Exercise Suppresses The Ubiquitin-proteasome System In The Skeletal Muscle Of Obese Women Following Bariatric Surgery

Abstract

Muscle wasting observed in obese women undergoing bariatric surgery is likely related to altered abnormal intramyocellular signaling. Exercise may reestablish the anabolic capacity in this condition. PURPOSE: We examined the effects of exercise training on the main pathways related to skeletal muscle plasticity in obese women undergoing bariatric surgery. METHODS: Women with severe obesity were randomly allocated to either bariatric surgery (RYGB) or bariatric surgery followed by exercise (RYGB+ET). A 6-month, three-times-a-week, supervised, combined aerobic and resistance training program started 3 months after surgery for RYGB+ET, while RYGB followed standard of care. We assessed the transcriptome (RNA-seq) from skeletal muscle samples obtained by muscle biopsies (n = 6 per group) at baseline (PRE) and 9 months after surgery (POST9). We tested whether a set of genes defined a priori were differentially expressed utilizing the Gene Set Enrichment Analysis. Significance was assumed at a fold change > 1.5, P-value < 0.05, and FDR (false discovery rate) < 0.1. To validate the RNA-seq findings, we performed real time-polymerase chain reaction assays (n = 15 per group) for targeted genes. RESULTS: Pathway-level analysis showed that exercise significantly suppressed ubiquitin mediated proteolysis pathway (normalized enrichment scores [NES]: 1.7, P=0.01, FDR=0.09). Atrogin-1 gene expression was suppressed in the exercised group at POST9 in comparison to PRE, and POST3, and also when compared with the non-exercised group at POST9 (estimated mean difference [RYGB vs. RYGB+ET at POST9]: -1.97, CI95%=-3.0 to -0.8, P=0.01). MuRF-1 gene expression decreased after surgery and kept reduced after the intervention for both groups (main time effect: P<0.01 for both). CONCLUSIONS: Our data suggest that a 6-month, exercise training program suppresses the ubiquitin-proteasome system via the downregulation of Atrogin-1 in obese woman undergoing bariatric surgery. This may elucidate a molecular mechanism that partially explains muscle wasting following bariatric surgery and the exercise-induced hypertrophic effect in this condition.Clinicaltrials.gov: NCT02441361