Abstract
Impaired skeletal muscle glucose oxidation in response to insulin is a hallmark characteristic of humans with severe obesity and Type 2 Diabetes. Roux‐en‐Y gastric bypass (RYGB) surgery is an effective treatment of these metabolic diseases by markedly improving metabolic health, including enhanced glucose oxidation and insulin action in skeletal muscle. However, the underlying mechanisms responsible for these improvements are not fully understood. Skeletal muscle mitochondria are critical in preserving cellular health, but exhibit defective functions in severely obese humans. Recent studies have suggested that dysregulated mitochondrial dynamics are associated with mitochondrial dysfunction and insulin resistance. This study aims to determine the effects of severe obesity and RYGB surgery on mitochondrial dynamic proteins and its association with insulin sensitivity and glucose oxidation in human skeletal muscle. Human skeletal muscle cell culture model was utilized by isolating human skeletal muscle cells from muscle biopsies obtained from lean subjects (n=6, BMI = 22.7 ± 1.2 kg/m2, HOMA‐IR = 1.9 ± 0.4) and RYGB patients prior to, 1‐month and 7‐months following surgery (n=6, BMI = 47.3 ± 2.8 kg/m2, 41.0 ± 2.9 kg/m2, 33.7 ± 2.2 kg/m2, HOMA‐IR = 3.4 ± 0.4, 2.9 ± 0.9, 1.7 ± 0.2, respectively). Human skeletal muscle cells were differentiated to myotubes. On day 7 of differentiation, myotubes were harvested for immunoblot analysis in order to assess the expressions of mitochondria dynamics proteins. Myotubes derived from severely obese patients had a 35% increase in mitochondrial fusion protein Optic Atrophy 1 (Opa1) expression before surgery when compared to lean controls (p <0.05). In addition, there was a trend towards a decrease of fusion proteins Opa1 and Mitofusin 1 (Mfn1) expressions in myotubes derived from the same patients at 7‐months following surgery (26% and 18%, p=0.065, respectively) in comparison to pre‐surgery state, and virtually no difference from lean controls. Furthermore, Opa1 expression negatively correlated with insulin‐stimulated glucose oxidation in myotubes (r = −0.614, p <0.05), while Mfn1 is positively correlated with HOMA‐IR (r = 0.495, p <0.05). Mitochondrial fission and mitophagy proteins observed no differences between lean, pre‐surgery, 1‐month and 7‐months following RYGB surgery. In conclusion, these data suggest that RYGB surgery corrected severe obesity‐induced dysregulation in mitochondrial fusion process in human myotubes, which may contribute to improved insulin sensitivity and skeletal muscle glucose oxidation in RYGB patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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