Cu nanowires (CuNWs) are considered as a promising candidate to develop high performance metal aerogels, yet the construction of robust and stable 3D porous structures remains challenging which severely limits their practical applications. Here, graphene-hybridized CuNW (CuNW@G) core-shell aerogels are fabricated by introducing a conformal polymeric coating and in situ transforming it into multilayered graphene seamlessly wrapped around individual CuNWs through a mild thermal annealing process. The existence of the outer graphene shell reinforces the 3D bulk structure and significantly slows down the oxidation process of CuNWs, resulting in improved mechanical property and highly stable electrical conductivity. When applied in electromagnetic interference shielding, the CuNW@G core-shell aerogels exhibit an average effectiveness of ≈52.5 dB over a wide range (from 8.2 to 18 GHz) with negligible degradation under ambient conditions for 40 d. Mechanism analysis reveals that the graphene shell with functional groups enables dual reflections on the core-shell and a multiple dielectric relaxation process, leading to enhanced dielectric loss and energy dissipation within the core-shell aerogels. The flexible core-shell-structured CuNW@G aerogels, with superior mechanical robustness and electrical stability, have potential applications in many areas such as advanced energy devices and functional composites.

Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers, mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo, but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source, regulating glucose transport capacity during moderate-intensity exercise.

Background Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF-β) superfamily, including activin A, which causes atrophy. TGF-β superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. Methods To elucidate if TGF-β superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB). Results Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (À24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. Conclusions We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-β superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans. X. Han et al. P < 0.05/0.01/ 0.001. Data are shown mean ± SEM with individual values shown when applicable.Follistatin-induced hypertrophy and muscle insulin action P < 0.01/0.001. Data are shown as mean ± SEM with individual values.Follistatin-induced hypertrophy and muscle insulin action P < 0.05/0.001/0.0001. Data are shown mean ± SEM and/or individual values when applicable.

Reactive oxygen species (ROS) act as intracellular compartmentalized second messengers mediating metabolic stress-adaptation. In skeletal muscle fibers, ROS have been suggested to stimulate glucose transporter 4 (GLUT4)-dependent glucose transport during artificially evoked contraction ex vivo but whether myocellular ROS production is stimulated by in vivo exercise to control metabolism is unclear. Here, we combined exercise in humans and mice with fluorescent dyes, genetically-encoded biosensors, and NADPH oxidase 2 (NOX2) loss-of-function models to demonstrate that NOX2 is the main source of cytosolic ROS during moderate-intensity exercise in skeletal muscle. Furthermore, two NOX2 loss-of-function mouse models lacking either p47phox or Rac1 presented striking phenotypic similarities, including greatly reduced exercise-stimulated glucose uptake and GLUT4 translocation. These findings indicate that NOX2 is a major myocellular ROS source regulating glucose transport capacity during moderate-intensity exercise.

Key points AMP‐activated protein kinase (AMPK)‐dependent Raptor Ser792 phosphorylation does not influence mechanistic target of rapamycin complex 1 (mTORC1)‐S6K1 activation by intense muscle contraction. α2‐AMPK activity‐deficient mice have lower contraction‐stimulated protein synthesis. Increasing glycogen activates mTORC1‐S6K1. Normalizing muscle glycogen content rescues reduced protein synthesis in AMPK‐deficient mice. AbstractThe mechansitic target of rapamycin complex 1 (mTORC1)‐S6K1 signalling pathway regulates muscle growth‐related protein synthesis and is antagonized by AMP‐activated protein kinase (AMPK) in multiple cell types. Resistance exercise stimulates skeletal muscle mTORC1‐S6K1 and AMPK signalling and post‐contraction protein synthesis. Glycogen inhibits AMPK and has been proposed as a pro‐anabolic stimulus. The present study aimed to investigate how muscle mTORC1‐S6K1 signalling and protein synthesis respond to resistance exercise‐mimicking contraction in the absence of AMPK and with glycogen manipulation. Resistance exercise‐mimicking unilateral in situ contraction of musculus quadriceps femoris in anaesthetized wild‐type and dominant negative α2 AMPK kinase dead transgenic (KD‐AMPK) mice, measuring muscle mTORC1 and AMPK signalling immediately (0 h) and 4 h post‐contraction, and protein‐synthesis at 4 h. Muscle glycogen manipulation by 5 day oral gavage of the glycogen phosphorylase inhibitor CP316819 and sucrose (80 g L−1) in the drinking water prior to in situ contraction. The mTORC1‐S6K1 and AMPK signalling axes were coactivated immediately post‐contraction, despite potent AMPK‐dependent Ser792 phosphorylation on the mTORC1 subunit raptor. KD‐AMPK muscles displayed normal mTORC1‐S6K1 activation at 0 h and 4 h post‐exercise, although there was impaired contraction‐stimulated protein synthesis 4 h post‐contraction. Pharmacological/dietary elevation of muscle glycogen content augmented contraction‐stimulated mTORC1‐S6K1‐S6 signalling and rescued the reduced protein synthesis‐response in KD‐AMPK to wild‐type levels. mTORC‐S6K1 signalling is not influenced by α2‐AMPK during or after intense muscle contraction. Elevated glycogen augments mTORC1‐S6K1 signalling. α2‐AMPK‐deficient KD‐AMPK mice display impaired contraction‐induced muscle protein synthesis, which can be rescued by normalizing muscle glycogen content.

Objective Reactive oxygen species (ROS) have been proposed as signaling molecules mediating exercise training adaptation, but the ROS source has remained unclear. This study aimed to investigate if increased NADPH oxidase (NOX)2-dependent activity during exercise is required for long-term high-intensity interval training (HIIT) in skeletal muscle using a mouse model lacking functional NOX2 complex due to absent p47phox ( Ncf1 ) subunit expression ( ncf1* mutation). Methods HIIT was investigated after an acute bout of exercise and after a chronic intervention (3x/week for 6 weeks) in wild-type (WT) vs. NOX2 activity-deficient ( ncf1* ) mice. NOX2 activation during HIIT was measured using an electroporated genetically-encoded biosensor. Immunoblotting and single-fiber microscopy was performed to measure classical exercise-training responsive endpoints in skeletal muscle. Results A single bout of HIIT increased NOX2 activity measured as p47-roGFP oxidation immediately after exercise but not 1 h or 4 h after exercise. After a 6-week HIIT regimen, improvements in maximal running capacity and some muscle training-markers responded less to HIIT in the ncf1* mice compared to WT, including superoxide dismutase 2, catalase, hexokinase II, pyruvate dehydrogenase and protein markers of mitochondrial oxidative phosphorylation complexes. Strikingly, HIIT-training increased mitochondrial network area and decreased fragmentation in WT mice only. Conclusion This study suggests that HIIT exercise increases NOX2 activity in skeletal muscle and shows that NOX2 activity is required for specific skeletal muscle adaptations to HIIT relating to antioxidant defense, glucose metabolism, and mitochondria.

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ObjectiveChronic ad libitum low protein-high carbohydrate diet (LPHC) increases health- and life-span in mice. A periodized (p) LPHC regimen would be a more practical long-term human lifestyle intervention, but the metabolic benefits of pLPHC are not known. Also, the interactions between LPHC diet and exercise training have not been investigated. Presently, we aimed to provide proof-of-concept data in mice of the efficacy of pLPHC and to explore the potential interactions with concurrent exercise training.MethodsA detailed phenotypic and molecular characterization of mice undergoing different durations of 14 d LPHC (5 E% protein)/14 d control diet cycles for up to 4 months with or without concurrent access to activity wheels allowing voluntary exercise training.ResultspLPHC conferred metabolic benefits similar to chronic LPHC, including increased FGF21 and adaptive thermogenesis, obesity-protection despite increased total energy intake and improved insulin sensitivity. The improved insulin sensitivity showed large fluctuations between diet periods and was lost within 14 days of switching back to control diet. Parallel exercise training improved weight maintenance but impaired the FGF21 response to pLPHC whereas repeated pLPHC cycles progressively augmented this response. Both the FGF21 suppression by exercise and potentiation by repeated cycles correlated tightly with Nupr1 mRNA in liver, suggesting dependence on liver integrated stress response.ConclusionThese results suggest that pLPHC may be a viable strategy to promote human health but also highlight the transient nature of the benefits and that the interaction with other lifestyle-interventions such as exercise training warrants consideration.