Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice

Autores
Zhang, Tan; Pereyra, Andrea Soledad; Wang, Zhong Min; Birbrair, Alexander; Reisz, Julie A.; Files, Daniel Clark; Purcell, Lina; Feng, Xin; Messi, Maria L.; Feng, Hanzhong; Chalovich, Joseph; Jin, Jian Ping; Furdui, Cristina; Delbono, Osvaldo
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.
Fil: Zhang, Tan. Wake Forest School of Medicine; Estados Unidos
Fil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina
Fil: Wang, Zhong Min. Wake Forest School of Medicine; Estados Unidos
Fil: Birbrair, Alexander. Wake Forest School of Medicine; Estados Unidos
Fil: Reisz, Julie A.. Wake Forest School of Medicine; Estados Unidos
Fil: Files, Daniel Clark. Wake Forest School of Medicine; Estados Unidos
Fil: Purcell, Lina. Wake Forest School of Medicine; Estados Unidos
Fil: Feng, Xin. Wake Forest School of Medicine; Estados Unidos
Fil: Messi, Maria L.. Wake Forest School of Medicine; Estados Unidos
Fil: Feng, Hanzhong. Wayne State University School of Medicine; Estados Unidos
Fil: Chalovich, Joseph. East Carolina University; Estados Unidos
Fil: Jin, Jian Ping. Wayne State University School of Medicine; Estados Unidos
Fil: Furdui, Cristina. Wake Forest School of Medicine; Estados Unidos
Fil: Delbono, Osvaldo. Wake Forest School of Medicine; Estados Unidos
Materia
AGING
CALCIUM CHANNEL
CALPAIN
EXCITATION-CONTRACTION COUPLING
SKELETAL MUSCLE
TROPONIN T
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/48887
Acceder
id CONICETDig_026875b324703d78716dd5f125a353bd
oai_identifier_str oai:ri.conicet.gov.ar:11336/48887
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary miceZhang, TanPereyra, Andrea SoledadWang, Zhong MinBirbrair, AlexanderReisz, Julie A.Files, Daniel ClarkPurcell, LinaFeng, XinMessi, Maria L.Feng, HanzhongChalovich, JosephJin, Jian PingFurdui, CristinaDelbono, OsvaldoAGINGCALCIUM CHANNELCALPAINEXCITATION-CONTRACTION COUPLINGSKELETAL MUSCLETROPONIN Thttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.Fil: Zhang, Tan. Wake Forest School of Medicine; Estados UnidosFil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; ArgentinaFil: Wang, Zhong Min. Wake Forest School of Medicine; Estados UnidosFil: Birbrair, Alexander. Wake Forest School of Medicine; Estados UnidosFil: Reisz, Julie A.. Wake Forest School of Medicine; Estados UnidosFil: Files, Daniel Clark. Wake Forest School of Medicine; Estados UnidosFil: Purcell, Lina. Wake Forest School of Medicine; Estados UnidosFil: Feng, Xin. Wake Forest School of Medicine; Estados UnidosFil: Messi, Maria L.. Wake Forest School of Medicine; Estados UnidosFil: Feng, Hanzhong. Wayne State University School of Medicine; Estados UnidosFil: Chalovich, Joseph. East Carolina University; Estados UnidosFil: Jin, Jian Ping. Wayne State University School of Medicine; Estados UnidosFil: Furdui, Cristina. Wake Forest School of Medicine; Estados UnidosFil: Delbono, Osvaldo. Wake Forest School of Medicine; Estados UnidosWiley Blackwell Publishing, Inc2016-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/48887Zhang, Tan; Pereyra, Andrea Soledad; Wang, Zhong Min; Birbrair, Alexander; Reisz, Julie A.; et al.; Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice; Wiley Blackwell Publishing, Inc; Aging Cell; 15; 3; 6-2016; 488-4981474-9718CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/acel.12453/fullinfo:eu-repo/semantics/altIdentifier/doi/10.1111/acel.12453info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:02:26Zoai:ri.conicet.gov.ar:11336/48887instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:02:26.619CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
title Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
spellingShingle Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
Zhang, Tan
AGING
CALCIUM CHANNEL
CALPAIN
EXCITATION-CONTRACTION COUPLING
SKELETAL MUSCLE
TROPONIN T
title_short Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
title_full Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
title_fullStr Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
title_full_unstemmed Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
title_sort Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
dc.creator.none.fl_str_mv Zhang, Tan
Pereyra, Andrea Soledad
Wang, Zhong Min
Birbrair, Alexander
Reisz, Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Maria L.
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian Ping
Furdui, Cristina
Delbono, Osvaldo
author Zhang, Tan
author_facet Zhang, Tan
Pereyra, Andrea Soledad
Wang, Zhong Min
Birbrair, Alexander
Reisz, Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Maria L.
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian Ping
Furdui, Cristina
Delbono, Osvaldo
author_role author
author2 Pereyra, Andrea Soledad
Wang, Zhong Min
Birbrair, Alexander
Reisz, Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Maria L.
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian Ping
Furdui, Cristina
Delbono, Osvaldo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AGING
CALCIUM CHANNEL
CALPAIN
EXCITATION-CONTRACTION COUPLING
SKELETAL MUSCLE
TROPONIN T
topic AGING
CALCIUM CHANNEL
CALPAIN
EXCITATION-CONTRACTION COUPLING
SKELETAL MUSCLE
TROPONIN T
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.
Fil: Zhang, Tan. Wake Forest School of Medicine; Estados Unidos
Fil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina
Fil: Wang, Zhong Min. Wake Forest School of Medicine; Estados Unidos
Fil: Birbrair, Alexander. Wake Forest School of Medicine; Estados Unidos
Fil: Reisz, Julie A.. Wake Forest School of Medicine; Estados Unidos
Fil: Files, Daniel Clark. Wake Forest School of Medicine; Estados Unidos
Fil: Purcell, Lina. Wake Forest School of Medicine; Estados Unidos
Fil: Feng, Xin. Wake Forest School of Medicine; Estados Unidos
Fil: Messi, Maria L.. Wake Forest School of Medicine; Estados Unidos
Fil: Feng, Hanzhong. Wayne State University School of Medicine; Estados Unidos
Fil: Chalovich, Joseph. East Carolina University; Estados Unidos
Fil: Jin, Jian Ping. Wayne State University School of Medicine; Estados Unidos
Fil: Furdui, Cristina. Wake Forest School of Medicine; Estados Unidos
Fil: Delbono, Osvaldo. Wake Forest School of Medicine; Estados Unidos
description Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca2+ channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.
publishDate 2016
dc.date.none.fl_str_mv 2016-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/48887
Zhang, Tan; Pereyra, Andrea Soledad; Wang, Zhong Min; Birbrair, Alexander; Reisz, Julie A.; et al.; Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice; Wiley Blackwell Publishing, Inc; Aging Cell; 15; 3; 6-2016; 488-498
1474-9718
CONICET Digital
CONICET
url http://hdl.handle.net/11336/48887
identifier_str_mv Zhang, Tan; Pereyra, Andrea Soledad; Wang, Zhong Min; Birbrair, Alexander; Reisz, Julie A.; et al.; Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice; Wiley Blackwell Publishing, Inc; Aging Cell; 15; 3; 6-2016; 488-498
1474-9718
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1111/acel.12453/full
info:eu-repo/semantics/altIdentifier/doi/10.1111/acel.12453
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269755266826240
score 13.13397

Publicaciones similares