Kynurenine Metabolism in the D2 <i>mdx</i> Mouse: A Muscle‐to‐Brain Connection
Bibliographic record
Abstract
Introduction The kynurenine (KYN) pathway has been implicated in depression and neurotoxicity. Derived from tryptophan, KYN can be further degraded along one of two distinct branches. The KYN‐KYNA branch is regulated by the enzyme kynurenine aminotransferase (KAT) and is considered neuroprotective, as it degrades KYN into the non‐blood brain barrier (BBB) transportable metabolite kynurenic acid (KYNA). The KYN‐NAD branch is regulated by the enzyme kynurenine monooxygenase (KMO) and is considered neurotoxic as it degrades KYN into the BBB transportable metabolite 3‐hydroxykynurenine (3‐HK) and, further in the cascade, quinolinic acid (QUIN). Recent studies have shown the importance of muscle health on directing kynurenine metabolism towards the neuroprotective branch, highlighting a novel muscle‐to‐brain axis. Specifically, exercise induced increases in the transcription factor PCG‐1⍺ amplifies the content of KAT enzymes that convert KYNA from KYN. Duchenne muscular dystrophy (DMD) is an X‐linked severe muscle disorder caused by a loss of dystrophin leading to muscle fragility, wasting, and weakness. In light of recent evidence revealing the cognitive and depressive behaviours in DMD patients and in the preclinical mdx mouse, we sought to determine whether KYN metabolism as well as PGC‐1α and KAT content would be altered in the mdx model. Methods 8‐10 week old male mdx and wild‐type (DBA/2J) mice were purchased from Jackson laboratories. Behavioural changes (ie., grooming activity, food and water intake) were measured using a Promethion metabolic cage system along with fear and anxiety‐like behaviour during a novel object recognition test (NORT). Mice were euthanized and serum KYN and KYNA were measured using commercially available ELISA kits. Extensor digitorum longus muscle was collected, homogenized, and Western blotting was performed for PGC‐1⍺, KAT1, and KAT3. Results Metabolic cage results showed that fine activity (‐5%), water intake (‐25%), and food intake (‐60%) were lower across light and dark stages in mdx mice compared to WT mice (main effect of genotype, p <0.0001 for all measures). The mdx mice also spent more time in the corners of the NORT arenas compared to their WT counterparts (+270s, p <0.0001). Though the change in serum KYN was insignificant across mdx and WT mice, the concentration of serum KYNA was lower in the mdx mice (‐57%, p = 0.01), therefore causing a lower KYN:KYNA ratio in mdx mice compared with WT (‐56%, p = 0.01). Western blotting demonstrated a reduction in PGC‐1⍺ (‐65%, p = 0.002) and KAT1 (‐35%, p = 0.02) content in mdx mice compared to WT mice, whereas the KAT3 content was elevated in mdx mice (1.5‐fold, p = 0.05). Conclusion Our results of lowered serum KYN:KYNA concentrations from mdx mice (compared to WT) correspond well with changes in affective and anxiety‐related behaviours. The observed reduction in muscle PGC‐1⍺ and KAT1 content likely contributes to these changes in KYN:KYNA ratio. Though KAT3 was upregulated in mdx muscle compared to WT, this could represent a failed compensatory response.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
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".