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.
A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration
A. Paul's present address is Novartis Institutes for BioMedical Research, Musculoskeletal Diseases, 100 Technology Square, Cambridge, MA 02139.
Abbreviations used in this paper: Cn, calcineurin; CnA, calcineurin A; CnAα* and CnAβ*, artificially truncated forms of CnAα and CnAβ2 lacking the autoinhibitory domain; CnB, calcineurin B; CsA, cyclosporine A; FoxO, Forkhead box O; IGF-1, insulin-like growth factor 1; NFAT, nuclear factor of activated T cells.
Enrique Lara-Pezzi, Nadine Winn, Angelika Paul, Karl McCullagh, Esfir Slominsky, Maria Paola Santini, Foteini Mourkioti, Padmini Sarathchandra, Satsuki Fukushima, Ken Suzuki, Nadia Rosenthal; A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration . J Cell Biol 17 December 2007; 179 (6): 1205–1218. doi: https://doi.org/10.1083/jcb.200704179
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