Characterization of M-cadherin's Role in Regulating Apoptosis and Myogenic Differentiation of Myoblasts by Interacting with Key Components of Canonical Wnt Signaling
Bibliographic record
Abstract
Activation, proliferation, and differentiation of satellite cells are the basic means for adult muscle regeneration. Apoptosis is concurrent to differentiation of satellite cells and dysregulated apoptosis contributes to the occurrence and progression of certain muscular dystrophies. This study investigated the role of M-cadherin-mediated signaling in regulating apoptosis versus survival of myoblasts during the process of myogenic differentiation. Inhibition of M-cadherin expression by RNAi (RNA interference) in confluent C2C12 myoblasts sensitized the cells to mitochondria-associated intrinsic apoptosis induced by either cell confluence or serum starvation. Manipulation of M-cadherin signaling regulated the Glycogen Synthase Kinase-3beta (GSK-3beta) activity via phosphoinositide-3 kinase (PI3K)/Akt pathway. Overexpession of wild-type (WT) GSK-3beta in confluent C2C12 myoblasts sensitized the cells to apoptotic insults, while GSK-3beta inhibition attenuated apoptosis and partially rescued the myogenic differentiation impaired by M-cadherin RNAi in both C2C12 myoblasts and Syndecan-4-positive primary myoblasts. These data suggest that M-cadherin-mediated signaling protects myoblasts against mitochondria-associated intrinsic apoptosis during myogenic differentiation via PI3K/Akt/GSK-3beta pathway. We further examined the role of M-cadherin in regulating the N-terminal phosphorylation status of beta-catenin and the effect of this regulation on myoblast fate specification. M-cadherin RNAi enhanced the GSK- 3beta-dependent phosphorylation of beta-catenin at N-terminus which can be reversed by GSK-3beta inhibition via LiCl treatment. N-terminus unphosphorylated beta-catenin was more responsive to LiCl treatment. In addition, M-cadherin RNAi led to an increase in TCF/LEF transcription activity but significantly abrogated the myogenic differentiation induced by LiCl or Wnt-3a treatment. beta-catenin RNAi also blocked the myogenic induction by LiCl or Wnt-3a. Although forced expression of a phosphorylation-resistant mutated beta-catenin (S33Y-beta-catenin) failed to increase myogenic differentiation, it partially rescued the impaired myogenic differentiation and attenuated the apoptosis caused by M-cadherin RNAi. These data indicate that M-cadherin-mediated signaling plays a positive role in maintaining a cytosolic pool of signaling-active N-terminal unphosphorylated beta-catenin, which is critical for the TCF/LEF-independent myogenesis-promoting effect of canonical Wnt signaling. Our findings in this research identify a novel role of M-cadherin in regulating myoblasts survival and differentiation and provide a potentially novel molecular mechanism for the regulation of adult muscle regeneration.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".