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A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration

The calcium-activated phosphatase calcineurin (Cn) transduces physiological signals through intracellular pathways to influence the expression of specific genes. Here, we characterize a naturally occurring splicing variant of the CnAβ catalytic subunit (CnAβ1) in which the autoinhibitory domain that...

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Detalles Bibliográficos
Autores principales: Lara-Pezzi, Enrique, Winn, Nadine, Paul, Angelika, McCullagh, Karl, Slominsky, Esfir, Santini, Maria Paola, Mourkioti, Foteini, Sarathchandra, Padmini, Fukushima, Satsuki, Suzuki, Ken, Rosenthal, Nadia
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2140042/
https://www.ncbi.nlm.nih.gov/pubmed/18086917
http://dx.doi.org/10.1083/jcb.200704179
Descripción
Sumario:The calcium-activated phosphatase calcineurin (Cn) transduces physiological signals through intracellular pathways to influence the expression of specific genes. Here, we characterize a naturally occurring splicing variant of the CnAβ catalytic subunit (CnAβ1) in which the autoinhibitory domain that controls enzyme activation is replaced with a unique C-terminal region. The CnAβ1 enzyme is constitutively active and dephosphorylates its NFAT target in a cyclosporine-resistant manner. CnAβ1 is highly expressed in proliferating myoblasts and regenerating skeletal muscle fibers. In myoblasts, CnAβ1 knockdown activates FoxO-regulated genes, reduces proliferation, and induces myoblast differentiation. Conversely, CnAβ1 overexpression inhibits FoxO and prevents myotube atrophy. Supplemental CnAβ1 transgene expression in skeletal muscle leads to enhanced regeneration, reduced scar formation, and accelerated resolution of inflammation. This unique mode of action distinguishes the CnAβ1 isoform as a candidate for interventional strategies in muscle wasting treatment.