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 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.
Lara-Pezzi
Enrique
E
European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Campus Buzzatti-Traverso, Monterotondo-Scalo, 00016 Rome, Italy.
Winn
Nadine
N
Paul
Angelika
A
McCullagh
Karl
K
Slominsky
Esfir
E
Santini
Maria Paola
MP
Mourkioti
Foteini
F
Sarathchandra
Padmini
P
Fukushima
Satsuki
S
Suzuki
Ken
K
Rosenthal
Nadia
N
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
D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D021122:Protein Subunits; D019703:Calcineurin