Role of the USP19 deubiquitinating enzyme in the activation of the ubiquitin proteasome system in skeletal muscle upon stimulation with dexamethasone
Bibliographic record
Abstract
Loss of skeletal muscle occurs with muscle disuse, aging, and in many diseases such as sepsis, chronic obstructive pulmonary disease, chronic heart failure, AIDS, cancer and diabetes. The muscle loss results from decreased protein synthesis and increased degradation. The increase in protein degradation is dependent on the activation of the ubiquitin proteasome system (UPS), a pathway in which selected proteins are labeled with ubiquitin that targets them for degradation. Understanding the precise molecular pathways behind muscle wasting is critical for the development of new therapies to prevent or treat the loss of muscle mass and function associated with many diseases. Many studies have revealed roles for ubiquitin ligases in muscle wasting but little is known about the roles of deubiquitinating enzymes. Our laboratory has previously shown that the induction of USP19, a deubiquitinating enzyme, occurs under different conditions of muscle atrophy including fasting, glucocorticoid treatment, muscle denervation and cancer bearing animals. To further evaluate the role of USP19, our laboratory tested the effects of inactivating USP19 in mice in dexamethasone-induced atrophy. Under dexamethasone induced muscle atrophy, USP19 KO mice lost 64% less tibialis anterior muscle mass than WT mice. In addition, the induction of atrophy genes, ubiquitin ligases MuRF1 and atrogin-1 seen in muscles in WT mice was significantly attenuated in the KO mice. Since these mice were deficient in USP19 in all tissues, I tested in this thesis whether USP19 could act directly on muscle cells. I first screened multiple muscle cell lines to identify ones in which dexamethasone could induce expression of atrogenes. To explore whether these muscle protective effects are likely due to the direct action of USP19 in muscles, I tested the effect of silencing USP19 in myotubes exposed to dexamethasone. Our results show that silencing USP19 in L6 myotubes attenuated the induction of atrophy genes, MuRF1 and atrogin-1, by dexamethasone. Another approach to loss of function is testing the effect of dexamethasone in USP19 KO primary myotubes. Primary myoblasts were isolated from tibialis anterior muscle of USP19 KO mice, and myoblasts were induced to differentiate. Our results show that the inactivation of USP19 in the primary culture attenuated the expression of MuRF1 in both basal and dexamethasone treated states, but had no effect on expression of atrogin-1. Taken together, these results indicate that USP19 modulates muscle atrophy in part by a direct action in skeletal muscle and suggest that inhibition of USP19 may be useful for the prevention of glucocorticoid-induced muscle atrophy.
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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 | 0.001 |
| 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 | 0.001 |
| 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".