg plawv ntawm nws tus kheej ntawm galactosylaminotransferase 2 (Galgt2) knockdown hauv mdx nas qauv ntawm DMD, yog li alleviating kab mob phenotype 101. Ua kom glycosygly tuaj yeem txhim kho kev sib cuam tshuam ECM, yog li feem ntau txo tus kab mob.Ntxiv mus, lawv tau pom tias sarcospan overexpression txo qhov kev cuam tshuam ntawm β1D integrin nrog DGCs, qhia txog lub luag haujlwm ua tau rau sarcospan hauv kev tswj hwm ntawm integrin complexes101.
Syntrophins yog ib tsev neeg ntawm cov proteins me me (58 kDa) uas nyob rau hauv DGCs, tsis yog lawv tus kheej muaj kev ua haujlwm hauv lub cev, thiab ua haujlwm raws li molecular adapters103,104.Tsib isoforms (α-1, β-1, β-2, γ-1 thiab γ-2) tau raug txheeb xyuas qhia cov ntaub so ntswg tshwj xeeb, nrog rau α-1 isoform feem ntau qhia hauv cov leeg nqaij 105.Syntrophins yog ib qho tseem ceeb adapter proteins uas pab txhawb kev sib txuas lus ntawm dystrophin thiab signaling molecules, xws li neuronal nitric oxide synthase (nNOS) nyob rau hauv skeletal leeg 106.α-syntrophin cuam tshuam ncaj qha nrog dystrophin 16-17 spectrin rov sau npe, uas nyob rau hauv lem khi rau nNOS106,107 PDZ-binding motif.
Syntrophins kuj cuam tshuam nrog dystrobrevin ntawm PH2 thiab SU kev sib txuas ua ke, thiab lawv kuj cuam tshuam nrog actin cytoskeleton 108.Tseeb tiag, syntrophins zoo li ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm cytoskeletal dynamics, thiab α thiab β isoforms tuaj yeem cuam tshuam ncaj qha nrog F-actin 108 thiab yog li yuav ua lub luag haujlwm hauv kev tswj hwm ntawm tensegrity thiab biomechanics ntawm cellular. nyhuv.Tsis tas li ntawd, syntrophins tau pom tias tswj cov cytoskeleton los ntawm Rac1109.
Modulating syntrophin qib tuaj yeem rov ua haujlwm, thiab kev tshawb fawb tsis ntev los no siv cov mini-dystrophin tau pom tias ΔR4-R23 / ΔCT tsim muaj peev xwm rov qab tau α-syntrophin nrog rau lwm cov DGC proteins rau qib piv rau WT mdx cardiomyocytes.
Ntxiv nrog rau lawv lub luag haujlwm hauv kev tswj hwm ntawm cytoskeleton, syntrophins kuj tau sau tseg zoo hauv kev tswj hwm ntawm ion channel 111,112,113.PDZ-binding motif ntawm syntrophins tswj lub plawv voltage-dependent Nav1.5111 channel, uas ua lub luag haujlwm tseem ceeb hauv kev tsim kom muaj lub plawv dhia thiab kev ua haujlwm.Interestingly, nyob rau hauv mdx nas qauv, Nav1.5 raws tau pom tias yuav downregulated thiab plawv arrhythmias tau pom nyob rau hauv cov tsiaj 111 .Tsis tas li ntawd, ib tsev neeg ntawm cov mechanosensitive ion channels, lub transient receptor muaj peev xwm channel (TRPC), tau pom tias tau tswj hwm los ntawm α1-syntrophin hauv plawv cov ntaub so ntswg 113 thiab TRPC6 inhibition tau pom los txhim kho arrhythmias hauv DMD112 nas qauv.Kev nce ntxiv ntawm TRPC6 kev ua hauv DMD tau tshaj tawm tias ua rau mob plawv tsis ua haujlwm, uas tau txo qis thaum ua ke nrog PKG 112.Mechanically, dystrophin depletion txhawb nqa kev ncab ntawm kev cuam tshuam ntawm [Ca2+]i uas ua rau dej ntws ntawm TRPC6 los qhib nws, raws li qhia hauv cardiomyocytes thiab vascular du leeg hlwb112,114.Hyperactivation ntawm TRPC6 mus ncab ua rau nws yog ib tug loj mechanosensor thiab muaj peev xwm kho lub hom phiaj nyob rau hauv DMD112,114.
Kev poob ntawm dystrophin ua rau lysis lossis cim kev txwv ntawm tag nrho DGC complex, nrog rau kev poob ntawm ntau yam kev tiv thaiv kev tiv thaiv thiab kev ua haujlwm mechanotransduction, uas ua rau muaj kev puas tsuaj loj uas pom hauv cov leeg nqaij striated hauv DMD.Yog li, nws yuav tsim nyog los txiav txim siab tias RSKs ua haujlwm hauv kev hais kwv txhiaj thiab cov khoom ntawm tus kheej yog nyob ntawm qhov muaj thiab ua haujlwm ntawm lwm cov khoom.Qhov no yog tshwj xeeb tshaj yog muaj tseeb rau dystrophin, uas zoo nkaus li yuav tsum tau rau kev sib dhos thiab localization ntawm lub sarcolemma complex nyob rau hauv cardiomyocytes.Txhua yam khoom siv ua lub luag haujlwm tshwj xeeb hauv kev txhawb nqa tag nrho kev ruaj ntseg ntawm sarcolemma, localization ntawm cov khoom siv tseem ceeb ntawm cov proteins, kev tswj cov ion channel thiab cov noob qhia, thiab kev poob ntawm ib qho protein ntau hauv DGC ua rau muaj kev cuam tshuam ntawm tag nrho cov myocardium.
Raws li qhia saum toj no, ntau DGC cov proteins tau koom nrog hauv mechanotransduction thiab teeb liab, thiab dystrophin tshwj xeeb tshaj yog haum rau lub luag haujlwm no.Yog tias DGC nyob rau hauv cov tav, qhov no lees paub qhov kev xav tias nws koom nrog hauv mechanotransduction nrog rau integrins.Yog li, DGCs lub cev tau txais kev hloov pauv anisotropic quab yuam thiab koom nrog hauv kev hloov kho mechanosensory thiab cytoskeletal rearrangement ntawm intracellular microenvironment, raws li tus qauv tensegrity.Tsis tas li ntawd, Dp427m buffers tuaj biomechanical rog los ntawm kev nthuav dav spectrin rov ua dua nyob rau hauv nws lub hauv paus tseem ceeb, yog li ua tus kws kho mob los ntawm kev tswj hwm 25 pN unwinding quab yuam tshaj qhov txuas ntxiv 800 nm.Los ntawm kev sib cais, dystrophin muaj peev xwm "tso" lub zog ntawm kev cog lus-so uas tsim los ntawm cardiomyocytes10.Muab qhov sib txawv ntawm cov proteins thiab phospholipids uas cuam tshuam nrog cov spectrin rov ua dua, nws yog qhov nthuav kom xav tias seb spectrin rov ua dua tshiab hloov pauv cov kev sib txuas ntawm cov kinetics ntawm cov proteins uas zoo ib yam li talin116,117,118.Txawm li cas los xij, qhov no tseem tsis tau txiav txim siab thiab xav tau kev tshawb nrhiav ntxiv.