Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis

Nat Cell Biol. 2022 May;24(5):793-804. doi: 10.1038/s41556-022-00893-0. Epub 2022 Apr 25.


A decline in skeletal muscle mass and low muscular strength are prognostic factors in advanced human cancers. Here we found that breast cancer suppressed O-linked N-acetylglucosamine (O-GlcNAc) protein modification in muscle through extracellular-vesicle-encapsulated miR-122, which targets O-GlcNAc transferase (OGT). Mechanistically, O-GlcNAcylation of ryanodine receptor 1 (RYR1) competed with NEK10-mediated phosphorylation and increased K48-linked ubiquitination and proteasomal degradation; the miR-122-mediated decrease in OGT resulted in increased RYR1 abundance. We further found that muscular protein O-GlcNAcylation was regulated by hypoxia and lactate through HIF1A-dependent OGT promoter activation and was elevated after exercise. Suppressed O-GlcNAcylation in the setting of cancer, through increasing RYR1, led to higher cytosolic Ca2+ and calpain protease activation, which triggered cleavage of desmin filaments and myofibrillar destruction. This was associated with reduced skeletal muscle mass and contractility in tumour-bearing mice. Our findings link O-GlcNAcylation to muscular protein homoeostasis and contractility and reveal a mechanism of cancer-associated muscle dysregulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylglucosamine / metabolism
  • Animals
  • Humans
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Muscle, Skeletal / metabolism
  • N-Acetylglucosaminyltransferases / genetics
  • Neoplasms* / metabolism
  • Protein Processing, Post-Translational
  • Proteolysis
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • MIRN122 microRNA, human
  • MicroRNAs
  • Mirn122 microRNA, mouse
  • Ryanodine Receptor Calcium Release Channel
  • N-Acetylglucosaminyltransferases
  • Acetylglucosamine