Essential amino acid supplementation alters the p53 transcriptional response and cytokine gene expression following total knee arthroplasty

J Appl Physiol (1985). 2020 Oct 1;129(4):980-991. doi: 10.1152/japplphysiol.00022.2020. Epub 2020 Sep 3.


Reducing muscle atrophy following orthopedic surgery is critical during the postoperative period. Our previous work in patients who underwent total knee arthroplasty (TKA) showed that the vast majority of atrophy occurs within 2 wk following surgery and that essential amino acid (EAA) supplementation attenuates this atrophy. We used RNA-sequencing (RNA-seq) to identify genes associated with atrophy after TKA with and without EAAs. Analysis of overrepresented gene-ontology terms revealed that p53 signaling and the cytokine-cytokine receptor pathways were highly upregulated after TKA. Relative to the placebo group, the EAA group had altered expression of p53 regulators such as MDM2. This altered expression may account for differences between groups in timing of upregulation of some p53 targets such as apoptosis genes, and may account for the reduction in muscle loss in the subjects receiving EAAs. Furthermore, we observed altered expression of a large number of cytokine-signaling genes including TNFRSF12A, which plays a critical role in muscle atrophy, myogenesis, fibrosis, and the noncanonical NF-κB pathway.NEW & NOTEWORTHY Total knee arthroplasty is the most frequently performed inpatient surgical procedure for those over 45 yr in the United States. Following surgery, patients lose a large amount of muscle, which impacts functional mobility. Previously, our laboratory found that supplementing patients' diets with essential amino acids (EAAs) reduces postsurgical muscle loss. Here, our goal was to characterize the transcriptional changes associated with surgery with and without EAA supplementation to uncover the underlying mechanisms by which EAAs attenuate this muscle loss.

Keywords: aging; atrophy gene signature; atrophy-attenuating gene signature; bioinformatics; muscle; transcriptomics.

Publication types

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

MeSH terms

  • Amino Acids, Essential
  • Arthroplasty, Replacement, Knee* / adverse effects
  • Cytokines / genetics
  • Dietary Supplements
  • Gene Expression
  • Humans
  • Muscle, Skeletal
  • Tumor Suppressor Protein p53 / genetics


  • Amino Acids, Essential
  • Cytokines
  • Tumor Suppressor Protein p53