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

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. St...

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Detalles Bibliográficos
Autores principales: Zhang, Tan, Pereyra, Andrea Soledad, Wang, Zhong-Min, Birbrair, Alexander, Reisz, † Julie A., Files, Daniel Clark, Purcell, Lina, Feng, Xin, Messi, Lina, Feng, Hanzhong, Chalovich, Joseph, Jin, Jian-Ping, Furdui, Cristina, Delbono, Osvaldo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2016
Materias:
Ciencias Médicas
Aging
Calcium channel
Calpain
Excitation-contraction coupling
Skeletal muscle
Troponin T
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/85773
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-85773
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
Aging
Calcium channel
Calpain
Excitation-contraction coupling
Skeletal muscle
Troponin T
spellingShingle Ciencias Médicas
Aging
Calcium channel
Calpain
Excitation-contraction coupling
Skeletal muscle
Troponin T
Zhang, Tan
Pereyra, Andrea Soledad
Wang, Zhong-Min
Birbrair, Alexander
Reisz, † Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Lina
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian-Ping
Furdui, Cristina
Delbono, Osvaldo
Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
topic_facet Ciencias Médicas
Aging
Calcium channel
Calpain
Excitation-contraction coupling
Skeletal muscle
Troponin T
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.
format Articulo
Articulo
author Zhang, Tan
Pereyra, Andrea Soledad
Wang, Zhong-Min
Birbrair, Alexander
Reisz, † Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Lina
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian-Ping
Furdui, Cristina
Delbono, Osvaldo
author_facet Zhang, Tan
Pereyra, Andrea Soledad
Wang, Zhong-Min
Birbrair, Alexander
Reisz, † Julie A.
Files, Daniel Clark
Purcell, Lina
Feng, Xin
Messi, Lina
Feng, Hanzhong
Chalovich, Joseph
Jin, Jian-Ping
Furdui, Cristina
Delbono, Osvaldo
author_sort Zhang, Tan
title Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice
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
publishDate 2016
url http://sedici.unlp.edu.ar/handle/10915/85773
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