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

Abstract

Reducing muscle atrophy following orthopedic surgery is critical during the post-operative period. Our previous work in total knee arthroplasty (TKA) patients showed that the vast majority of atrophy occurs within two weeks following surgery and that essential amino acid supplementation (EAAs) attenuates this atrophy. We used RNA-sequencing (RNA-seq) to identify genes associated with atrophy after TKA with and without EAAs. Analysis of over-represented gene-ontology (GO) terms revealed that p53 signaling and the Cytokine-Cytokine Receptor pathways were highly upregulated after TKA. Relative to Placebo, the EAAs 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 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 non-canonical NF-kB pathway.

Post-operative protein supplementation following orthopaedic surgery: A systematic review

“…Four surgical cohorts were identified: Anterior cruciate ligament reconstruction 35 , 36 , 37 , 38 (ACLR), total hip arthroplasty 39 , 40 , 41 (THA), hip fractures 41 , 42 , 43 (THA, revision THA, hip resurfacing), and total knee arthroplasty 44 , 45 , 46 , 47 , 48 (TKA). The ACLR, THA, and hip fracture cohorts were each composed of 3 studies, while there were 5 studies in the TKA cohort ( Table 1 ).…”

Essential amino acids in total knee and hip joint replacement: a narrative review

“…With detailed search of listed databases, we identified nine studies for inclusion in this review. [30][31][32][33][34][35][36][37][38] Among the included studies, seven evaluated EAAs in TKA. [30][31][32][33][34][35][36] and two assessed in THA.…”

“…[30][31][32][33][34][35][36][37][38] Among the included studies, seven evaluated EAAs in TKA. [30][31][32][33][34][35][36] and two assessed in THA. 37,38 Findings from these studies are briefed and reviewed in below sections.…”

“…In further understanding of the genetic linkage of muscle atrophy following TKA and effect of EAAs, Muyskens et al performed RNA-sequencing (RNA-seq) to find the genes linked to atrophy following TKA with and without EAAs. 32 A total of 156 samples were obtained (41 subjects x 4 biopsies per subject) and analysed for genetic assessments. Study results revealed that after TKA, the p53 signalling and cytokine-cytokine receptor mechanisms were significantly elevated.…”

Nutritional Considerations in Hip and Knee Arthroplasty

“…EAA supplementation following TKA on the cellular level has been examined by Muyskens et al 25 . The authors supplemented patients with 20 mg EAA twice a day for 1 week preoperatively and performed muscle biopsies during TKA and at 1 week and 2 weeks postoperatively 25 . Increased satellite cells necessary for myofiber regeneration were noted in all biopsy samples among the EAA supplementation cohort 25 .…”