Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy
The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocar...
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| Veröffentlicht in: | Nature communications 2015-11, Vol.6 (1), p.8803-8803, Article 8803 |
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| creator | Signore, Sergio Sorrentino, Andrea Borghetti, Giulia Cannata, Antonio Meo, Marianna Zhou, Yu Kannappan, Ramaswamy Pasqualini, Francesco O'Malley, Heather Sundman, Mark Tsigkas, Nikolaos Zhang, Eric Arranto, Christian Mangiaracina, Chiara Isobe, Kazuya Sena, Brena F. Kim, Junghyun Goichberg, Polina Nahrendorf, Matthias Isom, Lori L. Leri, Annarosa Anversa, Piero Rota, Marcello |
| description | The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na
+
current (
I
NaL
) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca
2+
cycling and contractility. These alterations increase force development and passive tension. Inhibition of
I
NaL
shortens the AP and corrects dynamics of Ca
2+
transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus,
I
NaL
offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
The aging myopathy is characterized by diastolic dysfunction of unknown aetiology. Rota
et al
. show that increased late Na
+
current (
I
NaL
) underlies diastolic dysfunction in the aged heart, and that inhibiting
I
NaL
improves diastolic indices and corrects the kinetics of cardiomyocyte contraction and relaxation in aged mice. |
| doi_str_mv | 10.1038/ncomms9803 |
| format | Article |
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+
current (
I
NaL
) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca
2+
cycling and contractility. These alterations increase force development and passive tension. Inhibition of
I
NaL
shortens the AP and corrects dynamics of Ca
2+
transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus,
I
NaL
offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
The aging myopathy is characterized by diastolic dysfunction of unknown aetiology. Rota
et al
. show that increased late Na
+
current (
I
NaL
) underlies diastolic dysfunction in the aged heart, and that inhibiting
I
NaL
improves diastolic indices and corrects the kinetics of cardiomyocyte contraction and relaxation in aged mice.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms9803</identifier><identifier>PMID: 26541940</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 14/34 ; 14/63 ; 631/443/592/75 ; 631/443/7 ; 631/80/86 ; 692/308 ; 9/74 ; Action Potentials ; Age ; Aging ; Aging - metabolism ; Animals ; Blood pressure ; Calcium - metabolism ; Cardiomyocytes ; Cardiomyopathies - metabolism ; Cardiomyopathies - physiopathology ; Collagen ; Disease Models, Animal ; Ejection fraction ; Etiology ; Heart - physiopathology ; Heart failure ; Heart Ventricles - metabolism ; Heart Ventricles - physiopathology ; Humanities and Social Sciences ; Mice ; Mice, Knockout ; multidisciplinary ; Myocardial Contraction ; Myocardium - metabolism ; Myocytes, Cardiac - metabolism ; Older people ; Patch-Clamp Techniques ; Physiology ; Sarcoplasmic Reticulum - metabolism ; Science ; Science (multidisciplinary) ; Sodium - metabolism ; Voltage-Gated Sodium Channel beta-1 Subunit - genetics ; Voltage-Gated Sodium Channel beta-1 Subunit - metabolism</subject><ispartof>Nature communications, 2015-11, Vol.6 (1), p.8803-8803, Article 8803</ispartof><rights>The Author(s) 2015</rights><rights>Copyright Nature Publishing Group Nov 2015</rights><rights>Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-bab1f0cb17187500b7bd404131c270343f9256ccf059d895577efbb77a7d1123</citedby><cites>FETCH-LOGICAL-c508t-bab1f0cb17187500b7bd404131c270343f9256ccf059d895577efbb77a7d1123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638135/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638135/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51555,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26541940$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Signore, Sergio</creatorcontrib><creatorcontrib>Sorrentino, Andrea</creatorcontrib><creatorcontrib>Borghetti, Giulia</creatorcontrib><creatorcontrib>Cannata, Antonio</creatorcontrib><creatorcontrib>Meo, Marianna</creatorcontrib><creatorcontrib>Zhou, Yu</creatorcontrib><creatorcontrib>Kannappan, Ramaswamy</creatorcontrib><creatorcontrib>Pasqualini, Francesco</creatorcontrib><creatorcontrib>O'Malley, Heather</creatorcontrib><creatorcontrib>Sundman, Mark</creatorcontrib><creatorcontrib>Tsigkas, Nikolaos</creatorcontrib><creatorcontrib>Zhang, Eric</creatorcontrib><creatorcontrib>Arranto, Christian</creatorcontrib><creatorcontrib>Mangiaracina, Chiara</creatorcontrib><creatorcontrib>Isobe, Kazuya</creatorcontrib><creatorcontrib>Sena, Brena F.</creatorcontrib><creatorcontrib>Kim, Junghyun</creatorcontrib><creatorcontrib>Goichberg, Polina</creatorcontrib><creatorcontrib>Nahrendorf, Matthias</creatorcontrib><creatorcontrib>Isom, Lori L.</creatorcontrib><creatorcontrib>Leri, Annarosa</creatorcontrib><creatorcontrib>Anversa, Piero</creatorcontrib><creatorcontrib>Rota, Marcello</creatorcontrib><title>Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na
+
current (
I
NaL
) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca
2+
cycling and contractility. These alterations increase force development and passive tension. Inhibition of
I
NaL
shortens the AP and corrects dynamics of Ca
2+
transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus,
I
NaL
offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
The aging myopathy is characterized by diastolic dysfunction of unknown aetiology. Rota
et al
. show that increased late Na
+
current (
I
NaL
) underlies diastolic dysfunction in the aged heart, and that inhibiting
I
NaL
improves diastolic indices and corrects the kinetics of cardiomyocyte contraction and relaxation in aged mice.</description><subject>13/1</subject><subject>14/34</subject><subject>14/63</subject><subject>631/443/592/75</subject><subject>631/443/7</subject><subject>631/80/86</subject><subject>692/308</subject><subject>9/74</subject><subject>Action Potentials</subject><subject>Age</subject><subject>Aging</subject><subject>Aging - metabolism</subject><subject>Animals</subject><subject>Blood pressure</subject><subject>Calcium - metabolism</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathies - metabolism</subject><subject>Cardiomyopathies - physiopathology</subject><subject>Collagen</subject><subject>Disease Models, Animal</subject><subject>Ejection fraction</subject><subject>Etiology</subject><subject>Heart - physiopathology</subject><subject>Heart failure</subject><subject>Heart Ventricles - metabolism</subject><subject>Heart Ventricles - physiopathology</subject><subject>Humanities and Social Sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>multidisciplinary</subject><subject>Myocardial Contraction</subject><subject>Myocardium - metabolism</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Older people</subject><subject>Patch-Clamp Techniques</subject><subject>Physiology</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Sodium - metabolism</subject><subject>Voltage-Gated Sodium Channel beta-1 Subunit - genetics</subject><subject>Voltage-Gated Sodium Channel beta-1 Subunit - metabolism</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkUFLJDEQhYOsqKgXf4AEvCzKaNJJJt2XBZHVFQa9eA_pdPVMS3cyVtLC_HszO-qOay4JqY9X7_EIOeHskjNRXnkXhiFWJRM75KBgkk-4LsSPrfc-OY7xmeUjKl5KuUf2i6mSvJLsgLiZTUAf7AV1IyL4RK1v6BJDQusSNBR6cAk7Z3uK4MIr4IpaBOqwS39_G0iAQ-etT5GGlqYFUDvv_JwOq7C0abE6Irut7SMcv9-H5On299PNn8ns8e7-5no2cYqVaVLbmrfM1VzzUivGal03MocQ3BWaCSnaqlBT51qmqqaslNIa2rrW2uqG80Ickl8b2eVYD9C4HAZtb5bYDRZXJtjOfJ34bmHm4dXIqSi5UFng57sAhpcRYjJDFx30vfUQxmi4FlyXQqkqo2f_oc9hRJ_TrSk21UrKtaPzDeUwxIjQfprhzKzbM__ay_Dptv1P9KOrDFxsgJhHfg64tfO73BuvlqXz</recordid><startdate>20151106</startdate><enddate>20151106</enddate><creator>Signore, Sergio</creator><creator>Sorrentino, Andrea</creator><creator>Borghetti, Giulia</creator><creator>Cannata, Antonio</creator><creator>Meo, Marianna</creator><creator>Zhou, Yu</creator><creator>Kannappan, Ramaswamy</creator><creator>Pasqualini, Francesco</creator><creator>O'Malley, Heather</creator><creator>Sundman, Mark</creator><creator>Tsigkas, Nikolaos</creator><creator>Zhang, Eric</creator><creator>Arranto, Christian</creator><creator>Mangiaracina, Chiara</creator><creator>Isobe, Kazuya</creator><creator>Sena, Brena F.</creator><creator>Kim, Junghyun</creator><creator>Goichberg, Polina</creator><creator>Nahrendorf, Matthias</creator><creator>Isom, Lori L.</creator><creator>Leri, Annarosa</creator><creator>Anversa, Piero</creator><creator>Rota, Marcello</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><general>Nature Pub. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Signore, Sergio</au><au>Sorrentino, Andrea</au><au>Borghetti, Giulia</au><au>Cannata, Antonio</au><au>Meo, Marianna</au><au>Zhou, Yu</au><au>Kannappan, Ramaswamy</au><au>Pasqualini, Francesco</au><au>O'Malley, Heather</au><au>Sundman, Mark</au><au>Tsigkas, Nikolaos</au><au>Zhang, Eric</au><au>Arranto, Christian</au><au>Mangiaracina, Chiara</au><au>Isobe, Kazuya</au><au>Sena, Brena F.</au><au>Kim, Junghyun</au><au>Goichberg, Polina</au><au>Nahrendorf, Matthias</au><au>Isom, Lori L.</au><au>Leri, Annarosa</au><au>Anversa, Piero</au><au>Rota, Marcello</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2015-11-06</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>8803</spage><epage>8803</epage><pages>8803-8803</pages><artnum>8803</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na
+
current (
I
NaL
) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca
2+
cycling and contractility. These alterations increase force development and passive tension. Inhibition of
I
NaL
shortens the AP and corrects dynamics of Ca
2+
transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus,
I
NaL
offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
The aging myopathy is characterized by diastolic dysfunction of unknown aetiology. Rota
et al
. show that increased late Na
+
current (
I
NaL
) underlies diastolic dysfunction in the aged heart, and that inhibiting
I
NaL
improves diastolic indices and corrects the kinetics of cardiomyocyte contraction and relaxation in aged mice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26541940</pmid><doi>10.1038/ncomms9803</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2041-1723 |
| ispartof | Nature communications, 2015-11, Vol.6 (1), p.8803-8803, Article 8803 |
| issn | 2041-1723 2041-1723 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4638135 |
| source | Open Access: PubMed Central; Nature Open Access; SpringerOpen; MEDLINE; DOAJ Directory of Open Access Journals; Alma/SFX Local Collection; EZB Electronic Journals Library |
| subjects | 13/1 14/34 14/63 631/443/592/75 631/443/7 631/80/86 692/308 9/74 Action Potentials Age Aging Aging - metabolism Animals Blood pressure Calcium - metabolism Cardiomyocytes Cardiomyopathies - metabolism Cardiomyopathies - physiopathology Collagen Disease Models, Animal Ejection fraction Etiology Heart - physiopathology Heart failure Heart Ventricles - metabolism Heart Ventricles - physiopathology Humanities and Social Sciences Mice Mice, Knockout multidisciplinary Myocardial Contraction Myocardium - metabolism Myocytes, Cardiac - metabolism Older people Patch-Clamp Techniques Physiology Sarcoplasmic Reticulum - metabolism Science Science (multidisciplinary) Sodium - metabolism Voltage-Gated Sodium Channel beta-1 Subunit - genetics Voltage-Gated Sodium Channel beta-1 Subunit - metabolism |
| title | Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T14%3A45%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Late%20Na+%20current%20and%20protracted%20electrical%20recovery%20are%20critical%20determinants%20of%20the%20aging%20myopathy&rft.jtitle=Nature%20communications&rft.au=Signore,%20Sergio&rft.date=2015-11-06&rft.volume=6&rft.issue=1&rft.spage=8803&rft.epage=8803&rft.pages=8803-8803&rft.artnum=8803&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/ncomms9803&rft_dat=%3Cproquest_pubme%3E3858302671%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1730675442&rft_id=info:pmid/26541940&rfr_iscdi=true |