MAFbx, MuRF1, and the stress-activated protein kinases are upregulated in muscle cells during total knee arthroplasty

Am J Physiol Regul Integr Comp Physiol. 2012 Aug 15;303(4):R376-86. doi: 10.1152/ajpregu.00146.2012. Epub 2012 Jul 3.


Total knee arthroplasty (TKA) is the most common and a cost-effective surgical remediation for older adults with long-standing osteoarthritis. In parallel with the expanding population of older adults, the number of TKAs performed annually is projected to be 3.48 million by 2030. During this surgery, a tourniquet is used to stop blood flow to the operative leg. However, the molecular pathways that are affected by tourniquet use during TKA continue to be elucidated. We hypothesized that components of the catabolic FoxO3a (i.e., MuRF1, MAFbx, and Bnip3) pathway, as well as the cellular stress pathways [i.e., stress-activated protein kinase (SAPK)/JNK and MAPKs], are upregulated during TKA. The purpose of this study was to measure changes in transcripts and proteins involved in muscle cell catabolic and stress-activated pathways. We obtained muscle biopsies from subjects, 70 ± 1.3 yr, during TKA, from the vastus lateralis at baseline (before tourniquet inflation), during maximal ischemia (just before tourniquet release), and during reperfusion. Total tourniquet time was 43 ± 2 min and reperfusion time was 16 ± 1. Significant increases in FoxO3a downstream targets, MAFbx and MuRF1, were present for mRNA levels during ischemia (MAFbx, P = 0.04; MuRF1, P = 0.04), and protein expression during ischemia (MAFbx, P = 0.002; MuRF1, P = 0.001) and reperfusion (MuRF1, P = 0.002). Additionally, stress-activated JNK gene expression (P = 0.01) and protein were elevated during ischemia (P = 0.001). The results of this study support our hypothesis that protein degradation pathways are stimulated during TKA. Muscle protein catabolism is likely to play a role in the rapid loss of muscle volume measured within 2 wk of this surgery.

Publication types

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

MeSH terms

  • Aged
  • Arthroplasty, Replacement, Knee*
  • Female
  • Humans
  • Ischemia / genetics
  • Ischemia / metabolism
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Knee Joint / metabolism*
  • Knee Joint / surgery
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Muscle Cells / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Osteoarthritis, Knee / genetics
  • Osteoarthritis, Knee / metabolism
  • Osteoarthritis, Knee / surgery
  • Proteolysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Quadriceps Muscle / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction / physiology
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Up-Regulation / physiology*


  • BNIP3 protein, human
  • Membrane Proteins
  • Muscle Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Tripartite Motif Proteins
  • FBXO32 protein, human
  • SKP Cullin F-Box Protein Ligases
  • TRIM63 protein, human
  • Ubiquitin-Protein Ligases
  • JNK Mitogen-Activated Protein Kinases