Targeted Disruption of the ATP2A1 Gene Encoding the Sarco(endo)plasmic Reticulum Ca2+ ATPase Isoform 1 (SERCA1) Impairs Diaphragm Function and Is Lethal in Neonatal Mice

Mutations in the ATP2A1 gene, encoding isoform 1 of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1), are one cause of Brody disease, characterized in humans by exercise-induced contraction of fast twitch (type II) skeletal muscle fibers. In an attempt to create a model for Brody disease, the mouse ATP2A1 gene was targeted to generate a SERCA1-null mutant mouse line. In contrast to humans, term SERCA1-null mice had progressive cyanosis and gasping respiration and succumbed from respiratory failure shortly after birth. The percentage of affected homozygote SERCA1−/− mice was consistent with predicted Mendelian inheritance. A survey of multiple organs from 10-, 15-, and 18-day embryos revealed no morphological abnormalities, but analysis of the lungs in term mice revealed diffuse congestion and epithelial hypercellularity and studies of the diaphragm muscle revealed prominent hypercontracted regions in scattered fibers and increased fiber size variability. The Vmaxof Ca2+ transport activity in mutant diaphragm and skeletal muscle was reduced by 80% compared with wild-type muscle, and the contractile response to electrical stimulation under physiological conditions was reduced dramatically in mutant diaphragm muscle. No compensatory responses were detected in analysis of mRNAs encoding other Ca2+ handling proteins or of protein levels. Expression of ATP2A1 is largely restricted to type II fibers, which predominate in normal mouse diaphragm. The absence of SERCA1 in type II fibers, and the absence of compensatory increases in other Ca2+ handling proteins, coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure in term SERCA1-null mice. Mutations in the ATP2A1 gene, encoding isoform 1 of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1), are one cause of Brody disease, characterized in humans by exercise-induced contraction of fast twitch (type II) skeletal muscle fibers. In an attempt to create a model for Brody disease, the mouse ATP2A1 gene was targeted to generate a SERCA1-null mutant mouse line. In contrast to humans, term SERCA1-null mice had progressive cyanosis and gasping respiration and succumbed from respiratory failure shortly after birth. The percentage of affected homozygote SERCA1−/− mice was consistent with predicted Mendelian inheritance. A survey of multiple organs from 10-, 15-, and 18-day embryos revealed no morphological abnormalities, but analysis of the lungs in term mice revealed diffuse congestion and epithelial hypercellularity and studies of the diaphragm muscle revealed prominent hypercontracted regions in scattered fibers and increased fiber size variability. The Vmaxof Ca2+ transport activity in mutant diaphragm and skeletal muscle was reduced by 80% compared with wild-type muscle, and the contractile response to electrical stimulation under physiological conditions was reduced dramatically in mutant diaphragm muscle. No compensatory responses were detected in analysis of mRNAs encoding other Ca2+ handling proteins or of protein levels. Expression of ATP2A1 is largely restricted to type II fibers, which predominate in normal mouse diaphragm. The absence of SERCA1 in type II fibers, and the absence of compensatory increases in other Ca2+ handling proteins, coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure in term SERCA1-null mice. sarco(endo)plasmic reticulum Ca2+-ATPase sarcolipin phospholamban 4-morpholinepropanesulfonic acid reverse transcription glyceraldehyde-3-phosphate dehydrogenase embryonic stem Sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs)1 are 110-kDa membrane proteins that catalyze the ATP-dependent transport of Ca2+ from the cytosol to the lumen of the sarco(endo)plasmic reticulum (1MacLennan D.H. Rice W.J. Green N.M. J. Biol. Chem. 1997; 272: 28815-28818Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar). Three different ATP2Agenes encode six different sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) proteins (2Lytton J. MacLennan D.H. J. Biol. Chem. 1988; 263: 15024-15031Abstract Full Text PDF PubMed Google Scholar, 3Brandl C.J. Green N.M. Korczak B. MacLennan D.H. Cell. 1986; 44: 597-607Abstract Full Text PDF PubMed Scopus (587) Google Scholar, 4Burk S.E. Lytton J. MacLennan D.H. Shull G.E. J. Biol. Chem. 1989; 264: 18561-18568Abstract Full Text PDF PubMed Google Scholar, 5MacLennan D.H. Brandl C.J. Korczak B. Green N.M. Nature. 1985; 316: 696-700Crossref PubMed Scopus (795) Google Scholar). SERCA1a and SERCA1b, the developmentally regulated isoforms of the ATP2A1 gene, arise through alternative splicing at the 3′-end of theATP2A1 transcript (6Brandl C.J. deLeon S. Martin D.R. MacLennan D.H. J. Biol. Chem. 1987; 262: 3768-3774Abstract Full Text PDF PubMed Google Scholar). SERCA1a accounts for more than 99% of SERCA isoforms expressed in adult rat fast twitch skeletal muscle, whereas SERCA1b is predominant in neonatal muscle (7Wu K.D. Lytton J. Am. J. Physiol. 1993; 264: C333-C341Crossref PubMed Google Scholar). SERCA2a is the major isoform in heart and slow twitch skeletal muscle, whereas SERCA2b and SERCA3 are more ubiquitously expressed. Brody disease is a rare inherited disorder of skeletal muscle, resulting in exercise-induced impairment of skeletal muscle relaxation, stiffness, and cramps (8Brody I.A. N. Engl. J. Med. 1969; 281: 187-192Crossref PubMed Scopus (132) Google Scholar). Sarcoplasmic reticulum Ca2+uptake and Ca2+-ATPase activities in muscle samples obtained from Brody's patients are reduced to levels ranging from 0 to 50% compared with activities measured in normal controls (9Karpati G. Charuk J. Carpenter S. Jablecki C. Holland P. Ann. Neurol. 1986; 20: 38-49Crossref PubMed Scopus (80) Google Scholar, 10Danon M.J. Karpati G. Charuk J. Holland P. Neurology. 1988; 38: 812-815Crossref PubMed Google Scholar, 11Taylor D.J. Brosnan M.J. Arnold D.L. Bore P.J. Styles P. Walton J. Radda G.K. J. Neurol. Neurosurg. Psychiatry. 1988; 51: 1425-1433Crossref PubMed Scopus (46) Google Scholar, 12Wevers R.A. Poels P.J. Joosten E.M. Steenbergen G.G. Benders A.A. Veerkamp J.H. J. Inherit. Metab. Dis. 1992; 15: 423-425Crossref PubMed Scopus (8) Google Scholar, 13Benders A.A. Veerkamp J.H. Oosterhof A. Jongen P.J. Bindels R.J. Smit L.M. Busch H.F. Wevers R.A. J. Clin. Invest. 1994; 94: 741-748Crossref PubMed Scopus (56) Google Scholar), suggesting that Brody disease might result from defects in theATP2A1 gene. Sequencing of ATP2A1 DNA from Brody disease patients has revealed a number of frameshift mutations that truncate SERCA1 (14Odermatt A. Taschner P.E. Khanna V.K. Busch H.F. Karpati G. Jablecki C.K. Breuning M.H. MacLennan D.H. Nat. Genet. 1996; 14: 191-194Crossref PubMed Scopus (175) Google Scholar, 15Odermatt A. Taschner P.E. Scherer S.W. Beatty B. Khanna V.K. Cornblath D.R. Chaudhry V. Yee W.C. Schrank B. Karpati G. Breuning M.H. Knoers N. MacLennan D.H. Genomics. 1997; 45: 541-553Crossref PubMed Scopus (128) Google Scholar) as well as a missense mutation (16Odermatt A. Barton K. Khanna V.K. Mathieu J. Escolar D. Kuntzer T. Karpati G. MacLennan D.H. Hum. Genet. 2000; 106: 482-491Crossref PubMed Scopus (58) Google Scholar). All of these mutations lead to loss of SERCA1a function. However, mutations inATP2A1 account for only about half of Brody disease cases, and the genetic basis for the other Brody syndrome patients remains to be discovered (17Karpati G. MacLennan D.H. Serratrice G. Pouget J. Azulay J.-P. Exercise Intolerance and Muscle Contracture. Springer-Verlag, Berlin1999: 45-54Crossref Google Scholar). Recent advances in transgenic mouse technology have made it possible to address the physiological relevance of increases or decreases in SERCA expression. Overexpression of SERCA2 in the myocardium resulted in enhanced myocardial function (18He H. Giordano F.J. Hilal-Dandan R. Choi D.J. Rockman H.A. McDonough P.M. Bluhm W.F. Meyer M. Sayen M.R. Swanson E. Dillmann W.H. J. Clin. Invest. 1997; 100: 380-389Crossref PubMed Scopus (275) Google Scholar, 19Baker D.L. Hashimoto K. Grupp I.L. Ji Y. Reed T. Loukianov E. Grupp G. Bhagwhat A. Hoit B. Walsh R. Marban E. Periasamy M. Circ. Res. 1998; 83: 1205-1214Crossref PubMed Scopus (177) Google Scholar, 20Greene A.L. Lalli M.J. Ji Y. Babu G.J. Grupp I. Sussman M. Periasamy M. J. Biol. Chem. 2000; 275: 24722-24727Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). By contrast, the ablation ofATP2A2 was lethal, and heterozygous SERCA2+/−mice manifested impaired cardiac contractility and delayed cardiomyocyte relaxation (21Periasamy M. Reed T.D. Liu L.H. Ji Y. Loukianov E. Paul R.J. Nieman M.L. Riddle T. Duffy J.J. Doetschman T. Lorenz J.N. Shull G.E. J. Biol. Chem. 1999; 274: 2556-2562Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Ablation of the ATP2A3 gene encoding SERCA3 was not lethal, but defects were noted in endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in SERCA3-null mice (22Liu L.H. Paul R.J. Sutliff R.L. Miller M.L. Lorenz J.N. Pun R.Y. Duffy J.J. Doetschman T. Kimura Y. MacLennan D.H. Hoying Shull G.E. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). The of the was to the of SERCA1 in physiological and the by which SERCA1 mutations cause Brody the ATP2A1 gene is expressed in fibers, it was of to the of the function of as the fast twitch fibers a of the fibers. SERCA1−/− mice were with normal and normal However, affected mice cyanosis and gasping respiration and shortly after birth. analysis of mice at term revealed congestion and hypercellularity of the consistent with failure of the respiratory to to the after birth. of the diaphragm muscle revealed increased fiber size and prominent hypercontracted regions in scattered muscle fibers. The loss of SERCA1 protein from diaphragm and skeletal was by a in Ca2+ activity in from these No compensatory responses were detected in or protein levels for other Ca2+ A impairment of the contractile response of diaphragm to electrical stimulation was that the loss of SERCA1 in the diaphragm of mice to neonatal from respiratory A of the mouse ATP2A1 gene was from a of J. and characterized by and DNA The the 3′-end of the and the to of the ATP2A1 gene, which encode In no acid were in the mouse to that of the of the gene Y. J. Karpati G. Yee W.C. Schrank B. Cornblath D.R. MacLennan D.H. Genomics. PubMed Scopus Google Scholar). was a of the was from the the the at the the and mouse ATP2A1 gene regions the the the size of the was in the The was with the II as a The and in and were in The was by of with the The was a gene of 1 and a The of the was the as that of theATP2A1 gene. The was at the from The was at the in the and by after the were to at and to gene and the gene, Three to were and after DNA from cell was with and by E. Kimura Y. S. Hoit MacLennan D.H. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) different 1 was a from was a for gene. cell the gene were for was by M. mice with were and to mice. of the gene was with only one and mouse was as a of the with targeted ablation of the ATP2A1 gene. was by analysis of DNA from 1 and and by analysis a of that wild-type and mutant the were 1 to in that was in the targeted to in and to the of the conditions for of the wild-type and the mutant were as at for for at and for at from or diaphragm muscle from mice of the were and a in of and were at for at The were for of the Ca2+ of as T. K. M. MacLennan D.H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). activity in was in of a and about of the of Ca2+ of Ca2+ Ca2+ were the of and A. J. Physiol. Google was at a activity of about The was by the of at for and by through a by with of the was measured by were with in Ca2+ were by and to a mouse were as SERCA2a and of was detected by and an enhanced were by the as a was from diaphragm or the in the DNA from was by of in a for at and with and with The of of the samples was by and the was by of from were to in a of II reverse to the of the The absence of DNA from was by by reverse from the of the reverse transcription were to of SERCA1b, and of the of the gene, glyceraldehyde-3-phosphate dehydrogenase was to the of of the of The was the of for The were by with Green and were detected the to the of the of the were to the of of SERCA1 number SERCA2 SERCA3 sarcolipin phospholamban and were to create for of SERCA1a and SERCA1b, and and and SERCA1 and and SERCA2 and and and and and and The and to and are in the of SERCA1a to SERCA1b SERCA1a and SERCA1b were to the SERCA1a and SERCA1b the in by with the the adult be and the levels of SERCA2a and of were to SERCA2a and SERCA2b the SERCA1 to SERCA2 and SERCA2 to SERCA3 the were the in to that be for and to and by a of was by with a The the for SERCA1 and SERCA2 and for SERCA2 and SERCA3 were the obtained with the in a a of was by with a The the for SERCA1 and SERCA2 and for SERCA2 and SERCA3 were the obtained with the were diaphragm muscle from ATP2A1 mice and wild-type contractile of diaphragm were measured in from neonatal mice by or of diaphragm muscle was with and and and and at diaphragm was and a for muscle was in a muscle a and a model to was by a A stimulation was with a of were a to a and the Muscle and and Muscle Muscle was to twitch and the of and relaxation were a twitch and a of stimulation from to was a stimulation of at are expressed as a percentage of the contractile and were the diaphragm muscle were of the of the and and an muscle fiber of muscle was by the muscle by the of muscle and the of skeletal muscle. were for muscle fiber samples from in were and by for of 10-, 15-, and 18-day embryos and term neonatal of and diaphragm from neonatal term and of and diaphragm of term mice. of neonatal or embryonic mice were by in in at with and and by and were after in by in and for diaphragm and were in by of and the and after The diaphragm and were 1 and in the at Muscle was for by with in for 1 in and with and were in at and with and were and a were from the of and SERCA1−/− as in C. N. M. N. S. Biol. 1997; PubMed Google Muscle from was by with by with and and of for at The was by the of were by the cell for 1 at in were with and in in with were the and the was to in The in was to theATP2A1 gene. The of of of mouse in which the gene for of the ATP2A1 gene, to a of the and a of the which of in and analysis 1 and not revealed that the that was of a targeted but the of only one of these mice the targeted in after with wild-type of with heterozygous mice were to and mutant as by analysis of DNA analysis of of heterozygous and mutant which is to a normal Mendelian All were and SERCA1−/− mice were from wild-type in at birth. The of and SERCA1−/− mice not SERCA1−/− that were characterized by gasping respiration, and progressive mice slow and delayed relaxation of skeletal that was of the that Brody contractile skeletal in these mice were not to the and size of the that the contractile of the be to with diaphragm muscle and be consistent with the of the SERCA1−/− mice to after birth. A survey of multiple organs from 10-, 15-, and 18-day revealed no morphological not of term SERCA1−/− mice that shortly after of respiratory failure revealed prominent hypercontracted regions in scattered fibers and and increased fiber size in diaphragm muscle. analysis of of SERCA1−/− and revealed fiber size and no in not of the of SERCA1−/− mice revealed diffuse congestion and hypercellularity In contrast, analysis of revealed in lungs absence of and a size of muscle fibers in the diaphragm of cardiac muscle of SERCA1−/− and mice revealed no A and of revealed of and prominent of which were to a in wild-type term not of the diaphragm muscle in SERCA1−/− mice revealed prominent hypercontracted regions in scattered fibers A and The in was to as as and were the to increased were restricted to in diaphragm muscle in affected mice. the loss of SERCA1 protein and compensatory and from diaphragm and were by and through analysis that SERCA1a and mRNAs are expressed in diaphragm and from mice but are in SERCA1−/− mice. that the of and and sarcolipin and phospholamban was not affected in SERCA1−/− mice. through that SERCA1 protein is in SERCA1−/− whereas of SERCA2a and other Ca2+ membrane proteins, the and not wild-type and affected neonatal mice. were from diaphragm and muscle from and SERCA1−/− mice and for Ca2+ of Ca2+uptake by the with the ablation of Ca2+ activity was reduced by 80% in diaphragm and muscle of SERCA1−/− mice compared with mice and of of and of of in Ca2+ by the reticulum is consistent with the SERCA1 protein levels in SERCA1−/− mice. In the Ca2+ expressed as was in samples from SERCA1−/− compared with samples from mice contractile of skeletal muscle of SERCA1 mice were muscle from the diaphragm of SERCA1−/− and mice. of obtained from in a muscle from a and a SERCA1−/− was dramatically in the of relaxation was in the SERCA1−/− muscle The was in SERCA1−/− muscle compared with a muscle at of with the of The from was compared with from SERCA1−/− muscle The of contraction and relaxation are in and stimulation and were in SERCA1−/− mice compared with mice. The response to a stimulation that an increased to in diaphragm muscle from SERCA1−/− mice. A and from the of embryos of and SERCA1−/− mice were in under conditions for and The of and of of from and SERCA1−/− mice were SERCA1 is a of a of Ca2+ expressed in the sarco(endo)plasmic reticulum of which SERCA1a and SERCA1b, is is largely to fast twitch muscle (2Lytton J. MacLennan D.H. J. Biol. Chem. 1988; 263: 15024-15031Abstract Full Text PDF PubMed Google Scholar, 3Brandl C.J. Green N.M. Korczak B. MacLennan D.H. Cell. 1986; 44: 597-607Abstract Full Text PDF PubMed Scopus (587) Google Scholar, 4Burk S.E. Lytton J. MacLennan D.H. Shull G.E. J. Biol. Chem. 1989; 264: 18561-18568Abstract Full Text PDF PubMed Google Scholar, 5MacLennan D.H. Brandl C.J. Korczak B. Green N.M. Nature. 1985; 316: 696-700Crossref PubMed Scopus (795) Google Scholar). or missense mutations in the ATP2A1 gene that lead to loss of SERCA1 with loss of of SERCA1 have to be of the muscle disorder Brody disease (14Odermatt A. Taschner P.E. Khanna V.K. Busch H.F. Karpati G. Jablecki C.K. Breuning M.H. MacLennan D.H. Nat. Genet. 1996; 14: 191-194Crossref PubMed Scopus (175) Google Scholar, A. S. Khanna V.K. K. E. D. MacLennan D.H. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Brody disease is not in humans but is characterized by a of exercise-induced muscle and muscle (9Karpati G. Charuk J. Carpenter S. Jablecki C. Holland P. Ann. Neurol. 1986; 20: 38-49Crossref PubMed Scopus (80) Google Scholar, 10Danon M.J. Karpati G. Charuk J. Holland P. Neurology. 1988; 38: 812-815Crossref PubMed Google Scholar, 11Taylor D.J. Brosnan M.J. Arnold D.L. Bore P.J. Styles P. Walton J. Radda G.K. J. Neurol. Neurosurg. Psychiatry. 1988; 51: 1425-1433Crossref PubMed Scopus (46) Google Scholar, 12Wevers R.A. Poels P.J. Joosten E.M. Steenbergen G.G. Benders A.A. Veerkamp J.H. J. Inherit. Metab. Dis. 1992; 15: 423-425Crossref PubMed Scopus (8) Google Scholar, 13Benders A.A. Veerkamp J.H. Oosterhof A. Jongen P.J. Bindels R.J. Smit L.M. Busch H.F. Wevers R.A. J. Clin. Invest. 1994; 94: 741-748Crossref PubMed Scopus (56) Google Scholar). In the targeted ablation of the ATP2A1 gene mice SERCA1 in skeletal muscle that and of the of SERCA1 be The absence of encoding SERCA1a and and the absence of SERCA1 protein in SERCA1−/− mice that had a SERCA1−/− mice were in the predicted Mendelian that SERCA1 ablation is not embryonic SERCA1−/− neonatal mice were from wild-type in and in at SERCA1−/− mice that were characterized by gasping respiration, and progressive In SERCA1−/− mice slow and that was of the in the skeletal muscle of Brody mice after of respiratory in contrast to humans, SERCA1 is for in mice. of and cardiac muscle from and SERCA1−/− mice not in from wild-type However, of the diaphragm muscle in SERCA1−/− mice revealed prominent hypercontracted regions in scattered fibers, of impaired muscle fiber relaxation and of the revealed hypercellularity of the and failure of of to impaired that absence of SERCA1 in mice to respiratory failure to impairment of function. are no studies of diaphragm muscle in Brody disease However, respiratory failure is not a of the is a marked in of the SERCA1a affected humans and which that compensatory for Ca2+ in Brody disease patients or that physiological mice and Ca2+ by the membrane Ca2+-ATPase or by in the Ca2+ or of the reticulum compensatory levels of SERCA2 or these possible compensatory only the be predicted to result in Ca2+ of the a for muscle contraction D.H. J. 2000; PubMed Scopus Google Scholar). compensatory responses of SERCA1 in mouse and analysis of SERCA1−/− were studies revealed that SERCA1 and protein were in and muscle but levels of and were and protein levels of membrane and not wild-type and affected mice. that was no compensatory to the loss of SERCA1 in diaphragm muscle. In response to muscle responses were in fast twitch skeletal muscle that a in SERCA isoform from SERCA1 to SERCA2 D. Res. 2000; PubMed Scopus Google Scholar, D. Biol. PubMed Scopus Google Scholar). was that the responses resulted from the in Ca2+ that with muscle stimulation can that had not in SERCA1−/− mice in is loss of Ca2+ be in in SERCA1−/− neonatal mice. compensatory increased in diaphragm muscle activity be and neonatal SERCA1−/− mice not have to the of after birth. The SERCA1−/− mice are of the increase in activity required of respiratory after birth. the of humans and that mice at a of S. H. A. M. J.J. J. H. Am. J. Biol. 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