Protein Arginine N‐Methyltransferase 4 Activation Contributes to Glucose‐Induced Skeletal Muscle Atrophy

Protein arginine N‐methyltransferase 4 (PRMT4; also known as Coactivator‐Associated Arginine Methyltransferase 1/CARM1) plays a crucial role in cell‐type‐specific biological processes. In skeletal muscle, PRMT4 has been demonstrated to manage plasticity by regulating skeletal muscle development, regeneration, and glycogen metabolism. However, its impact on skeletal muscle metabolic homeostasis under pathologic conditions remains obscure. Here, we investigated the role of PRMT4 in skeletal muscle atrophy under diabetes. In L6 myotubes, high glucose exposure increased mRNA expression and protein level of PRMT4, correlating with the induction of atrophy features. Notably, the pharmacological inhibition or small interfering RNA (siRNA)‐mediated downregulation of PRMT4 suppressed high glucose‐induced atrophy features. The high glucose exposure elevated asymmetric dimethylarginine (ADMA) via PRMT4 activation, disrupting insulin signaling in L6 myotubes. Further, we have established the activation of the ubiquitin‐proteasome‐mediated protein degradation pathway in the high glucose‐induced skeletal muscle atrophy program via PRMT4, without any significant effect on the autophagy pathway. Additionally, we have demonstrated that proteasome‐mediated protein degradation released free amino acids that triggered mammalian target of rapamycin (mTOR) signaling in a PRMT4‐dependent manner. Altogether, our findings establish PRMT4 as a critical regulator of glucose‐induced skeletal muscle atrophy and propose it as a potential therapeutic target for the management of diabetes‐associated skeletal muscle atrophy.

• Publication year

  2025

• Venue

  The FASEB Journal

• Publication date

  2025-10-13

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1096/fj.202502570RPMID 41078314
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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