Lactate-proton cotransport in skeletal muscle

Juel, Carsten

doi:10.1152/physrev.1997.77.2.321

Cited by 266 publications

(302 citation statements)

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“…MCT2 has a 10-fold higher affinity for substrates than does MCT1 and is, therefore, ideally suited for uptake at low substrate concentrations (Halestrap and Price, 1999). Additionally, because pH gradients drive transmembrane lactate movement (Poole and Halestrap, 1993;Juel, 1997), glycolytically generated lactic acid could initiate its own export. The expression patterns of LDH and MCT isoforms would tend to make astrocytes a lactate source and make axons a lactate sink.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Wender

Brown²,

Fern³

et al. 2000

J. Neurosci.

344

339

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We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for ϳ30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin, ␣-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid ( pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel. Key words: astrocytes; ␣-cyano-4-hydroxycinnamate; glucose; hypoglycemia; lactate; p-chloromercuribenzene sulfonic acid; quercetin; rat optic nerveThe function of brain glycogen is not well understood. Glycogen turns over rapidly in the brain, however, and turnover is enhanced when adjacent neural activity is increased (Orkand et al., 1973;Pentreath and Kai-Kai, 1982;Swanson et al., 1992). It is appealing to imagine that glycogen might serve to provide fuel to the brain when glucose is in short supply. Indeed, astrocytic glycogen in vitro is degraded rapidly when glucose is withdrawn (Dringen et al., 1993), and glycogen falls rapidly in vivo during ischemia, with a time course that is closely related to the depletion of ATP and the accumulation of lactate (Swanson et al., 1989a). These observations are consistent with the action of glycogen as a fuel source during glucose shortage, but they do not prove this hypothesis. Glycogen content varies by a factor of two or more between brain regions [it is highest in the brainstem and cerebellum and lowest in the striatum and white matter (Swanson et al., 1989a)]. Energy metabolism also varies significantly between different brain regions (Sokoloff et al., 1977). Therefore, glycogen could be more protective against glucose depletion in some areas than in others.Given all of the above, it is natural to wonder whether glycogen can enhance the survival and function of brain tissue in the absence of glucose. Surprisingly, only a single st...

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Section: Discussionmentioning

confidence: 99%

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Wender

Brown²,

Fern³

et al. 2000

J. Neurosci.

344

339

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“…The lactate production has been commonly seen as the first acidification mechanism of the microenvironment (7). The lactate accumulation results in the activation of the aerobic glycolytic metabolism (8) which increases the amount of cellular lactate that is transported outside the cell through the H + /lactate co-transporter (MCT) (9). The increase in aerobic glycolysis (8,10) provides to the tumor a metabolic environment characterized by low levels of serum, hypoxia and an acid extracellular pH.…”

Section: Introductionmentioning

confidence: 99%

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

Pérez-Sayáns¹

2009

Int J Oncol

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Abstract. Acidity is one of the main characteristics of OSCC (oral squamous cell carcinoma) as a solid tumor. The VATPase is the primary regulator of the tumor microenvironment, by means of proton extrusion to the extracellular medium. The decrease in extracellular pH confers the cells a resistant, highly invasive and metastatic phenotype. However, the acid medium confers an optimum pH to the degradative enzymes (such as proteases and MMPs) for their proper functioning. The C subunit (ATP6V1C) of V1 intra-membrane domain of the V-ATPase, is primarily responsible for its enzymatic function, through the control of a reversible dissociation of V0 and V1 domains. In this review, we describe the importance of V-ATPases in the control of tumor microenvironment, the potential strategies as protein targeting to improve the effectiveness of drug treatment and the role of the C subunit as the primarily responsible of the enzymatic control. The inhibition of the V-ATPase activity through PPIs (proton inhibitors) seems to reduce the destructive and metastatic capacity in tumors, such as hepatocellular carcinoma. Nevertheless, none of these inhibitors was proven to be useful in OSCC; therefore, it is highly important to carry out further studies in order to develop specific inhibitors of the C subunit, to control the devastating effects of OSCC. IntroductionThe main characteristics of the solid tumors (such as oral cancer) are the acidity and hypoxia, phenomena that result from the progression of metastatic cancer (1), the sensitivity to chemotherapeutic agents (2) and proliferation (3). In fact, a mechanism of resistance to cytotoxic drugs is the alteration of the pH gradient between the extracellular environment and cell cytoplasm (4).The cytosolic pH seems to be strictly regulated by four mechanisms: the family of sodium-proton exchangers (NHE), the family of bicarbonate transporters (BCT), the family of monocarboxylate transporters (MCT) and the proton pumps (ATPase) (5,6) ( Fig. 1). The lactate production has been commonly seen as the first acidification mechanism of the microenvironment (7). The lactate accumulation results in the activation of the aerobic glycolytic metabolism (8) which increases the amount of cellular lactate that is transported outside the cell through the H + /lactate co-transporter (MCT) (9). The increase in aerobic glycolysis (8,10) provides to the tumor a metabolic environment characterized by low levels of serum, hypoxia and an acid extracellular pH. This microenvironment increases the invasive ability of the tumor and the expression of growth and angiogenic factors/receivers (11). All this is correlated to an increment of the intracellular pH, an aggravation of the initial development of the interstitial acid microenvironment and a reversed transmembrane pH gradient (11,12). This increase in the intracellular pH is concomitant with an increment of DNA synthesis (8,13,14), cell cycle progression (15-17), serum and substrate-independent growth (8) and the in vivo growth of the tumor (8,18) and ...

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“…The latter assumption was demonstrated to be incorrect, as long as (i) lactate anions at equilibrium are mostly located in the extracellular phase (Roos 1975), so that (ii) lactate concentration gradients between intracellular and interstitial fluids exist, and (iii) a passive equilibrium in lactate concentration is not possible. The further characterization of lactate exchange in terms of lactate-proton co-transport shed new light on the equilibria of lactate dynamics (Bonen 2001;Juel 1997Juel , 1998Juel and Halestrap 1999), even at the subcellular level (Hashimoto and Brooks 2008). Under these circumstances, it is uneasy to calculate the precise amount of lactate that is .…”

Section: The Meaning Of Blood Lactate In Supramaximal Exercisementioning

confidence: 99%

Energetics of Muscular Exercise

Ferretti¹

2015

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Lactate-proton cotransport in skeletal muscle

Cited by 266 publications

References 0 publications

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

Energetics of Muscular Exercise

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