A randomized clinical trial on the effects of exercise on muscle remodelling following bariatric surgery

Saulo Gil, John P Kirwan, Igor H Murai, Wagner S Dantas, Carlos Alberto Abujabra Merege-Filho, Sujoy Ghosh, Samuel K Shinjo, Rosa M R Pereira, Walcy R Teodoro, Sheylla M Felau, Fabiana B Benatti, Ana L de Sá-Pinto, Fernanda Lima, Roberto de Cleva, Marco Aurélio Santo, Bruno Gualano, Hamilton Roschel, Saulo Gil, John P Kirwan, Igor H Murai, Wagner S Dantas, Carlos Alberto Abujabra Merege-Filho, Sujoy Ghosh, Samuel K Shinjo, Rosa M R Pereira, Walcy R Teodoro, Sheylla M Felau, Fabiana B Benatti, Ana L de Sá-Pinto, Fernanda Lima, Roberto de Cleva, Marco Aurélio Santo, Bruno Gualano, Hamilton Roschel

Abstract

Background: Muscle atrophy and strength loss are common adverse outcomes following bariatric surgery. This randomized, controlled trial investigated the effects of exercise training on bariatric surgery-induced loss of muscle mass and function. Additionally, we investigated the effects of the intervention on molecular and histological mediators of muscle remodelling.

Methods: Eighty women with obesity were randomly assigned to a Roux-en-Y gastric bypass (RYGB: n = 40, age = 42 ± 8 years) or RYGB plus exercise training group (RYGB + ET: n = 40, age = 38 ± 7 years). Clinical and laboratory parameters were assessed at baseline, and 3 (POST3) and 9 months (POST9) after surgery. The 6 month, three-times-a-week, exercise intervention (resistance plus aerobic exercise) was initiated 3 months post-surgery (for RYGB + ET). A healthy, lean, age-matched control group was recruited to provide reference values for selected variables.

Results: Surgery resulted in a similar (P = 0.66) reduction in lower-limb muscle strength in RYGB and RYGB+ET (-26% vs. -31%), which was rescued to baseline values in RYGB + ET (P = 0.21 vs. baseline) but not in RYGB (P < 0.01 vs. baseline). Patients in RYGB+ET had greater absolute (214 vs. 120 kg, P < 0.01) and relative (2.4 vs. 1.4 kg/body mass, P < 0.01) muscle strength compared with RYGB alone at POST9. Exercise resulted in better performance in timed-up-and-go (6.3 vs. 7.1 s, P = 0.05) and timed-stand-test (18 vs. 14 repetitions, P < 0.01) compared with RYGB. Fat-free mass was lower (POST9-PRE) after RYBG than RYGB + ET (total: -7.9 vs. -4.9 kg, P < 0.01; lower-limb: -3.8 vs. -2.7 kg, P = 0.02). Surgery reduced Types I (~ - 21%; P = 0.99 between-group comparison) and II fibre cross-sectional areas (~ - 27%; P = 0.88 between-group comparison), which were rescued to baseline values in RYGB+ET (P > 0.05 vs. baseline) but not RYGB (P > 0.01 vs. baseline). RYGB + ET showed greater Type I (5187 vs. 3898 μm2 , P < 0.01) and Type II (5165 vs. 3565 μm2 , P < 0.01) fCSA than RYGB at POST9. RYGB + ET also resulted in increased capillarization (P < 0.01) and satellite cell content (P < 0.01) than RYGB at POST9. Gene-set normalized enrichment scores for the muscle transcriptome revealed that the ubiquitin-mediated proteolysis pathway was suppressed in RYGB + ET at POST9 vs. PRE (NES: -1.7; P < 0.01), but not in RYGB. Atrogin-1 gene expression was lower in RYGB + ET vs. RYGB at POST9 (0.18 vs. 0.71-fold change, P < 0.01). From both genotypic and phenotypic perspectives, the muscle of exercised patients resembled that of healthy lean individuals.

Conclusions: This study provides compelling evidence-from gene to function-that strongly supports the incorporation of exercise into the recovery algorithm for bariatric patients so as to counteract the post-surgical loss of muscle mass and function.

Trial registration: ClinicalTrials.gov NCT02441361.

Keywords: Bariatric surgery; Muscle atrophy; Muscle function; Obesity.

Conflict of interest statement

The authors have declared that no conflict of interest exists.

© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

Figures

Figure 1
Figure 1
Changes in body composition. RYGB + ET (n = 28): Roux‐en‐Y gastric bypass plus exercise training group; RYGB (n = 27): Roux‐en‐Y gastric bypass plus non‐exercise. Body mass index (BMI), fat mass, fat‐free mass, and lower‐ and upper‐limb fat‐free mass in the experimental groups (Panels A, C, E, G, and I, respectively). Absolute changes (∆) from POST9 to PRE for BMI, fat mass, fat‐free mass, lower‐limb fat‐free mass (Panels B, D, F, H, and J, respectively). Data are expressed as mean ± SD. PRE, before surgery (baseline); POST3, 3 months following surgery; POST9, 9 months following surgery. ^ indicates P < 0.05 for main effect of time.
Figure 2
Figure 2
Muscular strength, functionality, and physical activity level. RYGB + ET (n = 28): Roux‐en‐Y gastric bypass plus exercise training group; RYGB (n = 27): Roux‐en‐Y gastric bypass plus non‐exercise. Absolute and relative lower‐limb (Panels A and B, respectively) and upper‐limb (Panels C and D, respectively) strength performance in the 1‐RM test. Functionality in the timed‐up‐and‐go test and timed‐stand test (Panels E and F, respectively). Time spent in sedentary behaviour and moderate‐to‐vigorous physical activity level (Panels G and H, respectively). Data are expressed as mean ± SD. PRE: before surgery (baseline); POST3: 3 months following surgery; POST9: 9 months following surgery; ^ indicates P < 0.05 for main effect of time. * indicates P < 0.05 in comparison with PRE; # indicates P < 0.05 in comparison with POST3; $ indicates P < 0.05 for between‐group comparison with POST9.
Figure 3
Figure 3
Muscle fibre cross‐sectional area, myonuclei content, myonuclear domain, muscle fibre capillarization, and satellite cell content. RYGB + ET (n = 11): Roux‐en‐Y gastric bypass plus exercise training group; RYGB (n = 11): Roux‐en‐Y gastric bypass plus non‐exercise. A representative image of the immunofluorescence staining for analysis of Types I and II muscle fibre cross‐sectional area (fCSA), myonuclei content, myonuclear domain (Panel A), satellite cells content (Panel H), and capillarization (Panel J). Types I and II muscle fibre cross‐sectional area (fCSA) (Panels B and C, respectively), myonuclei content (Panels D and E, respectively), myonuclear domain (Panels F and G, respectively), satellite cells content (Panel I), capillary contacts (CC) (Panel K), capillary‐to‐fibre ratio on an individual fibre basis (C/Fi) (Panel L), and capillary‐to‐fibre perimeter exchange index (CFPE) (Panel M). Data are expressed as mean ± SD. PRE: before surgery (baseline); POST3: 3 months following surgery; POST9: 9 months following surgery. ^ indicates P < 0.05 for main effect of time; * indicates P < 0.05 in comparison with PRE; # indicates P < 0.05 in comparison with POST3; $ indicates P < 0.05 for between‐group comparison with POST9.
Figure 4
Figure 4
Pathway enrichment analysis related to muscle plasticity, gene and protein expression of atrogin‐1 and MuRF‐1. RYGB+ET [n = 14(8 for western blot)]: Roux‐en‐Y gastric bypass plus exercise training group; RYGB [n = 14 (8 for western blot)]: Roux‐en‐Y gastric bypass plus non‐exercise. Gene set enrichment analysis (GSEA) related to muscle protein synthesis and breakdown (Panel A) and the GSEA‐plot of the ubiquitin mediated proteolysis pathway (Panel B). Gene and protein expression for Atrogin‐1 (Panels C and E, respectively) and MuRF‐1 (Panels D and F, respectively). Representative image of the Western blot bands for Atrogin‐1 and MuRF‐1 (Panel H). Data are expressed as mean ± SD. Red arrow indicates an enrichment with a false discovery rate (FDR) ≤ 10% and the absolute log2 fold‐change >1.5; PRE: before surgery (baseline); POST3: 3 months following surgery; POST9: 9 months following surgery. ^ indicates P < 0.05 for main effect of time; * indicates P < 0.05 in comparison to PRE; # indicates P < 0.05 in comparison to POST3; $ indicates P < 0.05 for between‐group comparison at POST9.
Figure 5
Figure 5
Normalized skeletal muscle cell signalling pathways and physiological outcomes. RYGB + ET: Roux‐en‐Y gastric bypass plus exercise training group; RYGB: Roux‐en‐Y gastric bypass plus non‐exercise. Venn diagram of the total number of differentially expressed genes (FDR ≤ 0.05), and gene set enrichment analysis (GSEA) related to muscle protein synthesis and breakdown in the RYGB + ET and RYGB groups at POST9 in comparison with healthy lean control group (Panels A and B, respectively). Comparison of the RYGB + ET and RYGB groups at POST9 with reference values from healthy lean control group: Z‐score for absolute and relative lower‐limb (Panels C and D, respectively) and upper‐limb (Panels E and F, respectively) strength performance in the 1‐RM test, functionality in the timed‐up‐and‐go test and timed‐stand test (Panels G and H, respectively), Types I and II muscle fibre cross‐sectional area (CSA) (Panels I and J, respectively), muscle fibre capillarization parameters (Panels K, L, and M, respectively) and satellite cell content (Panel N). Data are expressed as mean ± SD. Red arrow indicates an enrichment with a false discovery rate (FDR) ≤ 10% and the absolute log2 fold‐change >1.5; PRE: before surgery (baseline); POST3: 3 months following surgery; POST9: 9 months following surgery. * indicates P < 0.05 in comparison with healthy lean control group.

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