{"id":1642,"date":"2019-05-09T09:02:41","date_gmt":"2019-05-09T07:02:41","guid":{"rendered":"http:\/\/www.newslab.sk\/?p=1642"},"modified":"2019-05-09T09:13:21","modified_gmt":"2019-05-09T07:13:21","slug":"1642","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/1642\/","title":{"rendered":"ACTN3: \u2018The gene for speed\u2018"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/h4>\n

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\u00davod <\/strong><\/p>\n

\u0160portov\u00fd v\u00fdkon u \u010dloveka m\u00e1 s\u010dasti genetick\u00e9 pozadie, pri\u010dom genetika vpl\u00fdva z 30 % a\u017e 80 %, ale i environment\u00e1lne pozadie, ako je v\u00fd\u017eiva, fyzick\u00e1 aktivita, rasov\u00e1 pr\u00edslu\u0161nos\u0165, pohlavie a vek. Po\u010das posledn\u00fdch desa\u0165ro\u010d\u00ed sa v\u00fdskum v oblasti \u0161portu s\u00fastredil na objasnenie vplyvu genetickej predispoz\u00edcie na \u0161portov\u00fd v\u00fdkon, \u010do viedlo k identifik\u00e1cii mno\u017estva kandid\u00e1tnych g\u00e9nov asociovan\u00fdch s rozli\u010dn\u00fdmi \u0161portov\u00fdmi znakmi. Jedn\u00fdm z naj\u0161tudovanej\u0161\u00edch a najlep\u0161ie replikovan\u00fdch variantov asociovan\u00fdch s v\u00fdkonom kostrov\u00fdch svalov je p. R577X variant v ACTN3 <\/em>g\u00e9ne k\u00f3duj\u00facom \u0161truktur\u00e1lny svalov\u00fd prote\u00edn \u03b1-aktin\u00edn-3(1).<\/p>\n

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\u03b1-aktin\u00ednov\u00e1 g\u00e9nov\u00e1 rodina <\/strong><\/p>\n

\u03b1-aktin\u00edn-3 patr\u00ed medzi \u03b1-aktin\u00edny, jednu z najkonzervovanej\u0161\u00edch g\u00e9nov\u00fdch rod\u00edn s d\u00f4le\u017eitou funkciou v r\u00e1mci evol\u00facie, po\u010das ktorej doch\u00e1dzalo k formovaniu kontraktiln\u00e9ho syst\u00e9mu nevyhnutn\u00e9ho na bunkov\u00e9 procesy, ako je cytokin\u00e9za, pohyblivos\u0165 buniek a kontrakcia svalstva(2). S\u00fa to dim\u00e9rne prote\u00edny sp\u00e1jaj\u00face akt\u00ednov\u00e9 bielkoviny kontraktiln\u00e9ho apar\u00e1tu svalov\u00fdch vl\u00e1kien. U cicavcov doch\u00e1dza k expresii \u0161tyroch typov \u03b1-aktin\u00ednov\u00fdch izoforiem k\u00f3dovan\u00fdch g\u00e9nmi ACTN1-4 <\/em>s odli\u0161n\u00fdmi biochemick\u00fdmi vlastnos\u0165ami a rozdielnymi miestami expresie(3). U \u010dloveka s\u00fa pr\u00edtomn\u00e9 tri izoformy \u03b1-aktin\u00ednov, z nich dve, \u03b1-aktin\u00edn-2 a \u03b1-aktin\u00edn-3 k\u00f3dovan\u00e9 g\u00e9nmi ACTN2 <\/em>a ACTN3<\/em>, sa podie\u013eaj\u00fa na stavbe svalov\u00e9ho vl\u00e1kna(4). Nach\u00e1dzaj\u00fa sa v Z-l\u00ednii, kde sp\u00e1jaj\u00fa akt\u00ednov\u00e9 filamenty susediacich sarkom\u00e9r(5). \u03b1-aktin\u00ednov\u00e9 dim\u00e9ry s\u00fa usporiadan\u00e9 antiparalelne a pozost\u00e1vaj\u00fa z troch dom\u00e9n vykazuj\u00facich vysok\u00fa konzervovanos\u0165 sekvenci\u00ed: (i) N-termin\u00e1lnej dom\u00e9ny zlo\u017eenej z dvoch dom\u00e9n kalpon\u00ednovej homol\u00f3gie (CH dom\u00e9ny, z angl. calponin-homology<\/em>), ktor\u00e1 je zodpovedn\u00e1 za viazanie akt\u00ednov\u00fdch vl\u00e1kien; (ii) stredovej dom\u00e9ny pozost\u00e1vaj\u00facej zo \u0161tyroch opakovan\u00ed podobn\u00fdch spektr\u00ednu (SLR1-4, z angl. spectrin-like repeats 1-4<\/em>) a (iii) C-termin\u00e1lnej dom\u00e9ny podobnej kalmodul\u00ednu s dvomi p\u00e1rmi mot\u00edvov, tzv. EF-hand <\/em>(EF1\/2 a EF 3\/4)(6). V\u00e4zba akt\u00ednu sa uskuto\u010d\u0148uje cez CH1 dom\u00e9nu, pri\u010dom samotn\u00e1 CH2 t\u00fato vlastnos\u0165 nem\u00e1. Schopnos\u0165 viaza\u0165 akt\u00edn sa zvy\u0161uje, ak s\u00fa obe dom\u00e9ny skombinovan\u00e9(7).<\/p>\n

\u0160trukt\u00fara \u03b1-aktin\u00ednu a jeho lokaliz\u00e1cia v sarkom\u00e9re je schematicky zn\u00e1zornen\u00e1 na obr\u00e1zku 1<\/strong>. U \u013eud\u00ed sa vyskytuj\u00fa tri typy vl\u00e1kien kostrov\u00fdch svalov: typ I, IIA a IIB, ktor\u00e9 sa odli\u0161uj\u00fa obsahom glykog\u00e9nu, lipidov, myoglob\u00ednu a mitochondri\u00ed. Vl\u00e1kna I. typu sa vyzna\u010duj\u00fa pomal\u00fdm \u010dasom kontrakcie a s\u00fa rezistentn\u00e9 proti \u00fanave. Vl\u00e1kna II. typu maj\u00fa, naopak, r\u00fdchly a kr\u00e1tky \u010das kontrakcie a ich motorick\u00e9 jednotky s\u00fa v porovnan\u00ed s pomal\u00fdmi vl\u00e1knami n\u00e1chylnej\u0161ie na \u00fanavu(8). Vl\u00e1kna typu I a IIA s\u00fa oxidat\u00edvne a vyu\u017e\u00edvaj\u00fa ako zdroj energie pyruv\u00e1t, ktor\u00fd je oxidovan\u00fd v mitochondri\u00e1ch, preto maj\u00fa v porovnan\u00ed s r\u00fdchlymi vl\u00e1knami podstatne viac mitochondri\u00ed, generuj\u00fa v\u0161ak ove\u013ea menej sily na kontrakciu svalu. R\u00fdchle glykolytick\u00e9 vl\u00e1kna typu IIB maj\u00fa vysok\u00fd podiel glykog\u00e9nu, ktor\u00e9ho anaer\u00f3bnou glykol\u00fdzou je produkovan\u00e9 ATP sl\u00fa\u017eiace ako zdroj energie ATP na kontrakciu svalu(9). Zatia\u013e \u010do \u03b1-aktin\u00edn-2 je exprimovan\u00fd v srdcovom svale a kostrov\u00fdch svalov\u00fdch vl\u00e1knach, \u03b1-aktin\u00edn-3 sa exprimuje v\u00fdlu\u010dne v r\u00fdchlych svalov\u00fdch vl\u00e1knach (v\u0161etky IIB typy a pribli\u017ene v 50 % typu IIA), ktor\u00e9 s\u00fa zodpovedn\u00e9 za generovanie sily pri vysokej r\u00fdchlosti. Hoci s\u00fa si tieto izoformy ve\u013emi podobn\u00e9, rozdielny vzor ich expresie nazna\u010duje rozdielne funkcie vo svalovom vl\u00e1kne(10,11,12). Preh\u013ead rozdielov medzi jednotliv\u00fdmi typmi svalov\u00fdch vl\u00e1kien je uveden\u00fd v tabu\u013eke 1<\/em><\/strong>.<\/p>\n

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\u03b1-aktin\u00edn-3 <\/strong><\/p>\n

\u03b1-aktin\u00edny sa v\u010faka svojej lokaliz\u00e1cii, funkcii a vysokej evolu\u010dnej konzervovanosti stali vhodn\u00fdmi kandid\u00e1tmi na identifik\u00e1ciu kauzat\u00edvnych mut\u00e1ci\u00ed asociovan\u00fdch s muskul\u00e1rnymi dystrofiami u \u013eud\u00ed. V roku 1996 North a Beggs uviedli, \u017ee deficiencia \u03b1-aktin\u00ednu-3 je asociovan\u00e1 s kongenit\u00e1lnou muskul\u00e1rnou dystrofiou a \u017ee t\u00e1to deficiencia by mohla by\u0165 markerom tohto ochorenia v podskupine pacientov(10). Nesk\u00f4r sa v\u0161ak uk\u00e1zalo, \u017ee ide bu\u010f o sekund\u00e1rny jav, alebo nez\u00e1visl\u00fd fenom\u00e9n, ktor\u00fd nem\u00e1 s t\u00fdmto ochoren\u00edm absol\u00fatne \u017eiadnu s\u00favislos\u0165. T\u00e1to deficiencia bola tie\u017e n\u00e1jden\u00e1 u pacientov s rozli\u010dn\u00fdmi typmi muskul\u00e1rnej dystrofie, bola v\u0161ak vyl\u00fa\u010den\u00e1 v\u00e4zbovou anal\u00fdzou, pr\u00edpadne bola detegovan\u00e1 aj u pacientov, u ktor\u00fdch u\u017e bola kauzat\u00edvna mut\u00e1cia identifikovan\u00e1(13). Mut\u00e1cie v \u03b1-aktin\u00edne-3 ako jedinom z rodiny \u013eudsk\u00fdch \u03b1-aktin\u00ednov nie s\u00fa asociovan\u00e9 so \u017eiadnou patol\u00f3giou, a to pravdepodobne z d\u00f4vodu kompenz\u00e1cie jeho deficiencie \u03b1-aktin\u00ednom-2. Bola v \u0148om identifikovan\u00e1 jedin\u00e1 mut\u00e1cia NM_001104.3(ACTN3):c.1729C>T:p. Arg577Ter (p. R577X). Ide o jednonukleotidov\u00fa z\u00e1menu cytoz\u00ednu za tym\u00edn, ktor\u00e1 sp\u00f4sobuje vznik pred\u010dasn\u00e9ho stop kod\u00f3nu, \u010do v kone\u010dnom d\u00f4sledku vedie k \u00faplnej absencii \u03b1-aktin\u00ednu-3(14).<\/p>\n

T\u00e1to z\u00e1mena nevedie k patologick\u00e9mu fenotypu, \u010do nazna\u010duje aj frekvencia v\u00fdskytu minoritnej alely X, pri\u010dom sa predpoklad\u00e1, \u017ee nosite\u013eom XX genotypu je pribli\u017ene 1,5 miliardy \u013eud\u00ed. XX genotyp sa naj\u010dastej\u0161ie vyskytuje v \u00e1zijskej a kaukazskej popul\u00e1cii, kde s\u00fa jeho frekvencie 25 % a 18 %, v eti\u00f3pskej kontrolnej neatletickej popul\u00e1cii je to 12 %, v afroamerickej 4 %, jamajskej 2 % a v kenskej iba 1 %(15,16). V nig\u00e9rijskej popul\u00e1cii sa XX genotyp nevyskytoval ani v testovanej neatletickej skupine, ani u vrcholov\u00fdch \u0161portovcov(15). Frekvencie genotypov p.R577X s\u00fa graficky zn\u00e1zornen\u00e9 na obr\u00e1zku 2. <\/strong>Zv\u00fd\u0161en\u00e1 frekvencia X alely v niektor\u00fdch popul\u00e1ci\u00e1ch nazna\u010duje pozit\u00edvnu selekciu tejto alely ako v\u00fdsledok adapt\u00e1cie na ni\u017e\u0161iu teplotu okolia s obmedzen\u00fdm zdrojom potravy(17), ke\u010f\u017ee naj\u010dastej\u0161ie sa tento genotyp vyskytuje v seversk\u00fdch oblastiach s ni\u017e\u0161\u00edmi priemern\u00fdmi ro\u010dn\u00fdmi teplotami a zn\u00ed\u017eenou diverzitou druhov(18). Z\u00e1rove\u0148 je to jeden z m\u00e1la loss-offunction <\/em>variantov, ktor\u00e9 sa v popul\u00e1cii udr\u017eali pomocou pozit\u00edvnej selekcie vplyvom migra\u010dnej expanzie modern\u00fdch \u013eud\u00ed z Afriky do severnej\u0161\u00edch \u010dast\u00ed pred 40 000 a\u017e 60 000 rokmi(17).<\/p>\n

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Zmeny v \u03b1-aktin\u00edn-3 deficientn\u00fdch svaloch <\/strong><\/p>\n

MacArthur a kol. (2008) vyu\u017eili na \u0161t\u00fadium mechanizmu deficiencie \u03b1-aktin\u00ednu-3 Actn3 KO my\u0161ac\u00ed model, ktor\u00e9ho fenotyp rekapituluje fenotyp navrhnut\u00fd asocia\u010dn\u00fdmi \u0161t\u00fadiami u \u013eud\u00ed, pri\u010dom potvrdili dovtedy publikovan\u00e9 efekty ako zn\u00ed\u017een\u00fa silu v kostrov\u00fdch svaloch, zv\u00fd\u0161en\u00fd vytrvalostn\u00fd v\u00fdkon a r\u00fdchlej\u0161ie zotavenie z \u00fanavy navodenej kontrakciami svalov pri \u0161portovom v\u00fdkone v porovnan\u00ed s div\u00fdm typom my\u0161\u00ed. Ke\u010f\u017ee \u03b1-aktin\u00edny v\u0161eobecne interaguj\u00fa s mno\u017estvom cytoskelet\u00e1lnych, sarkom\u00e9rnych, sign\u00e1lnych a metabolick\u00fdch prote\u00ednov, v d\u00f4sledku absencie \u03b1-aktin\u00ednu-3 doch\u00e1dza k nevyhnutn\u00fdm zmen\u00e1m vo funkcii svalov na viacer\u00fdch \u00farovniach, a to na \u0161truktur\u00e1lnej, metabolickej, signaliza\u010dnej \u00farovni, a tie\u017e pri spracov\u00e1van\u00ed v\u00e1pnika(19). U Actn3 KO my\u0161\u00ed bola absentuj\u00faca expresia \u03b1-aktin\u00ednu-3 kompenzovan\u00e1 zv\u00fd\u0161enou tvorbou \u03b1-aktin\u00ednu-2, pri\u010dom r\u00fdchle svalov\u00e9 vl\u00e1kna boli transformovan\u00e9 na pomal\u00e9, pri ktor\u00fdch preva\u017euj\u00facim fenotypom bola redukcia svalovej hmoty v prierezovej oblasti, zmenen\u00e9 kontraktiln\u00e9 vlastnosti svalu a zmena metabolizmu z anaer\u00f3bneho glykolytick\u00e9ho na aer\u00f3bny oxidat\u00edvny, vplyvom \u010doho doch\u00e1dza k zv\u00fd\u0161en\u00e9mu usklad\u0148ovaniu glykog\u00e9nu a zv\u00fd\u0161enej aktivite oxidat\u00edvnych mitochondri\u00e1lnych enz\u00fdmov. Predpoklad\u00e1 sa, \u017ee pr\u00e1ve v\u010faka t\u00fdmto zmen\u00e1m, postihuj\u00facim ve\u013ekos\u0165 svalu a jeho metabolizmus, ke\u010f doch\u00e1dza k posunu k \u201eenergeticky v\u00fdhodnej\u0161ej\u201c forme, doch\u00e1dza k zv\u00fd\u0161en\u00e9mu vytrvalostn\u00e9mu v\u00fdkonu a efekt\u00edvnej\u0161ej regener\u00e1cii svalov(19). Absenciou \u03b1-aktin\u00ednu-3 doch\u00e1dza k zru\u0161eniu jeho interakcie s mno\u017estvom prote\u00ednov Z-l\u00ednie ako myotil\u00edn, tit\u00edn, nebul\u00edn, dystrof\u00edn a \u03b2-integr\u00edn, vplyvom \u010doho nast\u00e1va zmena kontraktiln\u00fdch vlastnost\u00ed Actn3 KO svalu. Prote\u00edny ZASP, myotil\u00edn, desm\u00edn a \u03b3-filam\u00edn s\u00fa nadregulovan\u00e9 a v pr\u00edpade myotil\u00ednu a desm\u00ednu m\u00f4\u017ee doch\u00e1dza\u0165 k ich agreg\u00e1cii, pri\u010dom obe tieto zmeny nazna\u010duj\u00fa akt\u00edvnu remodel\u00e1ciu t\u00fdchto deficientn\u00fdch svalov a tie\u017e zv\u00fd\u0161en\u00fa n\u00e1chylnos\u0165 na po\u0161kodenie(19).<\/p>\n

Nevyhnutn\u00fd je v\u0161ak \u010fal\u0161\u00ed v\u00fdskum zameran\u00fd na stanovenie \u00falohy \u03b1-aktin\u00ednu-3 pri oprave a remodel\u00e1cii svalstva. R\u00fdchle glykolytick\u00e9 svalov\u00e9 vl\u00e1kna vyu\u017e\u00edvaj\u00fa ATP generovan\u00e9 \u0161tiepen\u00edm glykog\u00e9nu, kde gluk\u00f3za je konvertovan\u00e1 na lakt\u00e1t pomocou enz\u00fdmu lakt\u00e1tdehydrogen\u00e1za (LDH) ako zdroj energie na rap\u00eddne a energetick\u00e9 svalov\u00e9 kontrakcie. Vplyvom absencie \u03b1-aktin\u00ednu-3 doch\u00e1dza k zmene na pomal\u00e9 svalov\u00e9 vl\u00e1kna, ktor\u00e9 ako zdroj energie vyu\u017e\u00edvaj\u00fa oxid\u00e1ciu pyruv\u00e1tu z gluk\u00f3zy cez cyklus kyseliny citr\u00f3novej, mitochondri\u00e1lny elektr\u00f3n-transportn\u00fd re\u0165azec a oxid\u00e1ciu mastn\u00fdch kysel\u00edn. U Actn3 KO my\u0161\u00ed doch\u00e1dza k zv\u00fd\u0161enej regul\u00e1cii mitochondri\u00e1lnych dr\u00e1h, redukcii LDH a akumul\u00e1cii glykog\u00e9nu, \u010do je k\u013e\u00fa\u010dovou vlastnos\u0165ou \u03b1-aktin\u00edn-3 deficientn\u00fdch svalov\u00fdch vl\u00e1kien u my\u0161\u00ed aj \u013eud\u00ed(17,19). My\u0161i deficientn\u00e9 na kalsarc\u00edn-2 vykazovali podobn\u00fd fenotyp ako Actn3 KO my\u0161i. \u03b1-aktin\u00edn-2, ktor\u00fd je v d\u00f4sledku absencie \u03b1-aktin\u00ednu-3 upregulovan\u00fd, sa via\u017ee na kalsarc\u00edn-2, pri\u010dom tento jav bol potvrden\u00fd aj u \u013eud\u00ed. Kalsarc\u00edn-2 je exprimovan\u00fd v r\u00fdchlych svalov\u00fdch vl\u00e1knach, kde je jeho \u00falohou inhib\u00edcia kalcineur\u00ednu, \u010do je ser\u00edn-treon\u00edn-fosfat\u00e1za dependentn\u00e1 od kalcia\/kalmodul\u00ednu, ktor\u00e1 sprostredkov\u00e1va transkripciu pomal\u00fdch oxidat\u00edvnych svalov\u00fdch vl\u00e1kien. Deficiencia kalsarc\u00ednu- 2 ru\u0161\u00ed t\u00fato inhib\u00edciu a umo\u017e\u0148uje spustenie transkripcie, \u010do vedie k fenotypu charakterizovan\u00e9ho zv\u00fd\u0161enou vytrvalostnou kapacitou a posunom k pomal\u0161iemu metabolizmu(20).<\/p>\n

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Zmeny v spracovan\u00ed v\u00e1pnika ako n\u00e1stroj pozit\u00edvnej selekcie <\/strong><\/p>\n

Vo svaloch prebieha spracovanie v\u00e1pnika v sarkoplazmatickom retikule (SR). V porovnan\u00ed s div\u00fdm typom my\u0161\u00ed u Actn3 KO my\u0161\u00ed bolo detegovan\u00e9 troj- a\u017e \u0161tvorn\u00e1sobne zv\u00fd\u0161en\u00e9 uvo\u013e\u0148ovanie v\u00e1pnika a jeho sp\u00e4tn\u00e9 vychyt\u00e1vanie v SR, pri\u010dom tieto vl\u00e1kna boli rezistentnej\u0161ie na \u00fanavu pre pomal\u0161iu mieru poklesu uvo\u013e\u0148ovania v\u00e1pnika po opakovanej stimul\u00e1cii svalov. U Actn3 KO my\u0161\u00ed bola zv\u00fd\u0161en\u00e1 expresia SR Ca2+ ATP\u00e1zy 1 (SERCA1) a SR Ca2+ pufruj\u00facich prote\u00ednov kalsekvestr\u00edn a sarkolumen\u00edn. Vplyvom nadexpresie SERCA1 kan\u00e1lov 45 <\/strong>doch\u00e1dza k nadmern\u00e9mu \u00faniku v\u00e1pnika zo SR, ktor\u00e9ho \u010das\u0165 je n\u00e1sledne vyu\u017eit\u00e1 v mitochondri\u00e1ch, kde zvy\u0161uje aktivitu mitochondri\u00e1lnych enz\u00fdmov.<\/p>\n

Tie m\u00f4\u017eu by\u0165 tie\u017e stimulovan\u00e9 kalcineur\u00ednom, ktor\u00fd bol uvo\u013enen\u00fd z inhib\u00edcie kalsarc\u00ednom- 2 vplyvom nadregul\u00e1cie \u03b1-aktin\u00ednu-2. Zv\u00fd\u0161en\u00e1 aktivita mitochondri\u00e1lnych enz\u00fdmov vedie k produkcii ATP, \u010do zvy\u0161uje rezistenciu svalov proti \u00fanave. Nadmern\u00fd \u00fanik v\u00e1pnika tie\u017e vy\u017eaduje jeho zv\u00fd\u0161en\u00e9 pumpovanie SERCA1 kan\u00e1lmi sp\u00e4\u0165 do SR, pri\u010dom na tomto transporte sa v l\u00famene SR podie\u013eaj\u00fa aj kalsekvestr\u00edn a sarkolumen\u00edn. Toto sp\u00e4tn\u00e9 vychyt\u00e1vanie sp\u00f4sobuje zv\u00fd\u0161en\u00fa hydrol\u00fdzu ATP, ktor\u00e9 je vy\u017eadovan\u00e9 SERCA1 na jeho fungovanie, pri\u010dom doch\u00e1dza ku generovaniu metabolick\u00e9ho tepla vo svale. Head a kol. (2015) navrhli, \u017ee tento posun od glykolytick\u00e9ho metabolizmu k v\u00fdkonnej\u0161ej aer\u00f3bnej dr\u00e1he generuj\u00facej teplo ako ved\u013eaj\u0161\u00ed produkt je mo\u017en\u00fdm vysvetlen\u00edm pozit\u00edvnej selekcie XX genotypu v popul\u00e1cii. Po\u010das migr\u00e1cie modern\u00fdch \u013eud\u00ed do chladnej\u0161\u00edch eur\u00e1zijsk\u00fdch klimatick\u00fdch podmienok sa dok\u00e1zali \u03b1-aktin\u00edn-3 deficientn\u00ed jedinci lep\u0161ie aklimatizova\u0165, \u010do im poskytovalo v\u00fdhodu na pre\u017eitie v chladnom prostred\u00ed(21).<\/p>\n

 <\/p>\n

ACTN3 a \u0161port <\/strong><\/p>\n

Mno\u017estvo v\u00fdskumov bolo zameran\u00fdch na \u0161t\u00fadium vplyvu deficiencie \u03b1-aktin\u00ednu-3 na \u0161portov\u00fd v\u00fdkon \u0161portovcov i be\u017enej neatletickej popul\u00e1cie. V porovnan\u00ed s be\u017enou popul\u00e1ciou bol XX genotyp v\u00fdrazne podreprezentovan\u00fd u vrcholov\u00fdch \u0161print\u00e9rov a silov\u00fdch atl\u00e9tov. \u017diaden olympijsk\u00fd v\u00ed\u0165az v silovej ani \u0161print\u00e9rskej discipl\u00edne neniesol XX genotyp, \u010do nasved\u010dovalo tomu, \u017ee tento genotyp nebol vhodn\u00fd pre r\u00fdchle a v\u00fdkonn\u00e9 svalov\u00e9 kontrakcie, \u010do bolo replikovan\u00e9 vo viacer\u00fdch \u0161t\u00fadi\u00e1ch a metaanal\u00fdzach zah\u0155\u0148aj\u00facich elitn\u00fdch \u0161portovcov( 22,23). Z tohto d\u00f4vodu bol ACTN3 <\/em>g\u00e9n pomenovan\u00fd \u201er\u00fdchlostn\u00fd g\u00e9n\u201c. N\u00edzka frekvencia tohto genotypu u \u0161print\u00e9rov koreluje so zisteniami MacArthura a kol. (2008), ktor\u00ed \u0161t\u00fadiom na my\u0161acom modeli zistili, \u017ee Actn3 KO svaly vykazuj\u00fa dlh\u0161\u00ed, polovi\u010dn\u00fd \u010das relax\u00e1cie ne\u017e svaly exprimuj\u00face \u03b1-aktin\u00edn-3, \u010do by pre aktivity ako \u0161print, ktor\u00e9 vy\u017eaduj\u00fa r\u00fdchle repetit\u00edvne kontrakcie, bolo obmedzuj\u00face(19). Naopak, u elitn\u00fdch vytrvalostn\u00fdch atl\u00e9tov boli zisten\u00e9 vy\u0161\u0161ie frekvencie v\u00fdskytu genotypu XX, signifikantnos\u0165 tejto asoci\u00e1cie v\u0161ak nebola potvrden\u00e1. Niektor\u00e9 v\u00fdskumy uv\u00e1dzaj\u00fa, \u017ee zv\u00fd\u0161en\u00e1 frekvencia tohto genotypu u vytrvalostn\u00fdch atl\u00e9tov nebola zisten\u00e1 alebo bola jeho frekvencia dokonca podreprezentovan\u00e1 v porovnan\u00ed s kontrolnou netr\u00e9novanou popul\u00e1ciou(23,24). Vy\u0161\u0161ia predispoz\u00edcia jedincov s genotypom RR na podanie efekt\u00edvnej\u0161ieho v\u00fdkonu v r\u00fdchlostn\u00fdch a silov\u00fdch \u0161portov\u00fdch discipl\u00ednach m\u00f4\u017ee by\u0165 tie\u017e spojen\u00e1 s lep\u0161ou odpove\u010fou na silov\u00fd tr\u00e9ning. \u00daloha \u03b1-aktin\u00ednu-3 pri generovan\u00ed vysokointenz\u00edvnej svalovej kontrakcie bola potvrden\u00e1 aj v popul\u00e1cii ne\u0161portovcov, ke\u010f netr\u00e9novan\u00ed jedinci nes\u00faci RR genotyp vyvinuli vy\u0161\u0161iu silu ne\u017e t\u00ed s XX genotypom(23,24). Vplyv deficiencie \u03b1-aktin\u00ednu-3 bol tie\u017e sk\u00faman\u00fd v s\u00favislosti s po\u0161koden\u00edm svalov, ktor\u00e9 bolo navoden\u00e9 cvi\u010den\u00edm, kedy doch\u00e1dza k mechanick\u00e9mu po\u0161kodeniu svalov\u00fdch vl\u00e1kien a n\u00e1sledne k z\u00e1palovej reakcii. V\u00fdsledky v\u00fdskumov v\u0161ak boli inkonzistentn\u00e9. Niektor\u00e9 \u0161t\u00fadie zistili u jedincov s XX genotypom vy\u0161\u0161ie koncentr\u00e1cie z\u00e1palov\u00fdch markerov v krvi, \u010do by nazna\u010dovalo protekt\u00edvnu \u00falohu \u03b1-aktin\u00ednu-3. In\u00e9 v\u00fdskumy nena\u0161li \u017eiadnu spojitos\u0165 medzi X alelou a po\u0161koden\u00edm svalov po\u010das cvi\u010denia(23). Pod\u013ea recentnej\u0161\u00edch \u0161t\u00fadi\u00ed pr\u00edtomnos\u0165 \u03b1-aktin\u00ednu- 3 m\u00f4\u017ee poskytova\u0165 \u0161truktur\u00e1lnu v\u00fdhodu v kostrovom svale spolu s in\u00fdmi dedi\u010dn\u00fdmi faktormi, ktor\u00fdch interakciou doch\u00e1dza k redukcii po\u0161kodenia svalov\u00fdch vl\u00e1kien pri tr\u00e9ningu(23,25). Predpoklad\u00e1 sa, \u017ee okrem po\u0161kodenia svalov pri cvi\u010den\u00ed m\u00f4\u017ee ma\u0165 genotyp ACTN3 <\/em>vplyv aj na zranenia svalov, ligamentov a k\u013abov, ktor\u00e9 m\u00f4\u017eu nasta\u0165 vplyvom dysfunkcie kapacity svalu dr\u017ea\u0165 k\u013ab po\u010das cvi\u010denia, pr\u00edpadne pre obmedzen\u00fd rozsah pohybu k\u013abu vplyvom flexibility svalov (23,24).<\/p>\n

Vzh\u013eadom na nejednozna\u010dn\u00e9 v\u00fdsledky \u0161t\u00fadi\u00ed vplyv deficiencie \u03b1-aktin\u00ednu-3 na uveden\u00e9 znaky mus\u00ed by\u0165 e\u0161te objasnen\u00fd. Okrem r\u00fdchlych svalov\u00fdch vl\u00e1kien je \u03b1-aktin\u00edn-3 tie\u017e exprimovan\u00fd v osteoblastoch. Jedinci nes\u00faci XX genotyp mali redukovan\u00fa kostn\u00fa miner\u00e1lnu hustotu(26), \u010do nazna\u010duje, \u017ee tento genotyp by mohol by\u0165 asociovan\u00fd s n\u00e1chylnos\u0165ou na zranenia kost\u00ed po\u010das tr\u00e9ningu, doteraz v\u0161ak \u017eiadna spojitos\u0165 nebola dok\u00e1zan\u00e1. Limit\u00e1cie, pre ktor\u00e9 s\u00fa v\u00fdsledky \u0161t\u00fadi\u00ed nejednozna\u010dn\u00e9, spo\u010d\u00edvaj\u00fa najm\u00e4 vo ve\u013ekosti testovanej skupiny, ke\u010f je po\u010det testovan\u00fdch subjektov v skupine pr\u00edli\u0161 n\u00edzky, v zahrnut\u00ed oboch pohlav\u00ed v r\u00e1mci jednej testovanej skupiny, a taktie\u017e v rozdieloch medzi kohortami, ke\u010f s\u00fa testovan\u00ed netr\u00e9novan\u00ed jedinci i profesion\u00e1lni \u0161portovci z r\u00f4znych discipl\u00edn. Vo v\u0161eobecnosti v\u0161ak v\u00fdsledky nazna\u010duj\u00fa, \u017ee jedinci nes\u00faci genotyp XX s\u00fa n\u00e1chylnej\u0161\u00ed na po\u0161kodenie svalov po\u010das excentrick\u00fdch typov cvikov a vytrvalostn\u00fdch cvi\u010den\u00ed, pri ktor\u00fdch sa pou\u017e\u00edvaj\u00fa z\u00e1va\u017eia. Maj\u00fa tie\u017e vy\u0161\u0161iu pravdepodobnos\u0165 zranenia, ni\u017e\u0161ie hladiny miner\u00e1lnej hustoty kost\u00ed a ni\u017e\u0161ie hodnoty sily svalov (preh\u013ead rozdielov je uveden\u00fd v tabu\u013eke 2<\/em><\/strong>). U my\u0161\u00ed bol genotyp XX asociovan\u00fd s vy\u0161\u0161ou v\u00fdkonnostnou kapacitou, \u010do v\u0161ak u \u013eud\u00ed potvrden\u00e9 nebolo(23,24).<\/p>\n

 <\/p>\n

Z\u00e1ver <\/strong><\/p>\n

Z doposia\u013e publikovan\u00fdch \u0161t\u00fadi\u00ed ACTN3 g\u00e9nu je zjavn\u00e9, \u017ee tento polymorfizmus m\u00f4\u017ee ovplyv\u0148ova\u0165 mno\u017estvo in\u00fdch znakov ne\u017e iba predispoz\u00edciu na silov\u00e9 alebo vytrvalostn\u00e9 \u0161portov\u00e9 aktivity, a to zotavenie po cvi\u010den\u00ed, riziko poranenia svalov, ligamentov, k\u013abov a kost\u00ed a tie\u017e adapt\u00e1ciu na tr\u00e9ning a regener\u00e1ciu po \u0161portovom v\u00fdkone, \u010do nazna\u010duje, \u017ee ACTN3 <\/em>je viac ako len \u201er\u00fdchlostn\u00fd g\u00e9n\u201c. Inform\u00e1cia o svojej genetickej predispoz\u00edcii umo\u017e\u0148uje \u0161portovcovi personalizova\u0165 tr\u00e9ningov\u00fd pl\u00e1n, jeho intenzitu a zameranie, a teda i maximalizova\u0165 jeho v\u00fdkon.<\/p>\n

 <\/p>\n

LITERAT\u00daRA <\/strong><\/p>\n

    \n
  1. Garton FC, North KN. The Effect of Heterozygosity for the ACTN3 Null Allele on Human Muscle Performance. Med Sci Sports Exerc 2016; 48(3): 509-520.<\/li>\n
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  3. Kao HY. The actinin family proteins: biological function and clinical implications. Cell Biosci 2015; 5: 48.<\/li>\n
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  5. Gautel M. The sarcomeric cytoskeleton: who picks up the strain? Curr Opin Cell Biol 2011; 23(1): 39-46.<\/li>\n
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  7. Gimona M, Winder SJ. Single calponin homology domains are not actin- binding domains. Curr Biol 1998; 8: R674-R675.<\/li>\n
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  9. Sanchez B, Li J, Bragos R, et al. Differentiation of the intracellular structure of slow-versus fast-twitch muscle fibers through evaluation of the dielectric properties of tissue. Phys Med Biol 2014; 59(10): 2369\u20112380.<\/li>\n
  10. North KN, Beggs AH. Deficiency of a skeletal muscle isoform of alpha- actinin (alpha-actinin-3) in merosin-positive congenital muscular dystrophy. Neuromuscul Disord 1996; 6: 229-235.<\/li>\n
  11. Mills M, Yang N, Weinberger R, et al. Differential expression of the actin- binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Hum Mol Genet 2001; 10(13): 1335-1346.<\/li>\n
  12. Yang N, MacArthur DG, Gulbin JP, et al. ACTN3 genotype is associated with human elite athletic performance. Am J Hum Genet 2003; 73(3): 627-631.<\/li>\n
  13. Vainzof M, Costa CS, Marie SK, et al. Deficiency of a-actinin-3 (ACTN3) occurs in different forms of muscular dystrophy. Neuropediatrics 1997; 28: 223-228.<\/li>\n
  14. North KN, Yang N, Wattanasirichaigoon D, et al. A common nonsense mutation results in alpha- actinin-3 deficiency in the general population. Nat Genet 1999; 21: 353-354.<\/li>\n
  15. Yang N, MacArthur DG, Wolde B, et al. The ACTN3 R577X polymorphism in East and West African athletes. Med Sci Sports Exerc 2007; 39(11): 1985-1988.<\/li>\n
  16. Scott RA, Irving R, Irwin L, et al. ACTN3 and ACE genotypes in elite Jamaican and US sprinters. Med Sci Sports Exerc 2010; 42(1): 107-112.<\/li>\n
  17. MacArthur DG, Seto JT, Raftery JM, et al. Loss of ACTN3 <\/em>gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nat Genet 2007; 39: 1261-1265.<\/li>\n
  18. Friedlander SM, Herrmann AL, Lowry DP, et al. ACTN3 allele frequency in humans covaries with global latitudinal gradient. PLoS ONE 2013; 8: e52282.<\/li>\n
  19. MacArthur DG, Seto JT, Chan S, et al. An Actn3 knockout mouse provides mechanistic insights into the association between alpha-actinin-3 deficiency and human athletic performance. Hum Mol Genet 2008; 17(8): 1076-1086.<\/li>\n
  20. Seto JT, Quinlan KG, Lek M, et al. ACTN3 genotype influences muscle performance through the regulation of calcineurin signaling. J Clin Invest 2013; 123: 4255-4263.<\/li>\n
  21. Head SI, Chan S, Houweling PJ, et al. Altered Ca2+ kinetics associated with \u03b1-actinin-3 deficiency may explain positive selection for ACTN3 null allele in human evolution. PLoS Genet 2015; 11(2): e1004862.<\/li>\n
  22. Eynon N, Hanson ED, Lucia A, et al. <\/em>Genes for elite power and sprint performance: ACTN3 leads the way. Sports Med 2013; 43, 803-817.<\/li>\n
  23. Del Coso J, Hiam D, Houweling P, et al. More than a \u201espeed gene\u201c: ACTN3 R577X genotype, trainability, muscle damage, and the risk for injuries. Eur J Appl Physiol 2018.<\/li>\n
  24. Pickering C, Kiely J. ACTN3: <\/em>More than Just a Gene for Speed. Front Physiol. 2017; 8: 1080.<\/li>\n
  25. Del Coso J, Valero M, Salinero JJ, et al. Optimum polygenic profile to resist exertional rhabdomyolysis during a marathon. PLoS One 2017; 12(3): e0172965.<\/li>\n
  26. Yang N, Schindeler A, McDonald MM, et al. \u03b1-Actinin-3 deficiency is associated with reduced bone mass in human and mouse. Bone 2011; 49(4): 790-798.<\/li>\n
  27. Houweling P, Papadimitriou I, Seto J, et al. Is evolutionary loss our gain? The role of ACTN3 p. Arg577Ter (R577X) genotype in athletic performance, ageing, and disease. Hum Mutat 2018; 39(12): 1774-1787.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod \u0160portov\u00fd v\u00fdkon u \u010dloveka m\u00e1 s\u010dasti genetick\u00e9 pozadie, pri\u010dom genetika vpl\u00fdva z 30 % a\u017e 80 %, ale i environment\u00e1lne pozadie, ako je v\u00fd\u017eiva, fyzick\u00e1 aktivita, rasov\u00e1 pr\u00edslu\u0161nos\u0165,<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[290],"tags":[1073,1075,1078,1077],"class_list":["post-1642","post","type-post","status-publish","format-standard","hentry","category-genetics","tag-actn3","tag-r577x","tag-sport-performance","tag--actinin-3","typ_clanku-original-work"],"acf":{"abstrakt":"

    p. R577X variant in ACTN3 gene is one of the most studied and replicated variants associated with the predisposition for sport performance. Due to the formation of premature stop codon in the synthesis of \u03b1-actinin-3 encoded by this gene, this protein is completely absent in the contractile apparatus of fast-twitch muscle fibers resulting in their transformation to slow-twitch fibers. This shift is accompanied with the changes in the structure, metabolism, signaling as well as calcium handling. Research focused on studying the effect of \u03b1-actinin-3 deficiency on sport performance in athletes, and non-athletic population revealed a significantly lower frequency of XX genotype in elite sprinters and power athletes suggesting that this genotype is not suitable for rapid and powerful muscle contractions. Therefore, the ACTN3 gene got the name \u2018gene for speed\u2019. This review provides information about \u03b1-actinin-3, the mechanism of its deficiency and the potential advantages and disadvantages in certain sport-associated traits. <\/p>\n

    Keywords: ACTN3, \u03b1-actinin-3, R577X, sport performance <\/p>\n","casopis":[{"ID":1633,"post_author":"7","post_date":"2019-05-09 08:56:48","post_date_gmt":"2019-05-09 06:56:48","post_content":"

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