The application of blood flow restriction (BFR) during resistance exercise is increasingly recognized for its ability to improve rehabilitation and for its effectiveness in increasing muscle hypertrophy and strength among healthy populations. However, direct comparison of the skeletal muscle adaptations to low-load resistance exercise (LL-RE) and low-load BFR resistance exercise (LL-BFR) performed to task failure is lacking. Using a within-subject design, we examined whole muscle group and skeletal muscle adaptations to 6 wk of LL-RE and LL-BFR training to repetition failure. Muscle strength and size outcomes were similar for both types of training, despite ~33% lower total exercise volume (load × repetition) with LL-BFR than LL-RE (28,544 ± 1,771 vs. 18,949 ± 1,541 kg, P = 0.004). After training, only LL-BFR improved the average power output throughout the midportion of a voluntary muscle endurance task. Specifically, LL-BFR training sustained an 18% greater power output from baseline and resulted in a greater change from baseline than LL-RE (19 ± 3 vs. 3 ± 4 W, P = 0.008). This improvement occurred despite histological analysis revealing similar increases in capillary content of type I muscle fibers following LL-RE and LL-BFR training, which was primarily driven by increased capillary contacts (4.53 ± 0.23 before training vs. 5.33 ± 0.27 and 5.17 ± 0.25 after LL-RE and LL-BFR, respectively, both P < 0.05). Moreover, maximally supported mitochondrial respiratory capacity increased only in the LL-RE leg by 30% from baseline ( P = 0.006). Overall, low-load resistance training increased indexes of muscle oxidative capacity and strength, which were not further augmented with the application of BFR. However, performance on a muscle endurance test was improved following BFR training.
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'
Key pointsr Blood flow restricted resistance exercise (BFR-RE) is capable of inducing comparable adaptations to traditional resistance exercise (RE), despite a lower total exercise volume.r It has been suggested that an increase in reactive oxygen species (ROS) production may be involved in this response; however, oxygen partial pressure (P O 2 ) is reduced during BFR-RE, and the influence of P O 2 on mitochondrial redox balance remains poorly understood.r In human skeletal muscle tissue, we demonstrate that both maximal and submaximal mitochondrial ROS emission rates are acutely decreased 2 h following BFR-RE, but not RE, occurring along with a reduction in tissue oxygenation during BFR-RE.r We further suggest that P O 2 is involved in this response because an in vitro analysis revealed that reducing P O 2 dramatically decreased mitochondrial ROS emissions and electron leak to ROS.r Altogether, these data indicate that mitochondrial ROS emission rates are attenuated following BFR-RE, and such a response is likely influenced by reductions in P O 2 .Abstract Low-load blood flow restricted resistance exercise (BFR-RE) training has been proposed to induce comparable adaptations to traditional resistance exercise (RE) training, however, the acute signalling events remain unknown. Although a suggested mechanism of BFR-RE is an increase in reactive oxygen species (ROS) production, oxygen partial pressure (P O 2 ) is H. L. Petrick and others J Physiol 597.15 reduced during BFR-RE, and the influence of O 2 tension on mitochondrial redox balance remains ambiguous. We therefore aimed to determine whether skeletal muscle mitochondrial bioenergetics were altered following an acute bout of BFR-RE or RE, and to further examine the role of P O 2 in this response. Accordingly, muscle biopsies were obtained from 10 males at rest and 2 h after performing three sets of single-leg squats (RE or BFR-RE) to failure at 30% one-repetition maximum. We determined that mitochondrial respiratory capacity and ADP sensitivity were not altered in response to RE or BFR-RE. Although maximal (succinate) and submaximal (non-saturating ADP) mitochondrial ROS emission rates were unchanged following RE, BFR-RE attenuated these responses by ß30% compared to pre-exercise, occurring along with a reduction in skeletal muscle tissue oxygenation during BFR-RE (P < 0.01 vs. RE). In a separate cohort of participants, evaluation of mitochondrial bioenergetics in vitro revealed that mild O 2 restriction (50 µM) dramatically attenuated maximal (ß4-fold) and submaximal (ß50-fold) mitochondrial ROS emission rates and the fraction of electron leak to ROS compared to room air (200 µM). Combined, these data demonstrate that mitochondrial ROS emissions are attenuated following BFR-RE, a response which may be mediated by a reduction in skeletal muscle P O 2 .
Key points Dietary nitrate is a prominent therapeutic strategy to mitigate some metabolic deleterious effects related to obesity. Mitochondrial dysfunction is causally linked to adipose tissue inflammation and insulin resistance. Whole‐body glucose tolerance is prevented by nitrate independent of body weight and energy expenditure. Dietary nitrate reduces epididymal adipose tissue inflammation and mitochondrial reactive oxygen species emission while preserving insulin signalling. Metabolic beneficial effects of nitrate consumption are associated with improvements in mitochondrial redox balance in hypertrophic adipose tissue. Abstract Evidence has accumulated to indicate that dietary nitrate alters energy expenditure and the metabolic derangements associated with a high fat diet (HFD), but the mechanism(s) of action remain incompletely elucidated. Therefore, we aimed to determine if dietary nitrate (4 mm sodium nitrate via drinking water) could prevent HFD‐mediated glucose intolerance in association with improved mitochondrial bioenergetics within both white (WAT) and brown (BAT) adipose tissue in mice. HFD feeding caused glucose intolerance (P < 0.05) and increased body weight. As a result of higher body weight, energy expenditure increased proportionally. HFD‐fed mice displayed greater mitochondrial uncoupling and a twofold increase in uncoupling protein 1 content within BAT. Within epididymal white adipose tissue (eWAT), HFD increased cell size (i.e. hypertrophy), mitochondrial H2O2 emission, oxidative stress, c‐Jun N‐terminal kinase phosphorylation and leucocyte infiltration, and induced insulin resistance. Remarkably, dietary nitrate consumption attenuated and/or mitigated all these responses, including rendering mitochondria more coupled within BAT, and normalizing mitochondrial H2O2 emission and insulin‐mediated Akt‐Thr308 phosphorylation within eWAT. Intriguingly, the positive effects of dietary nitrate appear to be independent of eWAT mitochondrial respiratory capacity and content. Altogether, these data suggest that dietary nitrate attenuates the development of HFD‐induced insulin resistance in association with attenuating WAT inflammation and redox balance, independent of changes in either WAT or BAT mitochondrial respiratory capacity/content.
Key points Ketone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstrate in vitro that maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate‐derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available. Abstract Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodium dl‐β‐hydroxybutyrate, β‐HB; lithium acetoacetate, AcAc) to stimulate in vitro mitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (∼30–35% of pyruvate), RG (∼10–30%), and human vastus lateralis (∼2–10%). In PmFb, the concentration of KBs required to half‐maximally drive respiration (LV: 889 µm β‐HB, 801 µm AcAc; RG: 782 µm β‐HB, 267 µm AcAc) were greater than KB content representative of the muscle microenvironment (∼100 µm). This would predict low rates (∼1–4% of pyruvate) of biological KB‐supported respiration in the LV (8–14 pmol s−1 mg−1) and RG (3–6 pmol s−1 mg−1) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 µm) reduced the ability of physiological β‐HB to drive respiration, and addition of other intracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB‐supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source.
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