Caspase 3 Activity Is Required for Skeletal Muscle Differentiation

The cellular alterations associated with skeletal muscle differentiation share a high degree of similarity with key phenotypic changes usually ascribed to apoptosis. For example, actin fiber disassembly/reorganization is a conserved feature of both apoptosis and differentiating myoblasts and the con...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-08, Vol.99 (17), p.11025-11030
Main Authors: Fernando, Pasan, Kelly, John F., Balazsi, Kim, Slack, Ruth S., Megeney, Lynn A.
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Apoptosis
Biochemistry
Biological Sciences
Caspase 3
Caspases - metabolism
Cell cycle
Cell Differentiation
Cells
Cells, Cultured
Cellular differentiation
Enzyme Activation
Enzymes
Hepatocytes
Histones
Humans
Muscle development
Muscle fibers
Muscle, Skeletal - cytology
Muscle, Skeletal - enzymology
Muscular system
Myoblasts
Open Reading Frames
Phenotype
Protein Biosynthesis
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Recombinant Proteins - metabolism
Skeletal muscle
T lymphocytes
Transfection
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Summary:The cellular alterations associated with skeletal muscle differentiation share a high degree of similarity with key phenotypic changes usually ascribed to apoptosis. For example, actin fiber disassembly/reorganization is a conserved feature of both apoptosis and differentiating myoblasts and the conserved muscle contractile protein, myosin light chain kinase, is required for the apoptotic feature of membrane blebbing. As such, these observations suggest that the induction of differentiation and apoptosis in the myogenic lineage may use overlapping cellular mechanisms. Here, we report that skeletal muscle differentiation depends on the activity of the key apoptotic protease, caspase 3. Peptide inhibition of caspase 3 activity or homologous deletion of caspase 3 leads to dramatic reduction in both myotube/myofiber formation and expression of muscle-specific proteins. Subsequently, we have identified Mammalian Sterile Twenty-like kinase as a crucial caspase 3 effector in this cellular process. Mammalian Sterile Twenty-like kinase is cleavage-activated by caspase 3, and restoration of this truncated kinase in caspase 3 null myoblasts restores the differentiation phenotype. Taken together, these results confirm a unique and unanticipated role for a caspase 3-mediated signal cascade in the promotion of myogenesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.162172899