title: A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration.
abstract: 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 CnAbeta catalytic subunit (CnAbeta1) in which the autoinhibitory domain that controls enzyme activation is replaced with a unique C-terminal region. The CnAbeta1 enzyme is constitutively active and dephosphorylates its NFAT target in a cyclosporine-resistant manner. CnAbeta1 is highly expressed in proliferating myoblasts and regenerating skeletal muscle fibers. In myoblasts, CnAbeta1 knockdown activates FoxO-regulated genes, reduces proliferation, and induces myoblast differentiation. Conversely, CnAbeta1 overexpression inhibits FoxO and prevents myotube atrophy. Supplemental CnAbeta1 transgene expression in skeletal muscle leads to enhanced regeneration, reduced scar formation, and accelerated resolution of inflammation. This unique mode of action distinguishes the CnAbeta1 isoform as a candidate for interventional strategies in muscle wasting treatment.
authors: European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Campus Buzzatti-Traverso, Monterotondo-Scalo, 00016 Rome, Italy.
authors: Enrique
authors: E
authors: Lara-Pezzi
authors: Nadine
authors: N
authors: Winn
authors: Angelika
authors: A
authors: Paul
authors: Karl
authors: K
authors: McCullagh
authors: Esfir
authors: E
authors: Slominsky
authors: Maria Paola
authors: MP
authors: Santini
authors: Foteini
authors: F
authors: Mourkioti
authors: Padmini
authors: P
authors: Sarathchandra
authors: Satsuki
authors: S
authors: Fukushima
authors: Ken
authors: K
authors: Suzuki
authors: Nadia
authors: N
authors: Rosenthal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051381:Rats; D012038:Regeneration
chemical_list: D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D021122:Protein Subunits; D019703:Calcineurin