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Compensatory responses of the insulin signaling pathway restore muscle glucose uptake following long-term denervation.

ABSTRACT: We investigated the role of muscle activity in maintaining normal glucose homeostasis via transection of the sciatic nerve, an extreme model of disuse atrophy. Mice were killed 3, 10, 28, or 56 days after transection or sham surgery. There was no difference in muscle weight between sham and transected limbs at 3 days post surgery, but it was significantly lower following transection at the other three time points. Transected muscle weight stabilized by 28 days post surgery with no further loss. Myocellular cross-sectional area was significantly smaller at 10, 28, and 56 days post transection surgery. Additionally, muscle fibrosis area was significantly greater at 56 days post transection. In transected muscle there was reduced expression of genes encoding transcriptional regulators of metabolism (PPARα, PGC-1α, PGC-1β, PPARδ), a glycolytic enzyme (PFK), a fatty acid transporter (M-CPT 1), and an enzyme of mitochondrial oxidation (CS) with transection. In denervated muscle, glucose uptake was significantly lower at 3 days but was greater at 56 days under basal and insulin-stimulated conditions. Although GLUT 4 mRNA was significantly lower at all time points in transected muscle, Western blot analysis showed greater expression of GLUT4 at 28 and 56 days post surgery. GLUT1 mRNA was unchanged; however, GLUT1 protein expression was also greater in transected muscles. Surgery led to significantly higher protein expression for Akt2 as well as higher phosphorylation of Akt. While denervation may initially lead to reduced glucose sensitivity, compensatory responses of insulin signaling appeared to restore and improve glucose uptake in long-term-transected muscle.

SUBMITTER: Callahan ZJ

PROVIDER: S-EPMC4425965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses.

Project description:BACKGROUND:Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. METHODS:To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. RESULTS:After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. CONCLUSIONS:These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

| S-EPMC6389241 | biostudies-literature

Redox responses in skeletal muscle following denervation.

Project description:Previous studies have shown a significant increase in the mitochondrial generation of hydrogen peroxide (H2O2) and other peroxides in recently denervated muscle fibers. The mechanisms for generation of these peroxides and how the muscle responds to these peroxides are not fully established. The aim of this work was to determine the effect of denervation on the muscle content of proteins that may contribute to mitochondrial peroxide release and the muscle responses to this generation. Denervation of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles in mice was achieved by surgical removal of a small section of the peroneal nerve prior to its entry into the muscle. An increase in mitochondrial peroxide generation has been observed from 7 days and sustained up to 21 days following denervation in the TA muscle fibers. This increased peroxide generation was reduced by incubation of skinned fibers with inhibitors of monoamine oxidases, NADPH oxidases or phospholipase A2 enzymes and the muscle content of these enzymes together with peroxiredoxin 6 were increased following denervation. Denervated muscle also showed significant adaptations in the content of several enzymes involved in the protection of cells against oxidative damage. Morphological analyses indicated a progressive significant loss of muscle mass in the TA muscle from 7 days up to 21 days following denervation due to fiber atrophy but without fiber loss. These results support the possibility that, at least initially, the increase in peroxide production may stimulate adaptations in an attempt to protect the muscle fibers, but that these processes are insufficient and the increased peroxide generation over the longer term may activate degenerative and atrophic processes in the denervated muscle fibers.

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Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle.

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| S-EPMC8125496 | biostudies-literature

Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake.

Project description:The skeletal muscle is the largest organ in the body, by mass. It is also the regulator of glucose homeostasis, responsible for 80% of postprandial glucose uptake from the circulation. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in exercise and metabolic disease. In this article, we give an overview of the importance of skeletal muscle in metabolism, describing its role in glucose uptake and the diseases that are associated with skeletal muscle metabolic dysregulation. We focus on the role of skeletal muscle in peripheral insulin resistance and the potential for skeletal muscle-targeted therapeutics to combat insulin resistance and diabetes, as well as other metabolic diseases like aging and obesity. In particular, we outline the possibilities and pitfalls of the quest for exercise mimetics, which are intended to target the molecular mechanisms underlying the beneficial effects of exercise on metabolic disease. We also provide a description of the molecular mechanisms that regulate skeletal muscle glucose uptake, including a focus on the SNARE proteins, which are essential regulators of glucose transport into the skeletal muscle. © 2020 American Physiological Society. Compr Physiol 10:785-809, 2020.

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Heparin impairs skeletal muscle glucose uptake by inhibiting insulin binding to insulin receptor.

Project description:AimHeparin, a widely used antithrombotic drug has many other anticoagulant-independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an approach for developing heparin-targeted therapies for diabetes.MethodsFor serum heparin levels and correlation analysis, 122 volunteer's plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2-NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle-specific loss-of-function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc-GLUT4-mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2-NBDG uptake, Western blot and co-immunoprecipitation.ResultsSerum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet-induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin's anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle-specific loss-of-function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis.ConclusionsHeparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin-mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.

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Insulin-Based Regulation of Glucose-functionalized Nanoparticle Uptake in Muscle Cells.

Project description:Effective regulation of nanoparticle (NP) uptake facilitates the NP-based therapeutics and diagnostics. Here, we report the use of insulin and 2-deoxyglucose (2-DG) to modulate the cellular uptake of glucose-functionalized quantum dots (Glc-QDs) in C2C12 muscle cells. The cellular uptake of Glc-QDs can be modulated up to almost two-fold under insulin stimulation while be down-regulated in the presence of 2-DG. These results demonstrate the use of secondary regulators to control the cellular uptake of NPs through membrane protein recognition in a specific and fine-tunable fashion.

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Glucose Uptake and Insulin Response in Tissue-engineered Human Skeletal Muscle.

Project description:BackgroundTissue-engineered muscles ("myobundles") offer a promising platform for developing a human in vitro model of healthy and diseased muscle for drug development and testing. Compared to traditional monolayer cultures, myobundles better model the three-dimensional structure of native skeletal muscle and are amenable to diverse functional measures to monitor the muscle health and drug response. Characterizing the metabolic function of human myobundles is of particular interest to enable their utilization in mechanistic studies of human metabolic diseases, identification of related drug targets, and systematic studies of drug safety and efficacy.MethodsTo this end, we studied glucose uptake and insulin responsiveness in human tissue-engineered skeletal muscle myobundles in the basal state and in response to drug treatments.ResultsIn the human skeletal muscle myobundle system, insulin stimulates a 50% increase in 2-deoxyglucose (2-DG) uptake with a compiled EC50 of 0.27 ± 0.03 nM. Treatment of myobundles with 400 µM metformin increased basal 2-DG uptake 1.7-fold and caused a significant drop in twitch and tetanus contractile force along with decreased fatigue resistance. Treatment with the histone deacetylase inhibitor 4-phenylbutyrate (4-PBA) increased the magnitude of insulin response from a 1.2-fold increase in glucose uptake in the untreated state to a 1.4-fold increase after 4-PBA treatment. 4-PBA treated myobundles also exhibited increased fatigue resistance and increased twitch half-relaxation time.ConclusionAlthough tissue-engineered human myobundles exhibit a modest increase in glucose uptake in response to insulin, they recapitulate key features of in vivo insulin sensitivity and exhibit relevant drug-mediated perturbations in contractile function and glucose metabolism.

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Transcription profiling of rat gastrocneumius muscle following short and long term denervation

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2009-04-15 | E-MEXP-1580 | biostudies-arrayexpress

Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake.

Project description:Adipose tissues provide circulating nutrients and hormones. We present in vivo mouse studies highlighting roles for Wnt signals in both aspects of metabolism. ?-catenin activation in PPAR?-expressing fat progenitors (PBCA) decreased fat mass and induced fibrotic replacement of subcutaneous fat specifically. In spite of lipodystrophy, PBCA mice did not develop the expected diabetes and hepatosteatosis, but rather exhibited improved glucose metabolism and normal insulin sensitivity. Glucose uptake was increased in muscle independently of insulin, associated with cell-surface translocation of glucose transporters and AMPK activation. Ex vivo assays showed these effects were likely secondary to blood-borne signals since PBCA sera or conditioned media from PBCA fat progenitors enhanced glucose uptake and activated AMPK in muscle cultures. Thus, adipose progenitor Wnt activation dissociates lipodystrophy from dysfunctional metabolism and highlights a fat-muscle endocrine axis, which may represent a potential therapy to lower blood glucose and improve metabolism.

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