Myosin 7b is a regulatory long noncoding RNA (lncMYH7b) in the human heart

Abstract

Myosin heavy chain 7b (MYH7b) is an ancient member of the myosin heavy chain motor protein family that is expressed in striated muscles. In mammalian cardiac muscle, MYH7b RNA is expressed along with two other myosin heavy chains, β-myosin heavy chain (β-MyHC) and α-myosin heavy chain (α-MyHC). However, unlike β-MyHC and α-MyHC, which are maintained in a careful balance at the protein level, the MYH7b locus does not produce a full-length protein in the heart due to a posttranscriptional exon-skipping mechanism that occurs in a tissue-specific manner. Whether this locus has a role in the heart beyond producing its intronic microRNA, miR-499, was unclear. Using cardiomyocytes derived from human induced pluripotent stem cells as a model system, we found that the noncoding exon-skipped RNA (lncMYH7b) affects the transcriptional landscape of human cardiomyocytes, independent of miR-499. Specifically, lncMYH7b regulates the ratio of β-MyHC to α-MyHC, which is crucial for cardiac contractility. We also found that lncMYH7b regulates beat rate and sarcomere formation in cardiomyocytes. This regulation is likely achieved through control of a member of the TEA domain transcription factor family (TEAD3, which is known to regulate β-MyHC). Therefore, we conclude that this ancient gene has been repurposed by alternative splicing to produce a regulatory long-noncoding RNA in the human heart that affects cardiac myosin composition. Myosin heavy chain 7b (MYH7b) is an ancient member of the myosin heavy chain motor protein family that is expressed in striated muscles. In mammalian cardiac muscle, MYH7b RNA is expressed along with two other myosin heavy chains, β-myosin heavy chain (β-MyHC) and α-myosin heavy chain (α-MyHC). However, unlike β-MyHC and α-MyHC, which are maintained in a careful balance at the protein level, the MYH7b locus does not produce a full-length protein in the heart due to a posttranscriptional exon-skipping mechanism that occurs in a tissue-specific manner. Whether this locus has a role in the heart beyond producing its intronic microRNA, miR-499, was unclear. Using cardiomyocytes derived from human induced pluripotent stem cells as a model system, we found that the noncoding exon-skipped RNA (lncMYH7b) affects the transcriptional landscape of human cardiomyocytes, independent of miR-499. Specifically, lncMYH7b regulates the ratio of β-MyHC to α-MyHC, which is crucial for cardiac contractility. We also found that lncMYH7b regulates beat rate and sarcomere formation in cardiomyocytes. This regulation is likely achieved through control of a member of the TEA domain transcription factor family (TEAD3, which is known to regulate β-MyHC). Therefore, we conclude that this ancient gene has been repurposed by alternative splicing to produce a regulatory long-noncoding RNA in the human heart that affects cardiac myosin composition. The myosin family of motor proteins that drives striated muscle contraction consists of ten genes with distinct functions (1Weiss A. Leinwand L. The mammalian myosin heavy chain gene family.Annu. Rev. Cell Dev. Biol. 1996; 12: 417-439Crossref PubMed Scopus (254) Google Scholar). Three of these genes are expressed in mammalian hearts (MYH6, MYH7, and MYH7b). MYH6 (α-MyHC) and MYH7 (β-MyHC) are the major sarcomeric myosin proteins expressed in mammalian hearts. In humans, >90% of the heart’s myosin protein composition is comprised of β-MyHC with the remaining <10% being α-MyHC and the two are antithetically regulated (1Weiss A. Leinwand L. The mammalian myosin heavy chain gene family.Annu. Rev. Cell Dev. Biol. 1996; 12: 417-439Crossref PubMed Scopus (254) Google Scholar, 2Nakao K. Minobe W. Roden R. Bristow M.R. Leinwand L.A. Myosin heavy chain gene expression in human heart failure.J. Clin. Invest. 1997; 100: 2362-2370Crossref PubMed Scopus (315) Google Scholar, 3Miyata S. Minobe W. Bristow M.R. Leinwand L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart.Circ. Res. 2000; 86: 386-390Crossref PubMed Scopus (364) Google Scholar, 4Lowes B.D. Gilbert E.M. Abraham W.T. Minobe W.A. Larrabee P. Ferguson D. Wolfel E.E. Lindenfeld J.A. Tsvetkova T. Robertson A.D. Quaife R.A. Bristow M.R. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.N. Engl. J. Med. 2002; 346: 1357-1365Crossref PubMed Scopus (413) Google Scholar, 5Hasegawa K. Lee S.J. Jobe S.M. Markham B.E. Kitsis R.N. cis-Acting sequences that mediate induction of beta-myosin heavy chain gene expression during left ventricular hypertrophy due to aortic constriction.Circulation. 1997; 96: 3943-3953Crossref PubMed Scopus (149) Google Scholar). However, various conditions can shift their relative proportions. The finely tuned balance of these two motors is critical for proper cardiac function since they have very different enzymatic properties, which determine the contractile velocity of the muscle (6Krenz M. Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress.J. Am. Coll. Cardiol. 2004; 44: 2390-2397Crossref PubMed Scopus (171) Google Scholar). It has been well established that disturbing the β-MyHC/α-MyHC ratio leads to compromised contractility in cardiomyocytes; in human heart failure, there is a shift to ∼100% β-MyHC and α-MyHC becomes undetectable (2Nakao K. Minobe W. Roden R. Bristow M.R. Leinwand L.A. Myosin heavy chain gene expression in human heart failure.J. Clin. Invest. 1997; 100: 2362-2370Crossref PubMed Scopus (315) Google Scholar, 3Miyata S. Minobe W. Bristow M.R. Leinwand L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart.Circ. Res. 2000; 86: 386-390Crossref PubMed Scopus (364) Google Scholar, 4Lowes B.D. Gilbert E.M. Abraham W.T. Minobe W.A. Larrabee P. Ferguson D. Wolfel E.E. Lindenfeld J.A. Tsvetkova T. Robertson A.D. Quaife R.A. Bristow M.R. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.N. Engl. J. Med. 2002; 346: 1357-1365Crossref PubMed Scopus (413) Google Scholar, 7Rundell V.L.M. Manaves V. Martin A.F. de Tombe P.P. Impact of beta-myosin heavy chain isoform expression on cross-bridge cycling kinetics.Am. J. Physiol. Heart Circ. Physiol. 2005; 288: H896-H903Crossref PubMed Scopus (95) Google Scholar). As β-MyHC is the slower, more efficient motor, this shift in expression is thought to be an initial compensatory mechanism to preserve energy in the failing heart. Heart failure patients that show functional improvement upon treatment with β-adrenergic receptor blockers have an increase in α-MyHC expression (4Lowes B.D. Gilbert E.M. Abraham W.T. Minobe W.A. Larrabee P. Ferguson D. Wolfel E.E. Lindenfeld J.A. Tsvetkova T. Robertson A.D. Quaife R.A. Bristow M.R. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.N. Engl. J. Med. 2002; 346: 1357-1365Crossref PubMed Scopus (413) Google Scholar). This suggests that maintenance of the β-MyHC/α-MyHC ratio is fundamental to proper cardiac function. While MYH6 and MYH7 have been studied for decades, MYH7b was not identified until the sequencing of the human genome and was initially annotated as a sarcomeric myosin based on sequence alignments with other known family members (8Desjardins P.R. Burkman J.M. Shrager J.B. Allmond L.A. Stedman H.H. Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family.Mol. Biol. Evol. 2002; 19: 375-393Crossref PubMed Scopus (60) Google Scholar). Based on phylogenetic analysis, MYH7b was identified as an ancient myosin, indicating that MYH7b was present before the gene duplication events that led to the other sarcomeric myosins (8Desjardins P.R. Burkman J.M. Shrager J.B. Allmond L.A. Stedman H.H. Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family.Mol. Biol. Evol. 2002; 19: 375-393Crossref PubMed Scopus (60) Google Scholar). The human MYH7b gene is located on chromosome 20, separate from the two canonical sarcomeric myosin clusters on chromosomes 14 (cardiac myosins) and 17 (skeletal muscle myosins), supporting the idea that MYH7b may have a specialized role in muscle biology (1Weiss A. Leinwand L. The mammalian myosin heavy chain gene family.Annu. Rev. Cell Dev. Biol. 1996; 12: 417-439Crossref PubMed Scopus (254) Google Scholar, 8Desjardins P.R. Burkman J.M. Shrager J.B. Allmond L.A. Stedman H.H. Evolutionary implications of three novel members of the human sarcomeric myosin heavy chain gene family.Mol. Biol. Evol. 2002; 19: 375-393Crossref PubMed Scopus (60) Google Scholar). In certain species, including snakes and birds, MYH7b is expressed as a typical sarcomeric myosin protein in the heart and skeletal muscle (9Lee L.A. Karabina A. Broadwell L.J. Leinwand L.A. The ancient sarcomeric myosins found in specialized muscles.Skelet. Muscle. 2019; 9: 1-15Crossref PubMed Scopus (8) Google Scholar). However, MYH7b has a unique expression pattern in mammals: the encoded protein is expressed in specialized muscles and nonmuscle tissues (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar, S. myosins in mammalian skeletal and are expressed in muscles and muscle Physiol. PubMed Scopus Google Scholar, R. of and function by distinct myosin PubMed Scopus Google Scholar). MYH7b RNA is expressed in mammalian cardiac and skeletal muscle, an alternative splicing an a that full-length protein expression (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar). This the of MYH7b RNA expression has been in the mammalian heart. is that MYH7b transcription is in mammalian heart and skeletal muscle in to the expression of an intronic MYH7b microRNA, miR-499, in tissues (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar). However, have cardiac skeletal muscle D. J.A. family of encoded by myosin genes myosin expression and muscle PubMed Scopus Google Scholar). It is that the regulation of myosin the of this model and that an role in human muscle (6Krenz M. Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress.J. Am. Coll. Cardiol. 2004; 44: 2390-2397Crossref PubMed Scopus (171) Google Scholar, S. J. R. myosin in a Scholar). is that a functional is expressed from the MYH7b in its expression in the sarcomeric muscle In this we a of this locus in to the role of MYH7b gene expression in human cardiomyocytes and found a novel noncoding RNA (lncMYH7b) with in cardiac gene to in beat rate and sarcomeric The human MYH7b locus is In certain a typical striated muscle myosin and full-length In tissues is the locus produce a from the the in and the long-noncoding RNA In the is encoded in We from and human heart and found that of the MYH7b RNA is undetectable of which is with that MYH7b has a tissue-specific alternative splicing pattern and (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar). This suggests that the full-length MYH7b protein is not present in the human heart. This is also with that expression of full-length MYH7b protein in the heart in cardiac and the full-length protein is known to have in other tissues R. of and function by distinct myosin PubMed Scopus Google Scholar, M. Lee L.A. Leinwand L.A. of myosin heavy chain 7b in the mammalian heart dilated Am. Heart 2019; PubMed Scopus Google Scholar, J. J. sequencing and novel with PubMed Scopus Google Scholar). β-MyHC which the β-MyHC/α-MyHC is a of heart (2Nakao K. Minobe W. Roden R. Bristow M.R. Leinwand L.A. Myosin heavy chain gene expression in human heart failure.J. Clin. Invest. 1997; 100: 2362-2370Crossref PubMed Scopus (315) Google Scholar, 3Miyata S. Minobe W. Bristow M.R. Leinwand L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart.Circ. Res. 2000; 86: 386-390Crossref PubMed Scopus (364) Google Scholar, 4Lowes B.D. Gilbert E.M. Abraham W.T. Minobe W.A. Larrabee P. Ferguson D. Wolfel E.E. Lindenfeld J.A. Tsvetkova T. Robertson A.D. Quaife R.A. Bristow M.R. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.N. Engl. J. Med. 2002; 346: 1357-1365Crossref PubMed Scopus (413) Google Scholar). we that MYH7b RNA with β-MyHC including the known increase in β-MyHC expression in human hearts and This the that there is a regulatory the MYH7b locus and β-MyHC full-length MYH7b protein and are in the human there are other from the MYH7b gene as The of these different the locus as a is that the MYH7b locus regulates β-MyHC through the miR-499, which is a encoded in of the MYH7b is to that regulates the expression of and the β-MyHC in the heart conditions of (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar, D. J.A. family of encoded by myosin genes myosin expression and muscle PubMed Scopus Google Scholar, in heart and cardiac on Cardiol. PubMed Scopus Google Scholar). as and encoded by the α-MyHC and β-MyHC have been to have on the β-MyHC/α-MyHC ratio in D. J.A. family of encoded by myosin genes myosin expression and muscle PubMed Scopus Google Scholar). However, the cardiac β-MyHC/α-MyHC ratio is to the human with regulation (6Krenz M. Robbins J. Impact of beta-myosin heavy chain expression on cardiac function during stress.J. Am. Coll. Cardiol. 2004; 44: 2390-2397Crossref PubMed Scopus (171) Google Scholar, S. J. R. myosin in a Scholar). Therefore, was to the β-MyHC to in in a human We a model of human induced pluripotent stem cells to cardiomyocytes which we treated with an that We in MYH7b β-MyHC Therefore, we conclude that does not regulate β-MyHC expression in human cardiomyocytes. The of as a of the β-MyHC/α-MyHC ratio left a and the lncMYH7b to The MYH7b locus full-length protein in the specialized and tissues and of the for (9Lee L.A. Karabina A. Broadwell L.J. Leinwand L.A. The ancient sarcomeric myosins found in specialized muscles.Skelet. Muscle. 2019; 9: 1-15Crossref PubMed Scopus (8) Google Scholar). We MYH7b RNA in with indicating that the exon-skipped RNA is to the (10Bell M. Leinwand L.A. of expression of an intronic and its myosin gene by Biol. PubMed Scopus Google Scholar). Using we that MYH7b RNA is to the in with and We these by for upon and with and we very along the which is T. and of Dev. PubMed Scopus Google Scholar). This suggests that not MYH7b RNA is by is also for being from which muscle contraction R. encoded by a annotated as noncoding RNA in PubMed Scopus Google Scholar, P. J.M. J. R. encoded by a noncoding RNA regulates muscle PubMed Scopus Google Scholar). Based on we the to the in is the regulate the β-MyHC/α-MyHC ratio in human cardiomyocytes. The is to be in and It is that has in full-length are and a has not been Therefore, we which is an that present in the full-length MYH7b in and the to for expression S. myosins in mammalian skeletal and are expressed in muscles and muscle Physiol. PubMed Scopus Google Scholar, M. Lee L.A. Leinwand L.A. of myosin heavy chain 7b in the mammalian heart dilated Am. Heart 2019; PubMed Scopus Google Scholar). As a we cells with an the and a protein of the and We human heart from dilated cardiomyopathy MYH7b are not In at the of a does have a regulatory we expression of the of and We found in the β-MyHC/α-MyHC ratio at the RNA level, and expressed genes which is with an and of a M. A. The of the PubMed Scopus Google Scholar). we conclude that is not expressed at in human cardiomyocytes and has on the expression of the regulatory of and in β-MyHC we that the lncMYH7b regulates We to the exon-skipped as we with we that this of which we have that is not from lncMYH7b We that this is due to the of that and other RNA This led to that a is to function. Therefore, we to with a we MYH7b RNA with and the of lncMYH7b and β-MyHC expression in treatment with MYH7b RNA was by which was maintained through we β-MyHC expression of MYH7b RNA supporting an role for the exon-skipped MYH7b RNA in β-MyHC the idea that lncMYH7b is β-MyHC/α-MyHC of miR-499, we the in lncMYH7b We in in the other two encoded by α-MyHC and β-MyHC and upon treatment with the MYH7b we that the in β-MyHC RNA upon MYH7b was at the protein As independent we from a different and a different myosin a of the β-MyHC/α-MyHC ratio upon of MYH7b RNA these a role for lncMYH7b in the β-MyHC/α-MyHC ratio in human cardiomyocytes. In to the regulatory of lncMYH7b in a more and we on MYH7b We the to gene expression A. S. J. A. P. S. 2019; Scopus Google Scholar). expression a with very with As of the RNA also protein this the of from the We found that the in the β-MyHC/α-MyHC ratio was also at the RNA level, that lncMYH7b is β-MyHC functional the role of lncMYH7b in cardiac gene we a of and found that with regulated by the in lncMYH7b expression This is with the in lncMYH7b in the from patients with heart expression of two members of the TEA domain transcription factor and and was in lncMYH7b As was the and has been to regulate β-MyHC we to on that transcription factor S. A. K. role of TEA domain transcription in the regulation of the gene by and its PubMed Scopus Google Scholar). We a in RNA which with being the transcription factor in family members are known to to and transcription at the β-MyHC and are in cardiomyopathy hearts S. A. K. role of TEA domain transcription in the regulation of the gene by and its PubMed Scopus Google Scholar). has not been well has a expression pattern A.F. J. The role of transcription in Med. PubMed Scopus (8) Google Scholar). family members can with transcription factor family which are of muscle formation and are known to β-MyHC transcription J. A. R. factor muscle and during skeletal muscle Biol. PubMed Scopus Google Scholar, S. S. A. gene in cardiac and skeletal muscle novel regulation of by Res. PubMed Scopus Google Scholar, of PubMed Scopus Google Scholar). of the a in the expression of also known as can also with in cardiomyocytes to its and in a model was in cardiomyocytes, protein de R. a with to to transcription in PubMed Scopus Google Scholar, W. and by in the of the cardiac Res. 2005; PubMed Scopus Google Scholar, A. J. S. R.A. and ventricular hypertrophy in S. A. PubMed Scopus Google Scholar). the is of the in has also been identified as an of transcriptional to regulates the Cell Biol. PubMed Scopus Google Scholar, The role of in stem Google Scholar). along with suggests that lncMYH7b is an of transcription in cardiomyocytes. As we upon the in we the beat rate lncMYH7b As by the we a in beat rate in the MYH7b cells as with the treated with the control P. A. of contractility and in pluripotent stem cardiomyocytes different PubMed Scopus Google Scholar). that this is due to the in expression in the we to protein of of the proteins by As in are and are This is with the in RNA in indicating that lncMYH7b is expression of proteins in the in cardiomyocytes. In to the we by the of the RNA of is known to a role in the formation of in and in K. R. S. M. M. A. R. regulates and sarcomere in striated Biol. PubMed Scopus Google Scholar, T. S. M. S. R. The protein is for and functional maintenance of the heart in Biol. PubMed Scopus Google Scholar, K. M.R. to in Scopus Google Scholar). was also a in the expression of upon lncMYH7b and are for sarcomere formation in K. M.R. to in Scopus Google Scholar). As we sarcomere formation in treated with the MYH7b We for for sarcomere two and found a distinct shift upon lncMYH7b with in the cells treated with the control In lncMYH7b cells have to these that lncMYH7b an role in sarcomeric and function. We have that the MYH7b gene not a myosin heavy chain protein and a also a regulatory we have This is the of a myosin heavy chain with a regulatory MYH7b protein is undetectable in the mammalian heart the of the we that the locus is to However, have cardiac at D. J.A. family of encoded by myosin genes myosin expression and muscle PubMed Scopus Google Scholar). MYH7b RNA are in is a locus we present that is the that has a regulatory role in cardiac gene have been of other in the heart. the of and are three of that regulate genes with heart P. the of PubMed Scopus Google Scholar, P. T. S. A. RNA an in cardiac Med. Scopus Google Scholar, M. A. R. T. M. A. A. in the noncoding RNA and heart in J. PubMed Scopus Google Scholar). However, known cardiac at the by a novel posttranscriptional mechanism of gene expression P. and regulation of cardiac PubMed Scopus Google Scholar, A. in the PubMed Scopus Google Scholar). are of annotated MYH7b full-length protein in other there is for derived from this locus in the human heart (9Lee L.A. Karabina A. Broadwell L.J. Leinwand L.A. The ancient sarcomeric myosins found in specialized muscles.Skelet. Muscle. 2019; 9: 1-15Crossref PubMed Scopus (8) Google Scholar, S. myosins in mammalian skeletal and are expressed in muscles and muscle Physiol. PubMed Scopus Google Scholar, R. of and function by distinct myosin PubMed Scopus Google Scholar, J. J. sequencing and novel with PubMed Scopus Google Scholar, R. encoded by a annotated as noncoding RNA in PubMed Scopus Google Scholar, P. J.M. J. R. encoded by a noncoding RNA regulates muscle PubMed Scopus Google Scholar). this is an of the of an ancient gene to produce a regulatory alternative The noncoding of the genome has been an of in and the of more more The of human cells was to this The ratio of β-MyHC and α-MyHC leads to in we are more to regulatory to We are also to In this we to two independent to show the lncMYH7b regulation of the myosin heavy This well for the of cardiac in in the of and gene This lncMYH7b of β-MyHC expression at the RNA and protein is an in the of cardiac increase in the β-MyHC/α-MyHC ratio is a of heart (2Nakao K. Minobe W. Roden R. Bristow M.R. Leinwand L.A. Myosin heavy chain gene expression in human heart failure.J. Clin. Invest. 1997; 100: 2362-2370Crossref PubMed Scopus (315) Google Scholar, 3Miyata S. Minobe W. Bristow M.R. Leinwand L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart.Circ. Res. 2000; 86: 386-390Crossref PubMed Scopus (364) Google Scholar). This in myosin heavy chain composition has been to the contractility of cardiomyocytes. Heart failure patients that to β-adrenergic receptor treatment have a shift the β-MyHC/α-MyHC ratio (4Lowes B.D. Gilbert E.M. Abraham W.T. Minobe W.A. Larrabee P. Ferguson D. Wolfel E.E. Lindenfeld J.A. Tsvetkova T. Robertson A.D. Quaife R.A. Bristow M.R. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents.N. Engl. J. Med. 2002; 346: 1357-1365Crossref PubMed Scopus (413) Google Scholar). Therefore, the regulation of β-MyHC expression is of to the cardiac show that lncMYH7b is in the we not that lncMYH7b to regulate transcription from the β-MyHC We the of lncMYH7b to that this we found expression of the transcription and upon lncMYH7b As these are known to regulate β-MyHC a we that this is a for the in the β-MyHC/α-MyHC ratio S. A. K. role of TEA domain transcription in the regulation of the gene by and its PubMed Scopus Google Scholar, J. A. R. factor muscle and during skeletal muscle Biol. PubMed Scopus Google Scholar). lncMYH7b this in and family member is an of However, is that the expression in these transcription are of in not affects the of is also a known of transcription to regulates the Cell Biol. PubMed Scopus Google Scholar, L.A. is critical to by in cardiac J. Physiol. Circ. Physiol. 2005; PubMed Scopus Google Scholar). of these and have major in heart function and to indicating that lncMYH7b may also have a role in cardiac gene expression regulation as well as a role in This is well by the to beat rate and sarcomere formation we of this regulatory is to role in the transcriptional landscape of the heart. this for to heart The was for and in was K. S.M. J. from human pluripotent stem cells of canonical S. A. PubMed Scopus Google Scholar). was for at in with and was for at in the The was to a with in for the of the cells for before treatment with from to and for from and to cardiomyocytes treated with a MYH7b at for was with was and by found in the treated with MYH7b for was with and RNA was at the human MYH7b the As there was a for with β-MyHC and α-MyHC due to sequence in the myosin these to they with the other two The sequences can be found in The from and with as in was with and an of the at for the at The through We for with β-MyHC and α-MyHC by cells with and to cardiomyocytes on in a the cardiomyocytes three with with for at to and at for at The was and RNA with was for at was in a a in of the was to of RNA of this was the in the The was with left in the at a and with for at in RNA with at for at and with with a and the was to and the ratio of two of in two independent for expression of and was as the S. A. S. S. Leinwand L.A. J.A. of human myosin with the cardiomyopathy show of motor Scopus Google Scholar). with a of of and from upon left ventricular from with a in for at at for to the Cell in the manner. a determine the myosin isoform in control MYH7b we the in and for cardiac myosin heavy chain by PubMed Scopus Google Scholar). of was on a and with of α-MyHC and β-MyHC for of protein was on a and to a was at S. myosins in mammalian skeletal and are expressed in muscles and muscle Physiol. PubMed Scopus Google Scholar, M. Lee L.A. Leinwand L.A. of myosin heavy chain 7b in the mammalian heart dilated Am. Heart 2019; PubMed Scopus Google Scholar). The was on a of The cells by treatment by three with in of and at for ten This was for at at The was The was three with and at for at in of at for and at for The was as the RNA was in RNA was RNA was with and in transcription was and was with the on a with the the of The can be found in RNA to for by and a sequencing of at The and control was the to and gene expression was in was with in R. are on for the human heart from the exon-skipped is not present in the we the exon-skipped for MYH7b to the human and the as to the of are in the as with a before treatment treatment was with from and the remaining cells to MYH7b by with in for at The cells by in for at cells in and in for at The of and was in the and cells left in in a at The cells three for in to and in for at in a three for in and for in in more in on with with a in the at the and the sarcomere with the This was for two separate three The three and upon a of from the in the not well the identified to be certain that we a the control treated on with as of with the rate to with the in the This of which with the in P. A. of contractility and in pluripotent stem cardiomyocytes different PubMed Scopus Google Scholar). This was for two separate three We a with to treated with control at a of the for is in and based on the the analysis, the the the are the as The for this are on and This supporting of We are to Bristow for and and for their on L. J. and analysis, M. J. S. and analysis, K. M. R. and analysis, J. S. and R. L. M. J. L. R. L. A. L. This was by L. A. the L. J. and L. J. The is the of the and does not the of the of

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