A naturally occurring calcineurin variant inhibits FoxO activity and enhances skeletal muscle regeneration
| Autor: | Nadia Rosenthal, Foteini Mourkioti, Maria Paola Santini, Padmini Sarathchandra, Ken Suzuki, Esfir Slominsky, Nadine Winn, Satsuki Fukushima, Karl J. A. McCullagh, Angelika Christina Paul, Enrique Lara-Pezzi |
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| Rok vydání: | 2007 |
| Předmět: |
Cellular differentiation
Transgene Myoblasts Skeletal Molecular Sequence Data Mice Transgenic Biology ATROPHY Article Cell Line PATHWAY Enzyme activator Mice KINASE medicine Myocyte Animals Humans Protein Isoforms Regeneration Amino Acid Sequence CARDIAC-HYPERTROPHY PHOSPHORYLATION Muscle Skeletal 11 Medical and Health Sciences Research Articles GENE-EXPRESSION Cell Proliferation FACTOR FKHRL1 Gene knockdown Science & Technology Calcineurin Skeletal muscle NFAT Cell Differentiation Forkhead Transcription Factors Cell Biology 06 Biological Sciences INSULIN Molecular biology Rats Protein Subunits medicine.anatomical_structure TRANSCRIPTION FACTORS INDUCE GROWTH Life Sciences & Biomedicine Developmental Biology |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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