Tsg101 positively regulates physiologic‐like cardiac hypertrophy through FIP3‐mediated endosomal recycling of IGF‐1R
Bibliographic record
Abstract
ABSTRACT Development of physiologic cardiac hypertrophy has primarily been ascribed to the IGF‐1 and its receptor, IGF‐1 receptor (IGF‐1R), and subsequent activation of the protein kinase B (Akt) pathway. However, regulation of endosome‐mediated recycling and degradation of IGF‐1R during physiologic hypertrophy has not been investigated. In a physiologic hypertrophy model of treadmill‐exercised mice, we observed that levels of tumor susceptibility gene 101 (Tsg101), a key member of the endosomal sorting complex required for transport, were dramatically elevated in the heart compared with sedentary controls. To determine the role of Tsg101 on physiologic hypertrophy, we generated a transgenic (TG) mouse model with cardiac‐specific overexpression of Tsg101. These TG mice exhibited a physiologic‐like cardiac hypertrophy phenotype at 8 wk evidenced by: 1 ) the absence of cardiac fibrosis, 2 ) significant improvement of cardiac function, and 3 ) increased total and plasma membrane levels of IGF‐1R and increased phosphorylation of Akt. Mechanistically, we identified that Tsg101 interacted with family‐interacting protein 3 (FIP3) and IGF‐1R, thereby stabilizing FIP3 and enhancing recycling of IGF‐1R. In vitro , adenovirus‐mediated overexpression of Tsg101 in neonatal rat cardiomyocytes resulted in cell hypertrophy, which was blocked by addition of monensin, an inhibitor of endosome‐mediated recycling, and by small interfering RNA—mediated knockdown (KD) of FIP3. Furthermore, cardiac‐specific KD of Tsg101 showed a significant reduction in levels of endosomal recycling compartment members (Rabila and FIP3), IGF‐1R, and Akt phosphorylation. Most interestingly, Tsg101‐KD mice failed to develop cardiac hypertrophy after intense treadmill training. Taken together, our data identify Tsg101 as a novel positive regulator of physiologic cardiac hypertrophy through facilitating the FIP3‐mediated endosomal recycling of IGF‐1R.—Essandoh, K., Deng, S., Wang, X., Jiang, M., Mu, X., Peng, J., Li, Y., Peng, T., Wagner, K.‐U., Rubinstein, J., Fan, G.‐C. Tsg101 positively regulates physiologic‐like cardiac hypertrophy through FIP3‐mediated endosomal recycling of IGF‐1R. FASEB J. 33, 7451–7466 (2019). www.fasebj.org
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".