Cargando…

Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts

The heart’s pumping capacity is determined by myofilament power generation. Power is work done per unit time and measured as the product of force and velocity. At a sarcomere level, these contractile properties are linked to the number of attached cross-bridges and their cycling rate, and many signa...

Descripción completa

Detalles Bibliográficos
Autores principales: Hanft, Laurin M., Robinett, Joel C., Kalogeris, Theodore J., Campbell, Kenneth S., Biesiadecki, Brandon J., McDonald, Kerry S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067705/
https://www.ncbi.nlm.nih.gov/pubmed/37000170
http://dx.doi.org/10.1085/jgp.202213290
_version_ 1785018532311859200
author Hanft, Laurin M.
Robinett, Joel C.
Kalogeris, Theodore J.
Campbell, Kenneth S.
Biesiadecki, Brandon J.
McDonald, Kerry S.
author_facet Hanft, Laurin M.
Robinett, Joel C.
Kalogeris, Theodore J.
Campbell, Kenneth S.
Biesiadecki, Brandon J.
McDonald, Kerry S.
author_sort Hanft, Laurin M.
collection PubMed
description The heart’s pumping capacity is determined by myofilament power generation. Power is work done per unit time and measured as the product of force and velocity. At a sarcomere level, these contractile properties are linked to the number of attached cross-bridges and their cycling rate, and many signaling pathways modulate one or both factors. We previously showed that power is increased in rodent permeabilized cardiac myocytes following PKA-mediated phosphorylation of myofibrillar proteins. The current study found that that PKA increased power by ∼30% in permeabilized cardiac myocyte preparations (n = 8) from human failing hearts. To address myofilament molecular specificity of PKA effects, mechanical properties were measured in rat permeabilized slow-twitch skeletal muscle fibers before and after exchange of endogenous slow skeletal troponin with recombinant human Tn complex that contains cardiac (c)TnT, cTnC and either wildtype (WT) cTnI or pseudo-phosphorylated cTnI at sites Ser23/24Asp, Tyr26Glu, or the combinatorial Ser23/24Asp and Tyr26Glu. We found that cTnI Ser23/24Asp, Tyr26Glu, and combinatorial Ser23/24Asp and Tyr26Glu were sufficient to increase power by ∼20%. Next, we determined whether pseudo-phosphorylated cTnI at Ser23/24 was sufficient to increase power in cardiac myocytes from human failing hearts. Following cTn exchange that included cTnI Ser23/24Asp, power output increased ∼20% in permeabilized cardiac myocyte preparations (n = 6) from the left ventricle of human failing hearts. These results implicate cTnI N-terminal phosphorylation as a molecular regulator of myocyte power and could serve as a regional target for small molecule therapy to unmask myocyte power reserve capacity in human failing hearts.
format Online
Article
Text
id pubmed-10067705
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-100677052023-09-30 Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts Hanft, Laurin M. Robinett, Joel C. Kalogeris, Theodore J. Campbell, Kenneth S. Biesiadecki, Brandon J. McDonald, Kerry S. J Gen Physiol Article The heart’s pumping capacity is determined by myofilament power generation. Power is work done per unit time and measured as the product of force and velocity. At a sarcomere level, these contractile properties are linked to the number of attached cross-bridges and their cycling rate, and many signaling pathways modulate one or both factors. We previously showed that power is increased in rodent permeabilized cardiac myocytes following PKA-mediated phosphorylation of myofibrillar proteins. The current study found that that PKA increased power by ∼30% in permeabilized cardiac myocyte preparations (n = 8) from human failing hearts. To address myofilament molecular specificity of PKA effects, mechanical properties were measured in rat permeabilized slow-twitch skeletal muscle fibers before and after exchange of endogenous slow skeletal troponin with recombinant human Tn complex that contains cardiac (c)TnT, cTnC and either wildtype (WT) cTnI or pseudo-phosphorylated cTnI at sites Ser23/24Asp, Tyr26Glu, or the combinatorial Ser23/24Asp and Tyr26Glu. We found that cTnI Ser23/24Asp, Tyr26Glu, and combinatorial Ser23/24Asp and Tyr26Glu were sufficient to increase power by ∼20%. Next, we determined whether pseudo-phosphorylated cTnI at Ser23/24 was sufficient to increase power in cardiac myocytes from human failing hearts. Following cTn exchange that included cTnI Ser23/24Asp, power output increased ∼20% in permeabilized cardiac myocyte preparations (n = 6) from the left ventricle of human failing hearts. These results implicate cTnI N-terminal phosphorylation as a molecular regulator of myocyte power and could serve as a regional target for small molecule therapy to unmask myocyte power reserve capacity in human failing hearts. Rockefeller University Press 2023-03-31 /pmc/articles/PMC10067705/ /pubmed/37000170 http://dx.doi.org/10.1085/jgp.202213290 Text en © 2023 Hanft et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Hanft, Laurin M.
Robinett, Joel C.
Kalogeris, Theodore J.
Campbell, Kenneth S.
Biesiadecki, Brandon J.
McDonald, Kerry S.
Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title_full Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title_fullStr Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title_full_unstemmed Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title_short Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
title_sort thin filament regulation of cardiac muscle power output: implications for targets to improve human failing hearts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10067705/
https://www.ncbi.nlm.nih.gov/pubmed/37000170
http://dx.doi.org/10.1085/jgp.202213290
work_keys_str_mv AT hanftlaurinm thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts
AT robinettjoelc thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts
AT kalogeristheodorej thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts
AT campbellkenneths thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts
AT biesiadeckibrandonj thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts
AT mcdonaldkerrys thinfilamentregulationofcardiacmusclepoweroutputimplicationsfortargetstoimprovehumanfailinghearts