The Utrophin A 5′-Untranslated Region Confers Internal Ribosome Entry Site-mediated Translational Control during Regeneration of Skeletal Muscle Fibers

Utrophin up-regulation in muscle fibers of Duchenne muscular dystrophy patients represents a potential therapeutic strategy. It is thus important to delineate the regulatory events presiding over utrophin in muscle in attempts to develop pharmacological interventions aimed at increasing utrophin expression. A number of studies have now shown that under several experimental conditions, the abundance of utrophin is increased without a corresponding elevation in its mRNA. Here, we examine whether utrophin expression is regulated at the translational level in regenerating muscle fibers. Treatment of mouse tibialis anterior muscles with cardiotoxin to induce muscle degeneration/regeneration led to a large (∼14-fold) increase in the levels of utrophin A with a modest change in expression of its transcript (40%). Isolation of the mouse utrophin A 5′-untranslated region (UTR) revealed that it is relatively long with a predicted high degree of secondary structure. In control muscles, the 5′-UTR of utrophin A caused an inhibition upon translation of a reporter protein. Strikingly, this inhibition was removed during regeneration, indicating that expression of utrophin A in regenerating muscles is translationally regulated via its 5′-UTR. Using bicistronic reporter vectors, we observed that this translational effect involves an internal ribosome entry site in the utrophin A 5′-UTR. Thus, internal ribosome entry site-mediated translation of utrophin A can, at least partially, account for the discordant expression of utrophin A protein and transcript in regenerating muscle. These findings provide a novel target for up-regulating levels of utrophin A in Duchenne muscular dystrophy muscle fibers via pharmacological interventions. Utrophin up-regulation in muscle fibers of Duchenne muscular dystrophy patients represents a potential therapeutic strategy. It is thus important to delineate the regulatory events presiding over utrophin in muscle in attempts to develop pharmacological interventions aimed at increasing utrophin expression. A number of studies have now shown that under several experimental conditions, the abundance of utrophin is increased without a corresponding elevation in its mRNA. Here, we examine whether utrophin expression is regulated at the translational level in regenerating muscle fibers. Treatment of mouse tibialis anterior muscles with cardiotoxin to induce muscle degeneration/regeneration led to a large (∼14-fold) increase in the levels of utrophin A with a modest change in expression of its transcript (40%). Isolation of the mouse utrophin A 5′-untranslated region (UTR) revealed that it is relatively long with a predicted high degree of secondary structure. In control muscles, the 5′-UTR of utrophin A caused an inhibition upon translation of a reporter protein. Strikingly, this inhibition was removed during regeneration, indicating that expression of utrophin A in regenerating muscles is translationally regulated via its 5′-UTR. Using bicistronic reporter vectors, we observed that this translational effect involves an internal ribosome entry site in the utrophin A 5′-UTR. Thus, internal ribosome entry site-mediated translation of utrophin A can, at least partially, account for the discordant expression of utrophin A protein and transcript in regenerating muscle. These findings provide a novel target for up-regulating levels of utrophin A in Duchenne muscular dystrophy muscle fibers via pharmacological interventions. Duchenne muscular dystrophy (DMD) 6The abbreviations used are: DMD, Duchenne muscular dystrophy; UTR, untranslated region; RT, reverse transcription; βGAL, β-galactosidase; CAT, chloramphenicol acetyltransferase; IRES, internal ribosome entry site; CMV, cytomegalovirus; TA, tibialis anterior; XIAP, X-chromosome-linked inhibitor of apoptosis protein. is the most prevalent inherited neuromuscular disorder, since it affects 1 of 3500 male births (1Emery A.E. Neuromuscul. Disord. 1991; 1: 19-29Abstract Full Text PDF PubMed Scopus (1182) Google Scholar). Although the genetic defect underlying DMD was identified 20 years ago (2Anderson M.S. Kunkel L.M. Trends Biochem. Sci. 1992; 17: 289-292Abstract Full Text PDF PubMed Scopus (55) Google Scholar, 3Cohn R.D. Campbell K.P. Muscle Nerve. 2000; 23: 1456-1471Crossref PubMed Scopus (426) Google Scholar), there is still no effective treatment to alter the relentless progression of this debilitating neuromuscular disease (4Chakkalakal J.V. Thompson J. Parks R.J. Jasmin B.J. FASEB J. 2005; 19: 880-891Crossref PubMed Scopus (97) Google Scholar). DMD is caused by deletions/mutations in the dystrophin gene, which prevents production of full-length dystrophin molecules in skeletal muscle fibers. One therapeutic strategy to treat DMD consists in up-regulating the endogenous levels of a protein in muscle fibers of affected patients, which, once expressed at the appropriate location, could functionally compensate for the absence of dystrophin. An ideal candidate for such a role is utrophin (5Jasmin B.J. Angus L.M. Belanger G. Chakkalakal J.V. Gramolini A.O. Lunde J.A. Stocksley M.A. Thompson J. J. Physiol. Paris. 2002; 96: 31-42Crossref PubMed Scopus (28) Google Scholar, 6Khurana T.S. Davies K.E. Nat. Rev. Drug Discov. 2003; 2: 379-390Crossref PubMed Scopus (186) Google Scholar). Utrophin is a large cytoskeletal protein that displays a high degree of structural and functional similarity to dystrophin. In this context, overexpression of utrophin in muscle fibers of a DMD mouse model has been shown to alleviate the dystrophic pathology (7Tinsley J.M. Blake D.J. Roche A. Fairbrother U. Riss J. Byth B.C. Knight A.E. Kendrick-Jones J. Suthers G.K. Love D.R. Edwards Y.H. Davies K.E. Nature. 1992; 360: 591-593Crossref PubMed Scopus (351) Google Scholar, 8Tinsley J.M. Potter A.C. Phelps S.R. Fisher R. Trickett J.I. Davies K.E. Nature. 1996; 384: 349-353Crossref PubMed Scopus (429) Google Scholar, 9Deconinck N. Tinsley J. De Backer F. Fisher R. Kahn D. Phelps S. Davies K. Gillis J.M. Nat. Med. 1997; 3: 1216-1221Crossref PubMed Scopus (213) Google Scholar), thereby demonstrating that increased expression of utrophin could indeed yield important clinical benefits. A major difference between utrophin and dystrophin relates to their pattern of expression in skeletal muscle fibers. Whereas dystrophin localizes along the cytoplasmic face of the entire muscle fiber, utrophin preferentially accumulates at the levels of the myotendinous and neuromuscular junctions (10Ohlendieck K. Ervasti J.M. Matsumura K. Kahl S.D. Leveille C.J. Campbell K.P. Neuron. 1991; 7: 499-508Abstract Full Text PDF PubMed Scopus (322) Google Scholar, 11Bewick G.S. Nicholson L.V. Young C. O'Donnell E. Slater C.R. Neuroreport. 1992; 3: 857-860Crossref PubMed Scopus (124) Google Scholar, 12Helliwell T.R. Man N.T. Morris G.E. Davies K.E. Neuromuscul. Disord. 1992; 2: 177-184Abstract Full Text PDF PubMed Scopus (154) Google Scholar). To be valid as a therapeutic strategy for DMD, utrophin expression must therefore be extended in extrasynaptic compartments of dystrophic muscle fibers. Thus, elucidating the nature of the molecular events controlling expression of utrophin in muscle fibers becomes important, since it could lead to the rational design of pharmacological interventions aimed at up-regulating utrophin in muscle fibers of DMD patients. Two full-length isoforms of utrophin have now been identified and named utrophin A (13Dennis C.L. Tinsley J.M. Deconinck A.E. Davies K.E. Nucleic Acids Res. 1996; 24: 1646-1652Crossref PubMed Scopus (89) Google Scholar) and utrophin B (14Burton E.A. Tinsley J.M. Holzfeind P.J. Rodrigues N.R. Davies K.E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 14025-14030Crossref PubMed Scopus (96) Google Scholar). These isoforms are encoded by mRNAs that are transcribed from two different promoters. These two mRNAs differ mostly in their 5′-untranslated region (UTR) as well as in their in protein that differ in their Utrophin A is the major full-length expressed in skeletal muscle expression of utrophin B is relatively in the E.A. G. Davies K.E. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). To most of the studies that have the utrophin A expression in muscle have the of utrophin A has been shown to the of the utrophin A an and the which is by A.O. Angus L.M. E.A. Tinsley J.M. Davies K.E. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar, T.S. J. S. S. 1999; PubMed Scopus Google Scholar). studies have shown that utrophin A is expressed at levels in extrasynaptic compartments of muscle fibers in this is to regulatory events the of J.V. Stocksley M.A. M.A. Angus L.M. J. S. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, J.V. M.A. S. E. Jasmin B.J. PubMed Scopus Google Scholar). In to there is indicating that utrophin expression in muscle. is with the that are to control expression of several in muscle J.V. Jasmin B.J. 2003; PubMed Scopus Google Scholar). In we have shown that the utrophin are important for controlling the of utrophin in muscle and for to A.O. Belanger G. Jasmin B.J. J. PubMed Scopus Google Scholar, A.O. Belanger G. Thompson J.M. Chakkalakal J.V. Jasmin B.J. J. Physiol. Physiol. PubMed Google Scholar). of that utrophin be regulated at the translational we have that utrophin levels are during muscle without a corresponding increase in expression of its A.O. G. Jasmin B.J. J. 1999; PubMed Scopus Google Scholar). In the we that utrophin levels are increased in muscle from DMD patients, levels of utrophin are to in muscle A.O. G. Jasmin B.J. J. 1999; PubMed Scopus Google Scholar, R. J. 2000; PubMed Scopus Google Scholar). several have discordant of expression of utrophin protein and E.A. G. Davies K.E. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) an increase in the abundance of utrophin A in muscle from with no elevation in the levels of utrophin A utrophin protein levels in muscle change during the of with in the expression of utrophin mRNAs J. F. A. PubMed Scopus Google Scholar). from several studies the that utrophin is regulated via translational A. Neuromuscul. Disord. 2002; Full Text Full Text PDF Scopus Google Scholar, R. N. Davies K.E. E. 2003; PubMed Scopus Google Scholar). this in we have therefore in the a of to examine whether the of utrophin A in involves translational of the utrophin A reverse and from and a E.A. G. Davies K.E. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). was to its It was the site of to 1 for utrophin A 5′-UTR was the site of the bicistronic C. C.L. Nat. 1999; 1: PubMed Scopus Google Scholar) to inhibitor of apoptosis protein the 5′-UTR C. C.L. Nat. 1999; 1: PubMed Scopus Google Scholar) was used in as a control for bicistronic and by the and of the was by with and to the in in as in A.O. E.A. Tinsley J.M. A. J. Davies K.E. Lunde J.A. Jasmin B.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Two of and with of control of to the the bicistronic of with of of reporter to the and the reporter was as and in of cardiotoxin at the tibialis anterior muscle of to induce muscle and as A.O. G. Jasmin B.J. J. 1999; PubMed Scopus Google Scholar). and muscles and in muscles in with To examine the expression of the reporter during muscle regeneration, of at in was in regenerating and control muscles cardiotoxin muscles and in muscles with a in 1 of reporter and for 20 at and for muscles the to the was by the of chloramphenicol to chloramphenicol by of A the was in a with levels for reporter by reporter in muscle and and was from muscle as by the To the levels of endogenous in and muscles, was to utrophin A and as in J.V. Stocksley M.A. M.A. Angus L.M. J. S. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). of in which was by of endogenous utrophin A and and the of the was levels of utrophin A to the of levels in the of reporter expression in and muscles, was for 1 to to the muscles with and and with was with to a of and a of of an that the reverse with was at for by an of of 1 and an at for 1 for and used for used for was by a at for It is important to that for used to the abundance of to be the of as in A.O. Belanger G. Thompson J.M. Chakkalakal J.V. Jasmin B.J. J. Physiol. Physiol. PubMed Google Scholar, B.J. Neuron. Full Text PDF PubMed Scopus Google Scholar, Jasmin B.J. J. PubMed Scopus Google Scholar). To control for the of an bicistronic reporter transcript and muscles with and was a of the and a of the that the utrophin A 5′-UTR strategy is in the and to their reverse was the with was the and an the to and for muscle with the bicistronic In to control for of was a by a for for at in a with of was with a for with the for 1 and 1 at with and for 1 at with was in and to utrophin A was as J.V. Stocksley M.A. M.A. Angus L.M. J. S. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). utrophin A was from production of the to the and muscles from in a R.J. J. Full Text Full Text PDF PubMed Scopus Google Scholar) a and and for at One of the protein a with a at for to at with with 20 and for 1 and for 1 with the in in and with a secondary for 1 was extended and to of the of protein was with the protein as by the and was a as J.V. Stocksley M.A. M.A. Angus L.M. J. S. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). the A was used to utrophin A expression of was used to to the of neuromuscular of between was level of was at are shown of Utrophin A and in of skeletal muscle with the cardiotoxin and muscle the is a well model to muscle M.A. Physiol. Rev. PubMed Scopus Google Scholar, S. R. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). conditions, we have shown that the of utrophin an that utrophin A and B is several cardiotoxin treatment A.O. G. Jasmin B.J. J. 1999; PubMed Scopus Google Scholar). Here, we the effect of cardiotoxin treatment expression of the utrophin A which is expressed in skeletal muscle E.A. G. Davies K.E. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J.V. Stocksley M.A. M.A. Angus L.M. J. S. Jasmin B.J. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). of muscles with cardiotoxin for revealed that the levels of utrophin A expression at cardiotoxin this we that utrophin A expression was increased with control muscles A and revealed that utrophin A expression in control muscles is to neuromuscular junctions A and (10Ohlendieck K. Ervasti J.M. Matsumura K. Kahl S.D. Leveille C.J. Campbell K.P. Neuron. 1991; 7: 499-508Abstract Full Text PDF PubMed Scopus (322) Google Scholar, 11Bewick G.S. Nicholson L.V. Young C. O'Donnell E. Slater C.R. Neuroreport. 1992; 3: 857-860Crossref PubMed Scopus (124) Google Scholar, 12Helliwell T.R. Man N.T. Morris G.E. Davies K.E. Neuromuscul. Disord. 1992; 2: 177-184Abstract Full Text PDF PubMed Scopus (154) Google Scholar), the increased expression of utrophin A in regenerating muscle fibers was observed along the entire of the and in to this of utrophin A levels increased in regenerating muscle relatively increase in the abundance of utrophin A is in to the increase in protein thereby that in protein in the translational of utrophin A could have an important regulatory A is expressed in extrasynaptic during muscle with of muscles a utrophin A and B the of utrophin A in the of control muscle fibers. neuromuscular as identified by of the and the absence of utrophin A in the of muscle fibers. and the increase of utrophin A at of regenerating muscle. Utrophin A 5′-UTR the of we the that utrophin is translationally regulated and to whether the utrophin A 5′-UTR could account for the between the levels of protein and transcript observed during muscle To this we the utrophin A 5′-UTR from from and that it was relatively long E.A. G. Davies K.E. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Using the this was predicted to have a high degree of secondary Nucleic Acids Res. 2003; PubMed Scopus Google Scholar). an effect we this a reporter of the reporter to examine whether the utrophin A 5′-UTR such translational inhibition of in utrophin A 5′-UTR reporter a control was control mouse An of the role that a 5′-UTR of in translational be by protein reporter and to the levels of reporter expressed from this J. J. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, F. Biochem. PubMed Scopus Google Scholar). of are thus expressed as a of reporter protein to reporter transcript shown in we observed in control muscles a in the of protein to transcript for muscles with the utrophin A 5′-UTR reporter with muscles with the that the 5′-UTR of utrophin A an effect translation in skeletal muscle fibers under In to the of muscle the of reporter protein to transcript we muscles with cardiotoxin to of the reporter the cardiotoxin In we that the 5′-UTR of utrophin A a role in the discordant expression of endogenous utrophin A protein and transcript during muscle and there be a increase in the of protein to transcript levels in regenerating muscles with In with the of protein to levels was increased in regenerating muscles with the the utrophin A 5′-UTR that the effect by the utrophin A 5′-UTR translation in control muscles was in These that the increase in utrophin A protein expression observed in regenerating muscles and involves a of translation inhibition by the long and utrophin A 5′-UTR. It be that is in regenerating muscle muscle A. S. PubMed Scopus Google Scholar), thereby it to the in of protein to it is important to that of the expression of the reporter in control and regenerating muscles, indicating that the utrophin A 5′-UTR of in the Utrophin A 5′-UTR in are with the that utrophin A is translationally regulated in regenerating muscles by that target the 5′-UTR. translational at the of translation One which mRNAs are during of involves translation by the of an N. Nat. Rev. 2005; PubMed Scopus Google Scholar). therefore that the utrophin A 5′-UTR an that during the of muscle A well to of consists in bicistronic reporter S. S. 2: PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). two reporter which the of in a of between the two is expressed the of an To this we thus the utrophin A 5′-UTR a bicistronic used to C. C.L. Nat. 1999; 1: PubMed Scopus Google Scholar). of this the represents and control muscles with the bicistronic reporter the as for with reporter shown in is as a of A that with the is of In control muscles with the bicistronic no was with the utrophin A since between and In muscles, there was a in the of for muscles with the there was a increase of in the of in regenerating muscles with the bicistronic the utrophin A 5′-UTR of in regenerating muscles was that that of regenerating of the expressed as levels of and revealed that the increased for the in regenerating muscles was caused by a in the level of the reporter and by an increase in Thus, the increased for the in is of a in translation by In the increased of by the of the utrophin A 5′-UTR between the and in muscles was to an increase in to was observed with the we a in with the to an to that with the It be that the levels of for and in the muscle the levels of in regenerating muscles with regenerating the utrophin A 5′-UTR translation of the reporter in muscle. that the utrophin A 5′-UTR an that becomes during muscle In we muscles a bicistronic the 5′-UTR of the XIAP, which is well to an C. C.L. Nat. 1999; 1: PubMed Scopus Google Scholar, 2000; PubMed Scopus Google Scholar). was in muscles with control muscles that the effect of muscle is To whether the that we observed in regenerating muscles could be to several control to that expression was to translation of an bicistronic to the relatively of in mouse skeletal it is to a of to control for the of was used to the region of the bicistronic the utrophin A 5′-UTR and of the and reporter mRNAs shown in we of the from muscles with of their Using this we to demonstrating that translation of utrophin A during muscle To control for the of we used to and of the bicistronic that the from muscles with the was to translation from full-length bicistronic and be by the in a of of the bicistronic in an increase of the to has in been used by S. K. K. F. A.C. FASEB J. PubMed Scopus Google Scholar). therefore from control and muscles with the 5′-UTR we a of that full-length mRNAs transcribed from and 5′-UTR in control and Utrophin A in we the of the utrophin A in muscle To this we with the utrophin A bicistronic vectors, the and by reporter that the of the utrophin A 5′-UTR a in the of with the the that the utrophin A translation in that to for no by the utrophin A 5′-UTR To that expression of the was caused by internal ribosome we the and shown in the increase in with the was caused by a large increase in To that this increased was to the of a in the utrophin A of bicistronic reporter in which the been the utrophin A 5′-UTR a expression in the of the of the from the and utrophin A 5′-UTR and in the of and reporter In with no expression of an the could be by with from with the that the of the utrophin A 5′-UTR is to To control for the of events the expression of the from the in the in we and to the of an bicistronic of from the and the of the in with is to the of the utrophin A 5′-UTR between the two a for was used to that the in the bicistronic was from a bicistronic in of the in with the bicistronic from with the bicistronic the utrophin A 5′-UTR revealed the of a with no a from with a the utrophin A 5′-UTR and CAT, βGAL, to a potential In full-length from from with the by a for that the by the utrophin A 5′-UTR is caused by internal ribosome entry and by In several have that utrophin is regulated via translational the discordant of expression in the levels of utrophin and its in muscle under a number of experimental that utrophin expression is regulated by translational protein was to examine this by the that utrophin in to by is to important translational events that the abundance of utrophin in muscle fibers. Here, we that the large increase in the expression of utrophin A during muscle is by a increase in utrophin A we that the utrophin A 5′-UTR has an effect translation of a reporter transcript in skeletal muscle fibers. Strikingly, a of this inhibition is observed in muscle fibers several we that the utrophin A 5′-UTR an becomes in regenerating muscle. translation is an to the of translation in PubMed Scopus Google Scholar). In the to the at the of an mRNA. of and the is to in a to a in a is and protein 2003; PubMed Scopus Google Scholar). in the 5′-UTR that are to to the of of the N. Nat. Rev. 2005; PubMed Scopus Google Scholar). Whereas mRNAs are in a there is a of mRNAs that are now to be via mRNAs long and Using bicistronic reporter vectors, we that the utrophin A 5′-UTR as no in in muscle to and by cardiotoxin the utrophin A 5′-UTR a increase in the expression of the control revealed that the bicistronic that the utrophin A 5′-UTR it therefore that the of the muscle as an appropriate to an of the utrophin A Thus, translation via the utrophin A 5′-UTR at least account for the large in protein and transcript levels observed in regenerating skeletal muscle. muscle that involves the of and of their entry the These and to muscle fibers M.A. Physiol. Rev. PubMed Scopus Google Scholar). and in with in we observed in the studies that the utrophin A 5′-UTR in in at over levels In to to we observed no is to be since to are to that are during muscle with as well as with muscle in are by the that translation is during and translation of under A. D. 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Full Text Full Text PDF PubMed Scopus Google Scholar). there are translational as an important control in the of in muscle. it has been shown that expression of the is regulated at the translational level in muscle J. PubMed Scopus Google Scholar). a in translation has been shown to account for the in expression in skeletal muscle treatment K. S. R. J. Biochem. PubMed Scopus Google Scholar). we have that a protein in and accumulates the of the neuromuscular G. Stocksley M.A. Jasmin B.J. J. 2003; PubMed Scopus Google Scholar). In we have that the utrophin A 5′-UTR translation during muscle an for the between utrophin A protein and transcript levels observed in Although findings the that such as in protein account for between protein and levels J. F. A. PubMed Scopus Google Scholar, R. N. Davies K.E. E. 2003; PubMed Scopus Google Scholar, R. J. B.J. 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