Skeletal Muscle Regeneration Impairment in Type 1 Diabetes Mellitus is Characterized by Dysregulated Sphingosine‐1‐Phosphate and Ceramide‐1‐Phosphate Responses
Bibliographic record
Abstract
Type 1 diabetes mellitus (T1DM) impairs regenerative capacity of skeletal muscle, one of several aspects of diabetic myopathy. It was hypothesized that accumulation of lipid species within the muscle (lipotoxicity) could cause this impairment. Although it has been demonstrated that diabetes causes increased lipid deposition in skeletal muscle, the muscle lipid response following tissue damage has not been investigated. To assess the effect of T1DM on lipid deposition in regenerating skeletal muscle, wild‐type (WT) and T1DM (Akita) mice (n=5) received cardiotoxin (CTX) injections into the left tibialis anterior (TA). TAs were collected at 5‐days post‐CTX and subsequently cryosectioned and stained with BODIPY 493/503 to visualize lipids. Microscope images were analyzed for proportion of area positive for lipid via thresholding. Injured Akita muscle was found to have more total lipid as compared to uninjured (control) Akita, and both injured and control WT muscle ( p <0.05). Next, we assessed individual lipid species via liquid chromatography‐mass spectrometry across a broader time‐course of muscle regeneration. Here, 22 WT and 21 Akita mice received CTX injections into the quadriceps which were harvested and frozen at 1, 3, 5, and 7 days post‐CTX (n=4‐6). 45 lipid species were analyzed via liquid chromatography‐mass spectrometry, including sphingosine‐1‐phosphate, a critical sphingolipid for stimulating satellite cell activity. Injured quadriceps were found to have significantly elevated concentrations of S1P as compared to control particularly at 5 days post‐CTX ( p <0.05), however this response was blunted in the Akita quadriceps. No differences were found between groups in concentration of the precursors of S1P (d18:1), sphingomyelin (d18:1/12:0; d18:1/14:0; d18:1/16:0; d18:1/17:0; d18:1/18:0), sphinganine (d18:0; d18:1; d18:2; d20:0), dihydroceramide (d18:0/16:0; d18:0/18:1 9Z; d18:0/24:0; d18:0/22:0; d18:0/22:6), ceramide (d18:1/16:0; d18:1/18:1; d18:1/20:0; d18:1/22:0; d18:1/24:0; d18:1/24:1) and sphingosine (d18:1), suggesting that low S1P in regenerating Akita muscle could be due to dysregulation of its regulating enzymes, sphingosine kinase (SpK1) and sphingosine lyase (SL). Elevated SL expression was found in Akita injured muscle ( p <0.05) while no changes were found in SpK1 expression or associated ERK1/2 signalling, suggesting that S1P breakdown is increased in T1DM. Ceramide‐1‐phosphate (C1P; d18:1, 16:0) was significantly elevated in Akita compared to WT muscle, peaking at 5 days post‐CTX ( p <0.05). The role of C1P in muscle regeneration is unknown. Taken together, these data indicate that at early time points, muscle regeneration is impaired in T1DM due to accelerated S1P breakdown while other lipid species such as C1P may play a role.
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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) | 0.001 | 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 | 0.001 |
| 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".