Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere
Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostas...
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| Veröffentlicht in: | American journal of physiology. Heart and circulatory physiology 2013-07, Vol.305 (1), p.H52-H65 |
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| container_title | American journal of physiology. Heart and circulatory physiology |
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| creator | Cheng, Y Wan, X McElfresh, T A Chen, X Gresham, K S Rosenbaum, D S Chandler, M P Stelzer, J E |
| description | Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations ( |
| doi_str_mv | 10.1152/ajpheart.00929.2012 |
| format | Article |
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The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.</description><identifier>ISSN: 0363-6135</identifier><identifier>EISSN: 1522-1539</identifier><identifier>DOI: 10.1152/ajpheart.00929.2012</identifier><identifier>PMID: 23666674</identifier><identifier>CODEN: AJPPDI</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Action Potentials ; Animals ; Binding sites ; Calcium - metabolism ; Calcium Signaling ; Cardiac arrhythmia ; Cardiovascular disease ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Heart - physiology ; Heart Rate ; Heart Ventricles - cytology ; Heterozygote ; Kinases ; Mice ; Muscle Contraction ; Muscle Mechanics and Ventricular Function ; Mutation ; Myocardium - metabolism ; Phosphorylation ; Rodents ; Sarcomeres - metabolism ; Sarcomeres - physiology ; Transcription, Genetic</subject><ispartof>American journal of physiology. Heart and circulatory physiology, 2013-07, Vol.305 (1), p.H52-H65</ispartof><rights>Copyright American Physiological Society Jul 1, 2013</rights><rights>Copyright © 2013 the American Physiological Society 2013 American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c433t-dc87a0c29fd1867ce97596f1a13879f8aaaaf8090f7426f72309135ebd4c76f93</citedby><cites>FETCH-LOGICAL-c433t-dc87a0c29fd1867ce97596f1a13879f8aaaaf8090f7426f72309135ebd4c76f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3027,27906,27907</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23666674$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Y</creatorcontrib><creatorcontrib>Wan, X</creatorcontrib><creatorcontrib>McElfresh, T A</creatorcontrib><creatorcontrib>Chen, X</creatorcontrib><creatorcontrib>Gresham, K S</creatorcontrib><creatorcontrib>Rosenbaum, D S</creatorcontrib><creatorcontrib>Chandler, M P</creatorcontrib><creatorcontrib>Stelzer, J E</creatorcontrib><title>Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere</title><title>American journal of physiology. Heart and circulatory physiology</title><addtitle>Am J Physiol Heart Circ Physiol</addtitle><description>Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.</description><subject>Action Potentials</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Calcium - metabolism</subject><subject>Calcium Signaling</subject><subject>Cardiac arrhythmia</subject><subject>Cardiovascular disease</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Heart - physiology</subject><subject>Heart Rate</subject><subject>Heart Ventricles - cytology</subject><subject>Heterozygote</subject><subject>Kinases</subject><subject>Mice</subject><subject>Muscle Contraction</subject><subject>Muscle Mechanics and Ventricular Function</subject><subject>Mutation</subject><subject>Myocardium - metabolism</subject><subject>Phosphorylation</subject><subject>Rodents</subject><subject>Sarcomeres - metabolism</subject><subject>Sarcomeres - physiology</subject><subject>Transcription, Genetic</subject><issn>0363-6135</issn><issn>1522-1539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdUctqHDEQFCEmXjv5gkAQ5JLLrPWY0eMSCEsSGwy-OGeh1bS8WmakiTQT8N9b4xdJ-iI1XV1dRSH0kZItpR27sMfpADbPW0I001tGKHuDNnXCGtpx_RZtCBe8EZR3p-islCMhpJOCv0OnjItast2gw9U42ZChxy7FOVs3hwGwX2L9pIj7BfCccA8ugy0ryuY-WIfH-1RCxPsQ-xDv8JTTDLXfPdJAnHFt5gPgYrNLI2R4j068HQp8eH7P0a8f3293l831zc-r3bfrxrWcz03vlLTEMe17qoR0oGWnhaeWciW1V7aWV0QTL1smvGSc6GoQ9n3rpPCan6OvT7zTsh-hd7C6GsyUw2jzvUk2mH8nMRzMXfpjuGSSElUJvjwT5PR7gTKbMRQHw2AjpKWYKoQSrUS33vr8H_SYlhyrvYrSqurvVFtR_Anlciolg38VQ4lZkzQvSZrHJM2aZN369LeP152X6PgDnAGd8A</recordid><startdate>20130701</startdate><enddate>20130701</enddate><creator>Cheng, Y</creator><creator>Wan, X</creator><creator>McElfresh, T A</creator><creator>Chen, X</creator><creator>Gresham, K S</creator><creator>Rosenbaum, D S</creator><creator>Chandler, M P</creator><creator>Stelzer, J E</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TS</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130701</creationdate><title>Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere</title><author>Cheng, Y ; Wan, X ; McElfresh, T A ; Chen, X ; Gresham, K S ; Rosenbaum, D S ; Chandler, M P ; Stelzer, J E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c433t-dc87a0c29fd1867ce97596f1a13879f8aaaaf8090f7426f72309135ebd4c76f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Action Potentials</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Calcium - metabolism</topic><topic>Calcium Signaling</topic><topic>Cardiac arrhythmia</topic><topic>Cardiovascular disease</topic><topic>Carrier Proteins - genetics</topic><topic>Carrier Proteins - metabolism</topic><topic>Heart - physiology</topic><topic>Heart Rate</topic><topic>Heart Ventricles - cytology</topic><topic>Heterozygote</topic><topic>Kinases</topic><topic>Mice</topic><topic>Muscle Contraction</topic><topic>Muscle Mechanics and Ventricular Function</topic><topic>Mutation</topic><topic>Myocardium - metabolism</topic><topic>Phosphorylation</topic><topic>Rodents</topic><topic>Sarcomeres - metabolism</topic><topic>Sarcomeres - physiology</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheng, Y</creatorcontrib><creatorcontrib>Wan, X</creatorcontrib><creatorcontrib>McElfresh, T A</creatorcontrib><creatorcontrib>Chen, X</creatorcontrib><creatorcontrib>Gresham, K S</creatorcontrib><creatorcontrib>Rosenbaum, D S</creatorcontrib><creatorcontrib>Chandler, M P</creatorcontrib><creatorcontrib>Stelzer, J E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheng, Y</au><au>Wan, X</au><au>McElfresh, T A</au><au>Chen, X</au><au>Gresham, K S</au><au>Rosenbaum, D S</au><au>Chandler, M P</au><au>Stelzer, J E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere</atitle><jtitle>American journal of physiology. Heart and circulatory physiology</jtitle><addtitle>Am J Physiol Heart Circ Physiol</addtitle><date>2013-07-01</date><risdate>2013</risdate><volume>305</volume><issue>1</issue><spage>H52</spage><epage>H65</epage><pages>H52-H65</pages><issn>0363-6135</issn><eissn>1522-1539</eissn><coden>AJPPDI</coden><abstract>Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca²⁺ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca²⁺ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca²⁺ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/- and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca²⁺ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca²⁺ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>23666674</pmid><doi>10.1152/ajpheart.00929.2012</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Action Potentials Animals Binding sites Calcium - metabolism Calcium Signaling Cardiac arrhythmia Cardiovascular disease Carrier Proteins - genetics Carrier Proteins - metabolism Heart - physiology Heart Rate Heart Ventricles - cytology Heterozygote Kinases Mice Muscle Contraction Muscle Mechanics and Ventricular Function Mutation Myocardium - metabolism Phosphorylation Rodents Sarcomeres - metabolism Sarcomeres - physiology Transcription, Genetic |
| title | Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere |
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