Short‐term bed rest‐induced insulin resistance cannot be explained by increased mitochondrial H₂O₂ emission

Abstract

Key pointsr We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance.r Bed rest decreased maximal and submaximal ADP-stimulated mitochondrial respiration. r Bed rest did not alter mitochondrial H 2 O 2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H 2 O 2 emission to mitochondrial O 2 consumption or markers of oxidative stress r The present data suggest strongly that mitochondrial H 2 O 2 does not contribute to bed rest-induced insulin resistance Abstract Mitochondrial H 2 O 2 has been causally linked to diet-induced insulin resistance, although it remains unclear if muscle disuse similarly increases mitochondrial H 2 O 2 . Therefore, we investigated the potential that an increase in skeletal muscle mitochondrial H 2 O 2 emission, potentially as a result of decreased ADP sensitivity, contributes to cellular redox stress and the induction of insulin resistance during short-term bed rest in 20 healthy males. Bed rest led to a decline in glucose infusion rate during a hyperinsulinaemic-euglycaemic clamp (−42 ± 2%; P < 0.001), and in permeabilized skeletal muscle fibres it decreased OXPHOS protein content (−16 ± 8%) and mitochondrial respiration across a range of ADP concentrations (−13 ± 5%). While bed rest tended to increase maximal mitochondrial H 2 O 2 emission rates (P = 0.053), H 2 O 2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H 2 O 2 emission to mitochondrial O 2 consumption, and markers of oxidative stress were not altered following bed rest. Altogether, while bed rest impairs mitochondrial ADP-stimulated respiration, an increase in mitochondrial H 2 O 2 emission does not contribute to the induction of insulin resistance following short-term bed rest.Marlou Dirks is a Sir Henry Wellcome Postdoctoral Fellow in the Department of Sport and Health Sciences at the University of Exeter, UK. Her research focuses on the impact of muscle disuse on metabolic health and the regulation of skeletal muscle protein turnover. Dr Dirks applies detailed in vivo metabolic techniques in experimental models of muscle disuse (i.e. bed rest, limb immobilization) to gain mechanistic insight into disuse-induced muscle atrophy and investigate potential interventional strategies for the preservation of muscle mass and metabolic health during muscle disuse. Clinical trial registration: NCT02521025 Methods SubjectsTwenty healthy, recreationally active males (age 25 ± 1 years) were included in the present study. Subjects'

Unlike a high‐fat diet model, mitochondrial ROS production does not appear to contribute to bed rest‐induced insulin resistance

“…It is duly noted that this study was conducted on healthy, young male adults, and further studies need to be conducted in order to confirm whether the previously discussed phenotype would persist in other patient populations that are confined to a hospital or other medical facility for extended periods of time. (Dirks et al 2020). Although the present investigators found that the mechanisms underlying bed rest-induced IR did not match previous findings with high-fat diet-induced IR, the study steers future research in a direction where the mechanism underlying bed rest-induced IR may be determined.…”

“…Furthermore, markers of oxidative stress (4-hydroxynonenal and reduced/oxidized glutathione levels) did not change following bed rest. This accords with the lack of an increase in ROS production measured by H 2 O 2 emission levels (Dirks et al 2020).…”

“…Due to the careful design and strict model of bed rest in this study by Dirks et al (2020), their findings suggest that bed rest-induced IR may result from a mechanism other than increased ROS production and oxidative stress in skeletal muscle. Furthermore, as previously shown by the same group, there is no increased lipid deposition in muscle following 7 days of bed rest, indicating that this is also not a part of the mechanism (Dirks et al 2016).…”

“…Consistent with previous findings, this group showed that insulin responsiveness decreased during hyperinsulinaemic conditions, suggesting that insulin signalling is impaired. J Physiol 598.12 As acknowledged by the authors, a limitation of all studies involving muscle disuse to date is the lack of understanding as to how bed rest specifically affects the mechanism of GLUT4 translocation (Dirks et al 2020). Thus, measuring GLUT4 translocation to the membrane would be a very valuable addition to current knowledge regarding the effects of bed rest.…”

Changes in insulin resistance do not occur in parallel with changes in mitochondrial content and function in male rats

“…Some values were excluded from the analysis due to technical errors, therefore final analysis was conducted on n = 7-8 per group. [32] we also reported total ETS subunit protein content.…”