Fuel oxidation in skeletal muscle is increased by nitric oxide/cGMP – evidence for involvement of cGMP‐dependent protein kinase

Young, Martin E.; Leighton, Brendan

doi:10.1016/s0014-5793(98)00143-4

Cited by 52 publications

(49 citation statements)

References 27 publications

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“…Such a positive effect of NO has also been found in insulin-resistant muscle cells derived from individuals with type 2 diabetes [21]. In addition, our observations, as those of several other groups, support the view that NO controls glucose transport via insulin-independent signalling pathways [48,49], including activation of cGMP-dependent protein kinase [50,51] and AMP-activated protein kinase-α1 [48,52]. Concerning the possible mechanisms involved, we found that restoration of endogenous nNOS in insulin-resistant muscle cells greatly improved translocation of GLUT4 at the plasma membrane in the presence of insulin, but not in basal conditions.…”

Section: Discussionsupporting

confidence: 89%

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Mezghenna¹,

Leroy²,

Azay-Milhau³

et al. 2013

Diabetologia

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Aims/hypothesis Insulin-mediated glucose transport and utilisation are decreased in skeletal muscle from type 2 diabetic and glucose-intolerant individuals because of alterations in insulin receptor signalling, GLUT4 translocation to the plasma membrane and microvascular blood flow. Catalytic activity of the muscle-specific isoform of neuronal nitric oxide synthase (nNOS) also participates in the regulation of glucose transport and appears to be decreased in a relevant animal model of drastic insulin resistance, the obese Zucker fa/fa rat. Our objective was to determine the molecular mechanisms involved in this defect. Methods Isolated rat muscles and primary cultures of myocytes were used for western blot analysis of protein expression, immunohistochemistry, glucose uptake measurements and GLUT4 translocation assays. Results nNOS expression was reduced in skeletal muscle from fa/fa rats. This was caused by increased ubiquitination of the enzyme and subsequent degradation by the ubiquitin proteasome pathway. The degradation occurred through a greater interaction of nNOS with the chaperone heat-shock protein 70 and the co-chaperone, carboxyl terminus of Hsc70-interacting protein (CHIP). In addition, an alteration in nNOS sarcolemmal localisation was observed. We confirmed the implication of nNOS breakdown in defective insulininduced glucose transport by demonstrating that blockade of proteasomal degradation or overexpression of nNOS improved basal and/or insulin-stimulated glucose uptake and GLUT4 translocation in primary cultures of insulin-resistant myocytes. Conclusions/interpretation Recovery of nNOS in insulinresistant muscles should be considered a potential new approach to address insulin resistance.

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Section: Discussionsupporting

confidence: 89%

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Mezghenna¹,

Leroy²,

Azay-Milhau³

et al. 2013

Diabetologia

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“…Conversely, cGMP increases the transport and utilization of fatty acids as metabolic substrates, which are associated with a more favorable respiratory quotient (6,14). Further, cGMP shifts the balance of flux of metabolic substrates from glycolysis to oxidative phosphorylation, optimizing ATP generation (15). The role of cGMP in regulating the supply of cellular energy is underscored by the recent discovery that NO induces mitochondrial biogenesis in a variety of cells by activation of sGC associated with cGMP-dependent induction of peroxisome proliferator-activated receptor ␥ coactivator 1␣, a master regulator of mitochondrial biogenesis (17).…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, in some models of severe hypoxic stress, NO induces complete and reversible metabolic stasis required to survive the insult (19). The importance of NO in defending against ischemia is underscored by its regulation of the transcription factor hypoxia inducible factor 1, a master regulator of cellular homeostasis in the context of oxygen insufficiency (20).Coordination of energy supply and demand is mediated, in part, by NO activation of soluble guanylyl cyclase (sGC) and the associated accumulation of intracellular cGMP concentration ([cGMP] i ) (9,10,12,15,16,18), yet the mechanisms coordinating cGMP-dependent and metabolic signaling, beyond the production of NO, remain undefined. Recently, a novel mechanism was identified by which adenine nucleotides inhibit GCs (21,22) that is analogous to P site inhibition of adenylyl cyclases (23).…”

mentioning

confidence: 99%

“…Metabolic stress, such as ischemia, stimulates NO synthases to produce NO from arginine (3). In turn, NO regulates the supply of energy by improving the delivery of substrates and oxygen to deprived tissues (4)(5)(6), regulating the intracellular delivery of metabolic substrates (7)(8)(9)(10), selection of substrates that support metabolism (6,(10)(11)(12)(13)(14), oxidation of metabolic substrates (15), generation of ATP by improving metabolic efficiency (16), and biogenesis of mitochondria (17). Conversely, NO reduces the demand for ATP by decreasing energyconsuming cell functions, for example, by reducing the activity of the contractile apparatus in muscle cells (ref.…”

mentioning

confidence: 99%

“…Coordination of energy supply and demand is mediated, in part, by NO activation of soluble guanylyl cyclase (sGC) and the associated accumulation of intracellular cGMP concentration ([cGMP] i ) (9,10,12,15,16,18), yet the mechanisms coordinating cGMP-dependent and metabolic signaling, beyond the production of NO, remain undefined. Recently, a novel mechanism was identified by which adenine nucleotides inhibit GCs (21,22) that is analogous to P site inhibition of adenylyl cyclases (23).…”

mentioning

confidence: 99%

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Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism

Ruiz-Stewart

Tiyyagura

Lin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Defending cellular integrity against disturbances in intracellular concentrations of ATP ([ATP]M etabolically active cells with high-energy requirements are particularly susceptible to structural and functional impairment when deprived of oxygen and substrates obligatory for generating ATP (1, 2). Maintenance of homeostasis requires these cells to respond to rapidly fluctuating energy demands in the context of varying supplies of metabolic substrates. Tight coordination between energy supply and demand is predicated on efficient communication and integration between metabolism, the steady-state and local availability of high-energy phosphates, and signaling mechanisms regulating cell functions. Although specific components and their interactions that transduce metabolic and energetic signaling have been described (1), molecular mechanisms mediating their coordination with cellular signaling remain incompletely understood.Production and release of NO represents one paracrine͞ autocrine mechanism coordinating energy supply and demand in tissues. Metabolic stress, such as ischemia, stimulates NO synthases to produce NO from arginine (3). In turn, NO regulates the supply of energy by improving the delivery of substrates and oxygen to deprived tissues (4-6), regulating the intracellular delivery of metabolic substrates (7-10), selection of substrates that support metabolism (6, 10-14), oxidation of metabolic substrates (15), generation of ATP by improving metabolic efficiency (16), and biogenesis of mitochondria (17). Conversely, NO reduces the demand for ATP by decreasing energyconsuming cell functions, for example, by reducing the activity of the contractile apparatus in muscle cells (ref. 18 and references therein). Moreover, in some models of severe hypoxic stress, NO induces complete and reversible metabolic stasis required to survive the insult (19). The importance of NO in defending against ischemia is underscored by its regulation of the transcription factor hypoxia inducible factor 1, a master regulator of cellular homeostasis in the context of oxygen insufficiency (20).Coordination of energy supply and demand is mediated, in part, by NO activation of soluble guanylyl cyclase (sGC) and the associated accumulation of intracellular cGMP concentration ([cGMP] i ) (9,10,12,15,16,18), yet the mechanisms coordinating cGMP-dependent and metabolic signaling, beyond the production of NO, remain undefined. Recently, a novel mechanism was identified by which adenine nucleotides inhibit GCs (21,22) that is analogous to P site inhibition of adenylyl cyclases (23). Indeed, the two-substituted adenine nucleotides 2-methylthio-ATP and 2-chloro-ATP inhibit NO-dependent cGMP production by directly binding to sGC (22). Synthetic two-substituted adenine nucleotides presumably exploit allosteric mechanisms regulated by endogenous cell products. The present study revealed that ATP is the native ligand mediating adenine nucleotide-dependent inhibition of sGC by binding directly to an allosteric purinergic site on the enzyme. More...

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Skeletal muscle glucose uptake during exercise: A focus on reactive oxygen species and nitric oxide signaling

Merry

McConell

2009

IUBMB Life

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SummaryLike insulin, muscle contraction (in vitro or in situ) and exercise increase glucose uptake into skeletal muscle. However, the contraction/exercise pathway of glucose uptake in skeletal muscle is an independent pathway to that of insulin. Indeed, skeletal muscle glucose uptake is normal during exercise in those who suffer from insulin resistance and diabetes. Thus, the pathway of contraction-mediated glucose uptake into skeletal muscle provides an attractive potential target for pharmaceutical treatment and prevention of such conditions, especially as skeletal muscle is the major site of impaired glucose disposal in insulin resistance. The mechanisms regulating skeletal muscle glucose uptake during contraction have not been fully elucidated. Potential regulators include Ca 21(via CaMK's and/or CaMKK), AMPK, ROS, and NO signaling, with some redundancy likely to be evident within the system. In this review, we attempt to briefly synthesize current evidence regarding the potential mechanisms involved in regulating skeletal muscle glucose uptake during contraction, focusing on ROS and NO signaling. While reading this review, it will become clear that this is an evolving field of research and that much more work is required to elucidate the mechanism(s) regulating skeletal muscle glucose uptake during contraction.

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Fuel oxidation in skeletal muscle is increased by nitric oxide/cGMP – evidence for involvement of cGMP‐dependent protein kinase

Cited by 52 publications

References 27 publications

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Counteracting neuronal nitric oxide synthase proteasomal degradation improves glucose transport in insulin-resistant skeletal muscle from Zucker fa/fa rats

Guanylyl cyclase is an ATP sensor coupling nitric oxide signaling to cell metabolism

Skeletal muscle glucose uptake during exercise: A focus on reactive oxygen species and nitric oxide signaling

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