Investigating the Function of Co‐activator‐associated Arginine Methyltransferase 1 (CARM1) During Denervation‐induced Skeletal Muscle Atrophy
Bibliographic record
Abstract
CARM1 is a type I protein arginine methyltransferase (PRMT) that forms asymmetric dimethylarginines (ADMA) by transferring monomethyl groups to arginine residues on target proteins. We previously observed elevated CARM1 expression and methyltransferase activity in response to neurogenic muscle disuse. Transient knockdown of CARM1 in muscle also represses the progression of muscle wasting and the expression of atrophy‐related genes following denervation. Notably, CARM1 regulates intracellular signaling molecules that are important for atrophy such as AMP‐activated protein kinase (AMPK) and downstream unc‐51 like autophagy activating kinase 1 (ULK1), forkhead box class O (FOXO), and transcription factor EB (TFEB) in non‐muscle tissues. The purpose of this study was to more comprehensively elucidate the function of CARM1 during neurogenic muscle disuse. We employed the Cre/loxP system to generate skeletal muscle‐specific CARM1 knockout (mKO) mice. Following unilateral sectioning of the sciatic nerve, mKO and wild type (WT) mice were subjected to 3 and 7 days of denervation. The contralateral limb served as an internal control. Hematoxylin and eosin staining analyses were performed to assess cross‐sectional area (CSA) in the extensor digitorum longus (EDL) muscle. We also employed Western blot and immunoprecipitation analyses to evaluate protein expression and protein interaction levels, respectively, in the non‐denervated and denervated tibialis anterior muscles. Our CSA analyses revealed that the absence of CARM1 mitigated denervation‐induced atrophy in the EDL muscle after 7 days of disuse (p < 0.05). Compared to WT animals, phosphorylation levels of AMPK and ULK1 were lower (p < 0.05) in mKO mice following 3 days of neurogenic muscle disuse. We also report that CARM1 interacts with AMPK, FOXO1, and TFEB in skeletal muscle. Relative to the contralateral, non‐denervated control (CON) limb, the interactions between CARM1‐AMPK and CARM1‐FOXO1 increased (p < 0.05) after 3 days of denervation in WT mice. When compared to the CON limb, the CARM1‐TFEB interaction was lower (p < 0.05) in WT mice following 7 days of neurogenic muscle disuse. In comparison to WT animals, the methylation of AMPK was significantly blunted in mKO mice after 3 days of denervation, suggesting that CARM1 methyltransferase activity regulates AMPK signaling. Collectively, these results suggest that CARM1 interacts with intracellular signaling molecules that are integral for muscle wasting. Importantly, targeting the interplay between CARM1‐AMPK, CARM1‐FOXO1, and CARM1‐TFEB may provide a novel therapeutic strategy for mitigating neurogenic skeletal muscle atrophy. Support or Funding Information Natural Sciences and Engineering Research Council of Canada Canada Research Chairs
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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".