RESUMEN
During the past decade, a detailed understanding has emerged of the aminergic and peptidergic neural pathways present within the brain that regulate appetite. Central among the peptide regulators is neuropeptide Y (NPY), a potent orexigenic agent that acts through five different receptor subtypes. Efforts to find novel appetite suppressant drugs that inhibit the interaction of NPY with either the NPY Y1 or NPY Y5 receptor subtypes have proven disappointing. Attempts have now been made to identify an NPY Y2 stimulator that will suppress appetite. Within the hypothalamus, NPY Y2 receptors have a predominantly presynaptic location where they act to inhibit NPY release. Stimulation of NPY Y2 receptors with synthetic peptide ligands or the gut derived peptide PY3-36 has been shown to reduce food intake. The NPY Y2 receptor has a wide distribution both within the brain and in the periphery. Stimulation of the NPY Y2 subtype at these sites produces a wide array of effects unrelated to changes in food intake. In consequence, the administration of both endogenous and exogenous agonists of the NPY Y2 receptor is likely to cause side effects, particularly regarding pituitary hormone release, as well as on the cardiovascular and gastrointestinal systems. The possibility that long-term NPY Y2 agonism could cause bone thinning and retinal angiogenesis are of particular concern and will need to be investigated as drug discovery moves forward.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Obesidad/tratamiento farmacológico , Receptores de Neuropéptido Y/metabolismo , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/química , Humanos , Ligandos , Estructura Molecular , Obesidad/metabolismoRESUMEN
1. Endothelin-1 (ET-1) and tumor necrosis factor alpha (TNFalpha) by their action on adipocytes have been independently linked to the pathogenesis of insulino-resistance. In isolated adipocytes, TNFalpha induces the expression of the inducible nitric oxide synthase (iNOS). The purpose of the present work was, in the 3T3-F442A adipocyte cell line, to characterise TNFalpha-induced iNOS expression and to determine whether or not ET-1 could influence TNFalpha-induced iNOS expression and NO production. 2. In differentiated 3T3-F442A, treatment with TNFalpha (20 ng ml(-1)) induced the expression of a functional iNOS as demonstrated by nitrite assay, Western blot, reverse transcription-polymerase chain reaction and Northern blot analysis. TNFalpha-induced iNOS expression requires nuclear factor kappaB activation, but does not necessitate the activation of the PI-3 kinase/Akt and P38-MAP kinase pathways. 3. ET-1, but not ET-3, inhibited the TNFalpha-induced expression of iNOS protein and mRNA as well as nitrite production. The effects of ET-1 were blocked by a specific ETA (BQ123, pA(2) 7.4) but not by a specific ETB receptor antagonist (BQ788). 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype. 4. The inhibitory effect of ET-1 was not affected by bisindolylmaleimide, SB 203580 or indomethacin, inhibitors of protein kinase C, p38-MAP kinase and cyclooxygenase, respectively, and was not associated with cAMP production. However, the effect of ET-1 was partially reversed by wortmannin, suggesting the involvement of PI3 kinase in the transduction signal of ET-1. 5. Differentiated 3T3-F442A adipocytes did not release ET-1 with or without exposure to TNFalpha, although the mRNA for preproET-1 was detected in both pre- and differentiated adipocytes. 6. Thus, these results confirm that adipocytes are a target for circulating ET-1 and demonstrate that the activation of the ETA receptor subtype can prevent TNFalpha-induced iNOS expression.
Asunto(s)
Adipocitos/enzimología , Endotelina-1/fisiología , Regulación Enzimológica de la Expresión Génica/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Factor de Necrosis Tumoral alfa/farmacología , Células 3T3 , Adipocitos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ratones , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
Experiments were designed to investigate whether or not oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in the aorta of spontaneously hypertensive rat (SHR). Isometric tension was measured in aortic rings taken from adult male SHR and Wistar-Kyoto rat (WKY) in the presence of NG-nitro-L-arginine. Endothelium-dependent contractions to acetylcholine were significantly greater in rings from SHR compared to WKY. Oxygen-derived free radicals, generated from xanthine plus xanthine oxidase, induced contractions that were larger in aortas from SHR than from WKY. Contractions to acetylcholine and free radicals were abolished by a selective TP-receptor antagonist, S 18886, and a preferential inhibitor of cyclo-oxygenase-1, valeryl salicylate, but not by a preferential inhibitor of cyclo-oxygenase-2, NS-398. Allopurinol, deferoxamine and the combination of superoxide dismutase plus catalase inhibited the contractions to oxygen-derived free radicals but did not significantly affect those to acetylcholine. In contrast, diethyldithiocarbamic acid, an inhibitor of superoxide dismutase, or Tiron, a scavenger of superoxide anion, reduced endothelium-dependent contractions to acetylcholine in aortas from SHR. The effect of these two drugs was additive. In SHR chronically treated with dimethylthiourea endothelium-dependent contractions to acetylcholine were decreased, and reduced further by acute in vitro exposure to deferoxamine or the combination of superoxide dismutase plus catalase. These results suggest that in the SHR aorta acetylcholine-induced endothelium-dependent contractions involve endothelial superoxide anion production and the subsequent dismutation into hydroxyl radicals and/or hydrogen peroxide. The free radicals activate cyclo-oxygenase-1, most likely to produce endoperoxides. Activation of TP-receptors is required to observe endothelium-dependent contractions to acetylcholine or endothelium-independent contractions in response to free radical generation.
Asunto(s)
Acetilcolina/farmacología , Endotelio Vascular/fisiología , Músculo Liso Vascular/fisiología , Oxígeno/metabolismo , Tiourea/análogos & derivados , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiología , Depuradores de Radicales Libres/farmacología , Radicales Libres/metabolismo , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especificidad de la Especie , Tiourea/farmacologíaRESUMEN
This review outlines the physiology of protein tyrosine phosphatase 1B (PTP1B) and its potential involvement in the states of insulin resistance that characterizes both obesity and type 2 diabetes. The primary focus of this review is upon the elucidation of the role and control of PTP1B enzyme activity in obesity and type 2 diabetes. Furthermore, since selectivity and cell permeability are the two most important requirements for the development of successful PTP1B inhibitors, recent progress in finding compounds meeting these criteria are discussed.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/farmacología , Inhibidores Enzimáticos/farmacología , Humanos , Hipoglucemiantes/farmacología , Insulina/fisiología , Ratones , Ratones Noqueados , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Especificidad por SustratoRESUMEN
Neuropeptide Y (NPY) is present in the hypothalamus, where it is believed to play a key role in the control of food intake. Evidence for this assertion has come from studies demonstrating that acute administration of NPY into the hypothalamus or into the brain ventricles leads to increased food intake. In the case of chronic administration, the hyperphagic effects of NPY are prolonged, leading to the development of an obese state. NPY levels in the hypothalamus are temporally correlated with food intake and are markedly elevated in response to energy depletion. However, attempts to demonstrate an important role for NPY in the control of food intake using NPY knockout mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies has produced equivocal results. Despite this, many pharmaceutical companies have moved ahead with the search for antagonists of NPY receptor subtypes as appetite suppressant/anti-obesity agents. Antagonists of the NPY Y5 subtype seemed initially promising since analogs of NPY with high selectivity for this receptor strongly stimulated food intake. However, once again, attempts to inhibit the signaling of NPY through the NPY Y5 receptor produced equivocal effects on food intake. Many thousands of NPY Y5 antagonists have been made which fall into two main categories: those that influence food intake and those that do not. Those compounds that do inhibit food intake appear to do so by interactions with non-NPY Y5 related mechanisms. Thus, current evidence would suggest that antagonists of NPY acting through the NPY Y5 receptor subtype will not be useful appetite suppressant/anti-obesity agents.
Asunto(s)
Fármacos Antiobesidad/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Ingestión de Alimentos/fisiología , Humanos , Ratones , Ratones Noqueados , Neuropéptido Y/fisiologíaRESUMEN
The potency of three sulphonylureas, glibenclamide, glimepiride and gliclazide in antagonizing the vasorelaxant action of openers of adenosine triphosphate (ATP)-regulated K+ channel (KATP) was studied in vivo and in vitro in micro- and macrovessels, respectively. In the hamster cheek pouch, the vasodilatation and the increase in vascular diameter and blood flow induced by diazoxide were markedly reduced by the addition of either glibenclamide or glimepiride (0.8 microm) while they were not affected by gliclazide up to 12 microm. Similarly, in rat and guinea-pig isolated aortic rings, glibenclamide, glimepiride and gliclazide reduced the vasodilator activity of cromakalim. However, the inhibitory effect of gliclazide was considerably less when compared with either glimepiride or glibenclamide. These results suggest that, in contrast to glibenclamide and glimepiride, therapeutically relevant concentrations of gliclazide do not block the vascular effects produced by KATP channel openers in various in vitro and in vivo animal models.
Asunto(s)
Hipoglucemiantes/farmacología , Canales de Potasio/efectos de los fármacos , Compuestos de Sulfonilurea/farmacología , Vasodilatación/efectos de los fármacos , Adenosina Trifosfato/fisiología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Cricetinae , Cromakalim/antagonistas & inhibidores , Cromakalim/farmacología , Diazóxido/antagonistas & inhibidores , Diazóxido/farmacología , Interacciones Farmacológicas , Gliclazida/farmacología , Gliburida/farmacología , Cobayas , Técnicas In Vitro , Activación del Canal Iónico , Masculino , Canales de Potasio/fisiología , Ratas , Ratas Wistar , Especificidad de la Especie , Vasodilatadores/antagonistas & inhibidores , Vasodilatadores/farmacologíaAsunto(s)
Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Sistemas de Liberación de Medicamentos/tendencias , Ácidos Grasos/metabolismo , Adipocitos/química , Tejido Adiposo/química , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Diseño de Fármacos , Ingestión de Energía , Humanos , Esperanza de Vida , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/prevención & control , Oxidación-ReducciónRESUMEN
The plant fenugreek has been used for centuries as a treatment for diabetes. This article presents evidence that the major isomer of 4-hydroxyisoleucine, an atypical branched-chain amino acid derived from fenugreek, is responsible for the effects of this plant on glucose and lipid metabolism. 4-Hydroxyisoleucine was demonstrated to stimulate glucose-dependent insulin secretion by a direct effect on pancreatic islets. In addition to stimulating insulin secretion, 4-hydroxyisoleucine reduced insulin resistance in muscle and/or liver by activating insulin receptor substrate-associated phosphoinositide 3 (PI3) kinase activity. 4-Hydroxyisoleucine also reduced body weight in diet-induced obese mice. The decrease in body weight was associated with a marked decrease in both plasma insulin and glucose levels, both of which are elevated in this animal model. Finally, 4-hydroxyisoleucine decreased elevated plasma triglyceride and total cholesterol levels in a hamster model of diabetes. Based on the beneficial metabolic properties that have been demonstrated, 4-hydroxyisoleucine, a simple, plant-derived amino acid, may represent an attractive new candidate for the treatment of type 2 diabetes, obesity and dyslipidemia, all key components of metabolic syndrome.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Isoleucina/análogos & derivados , Síndrome Metabólico/tratamiento farmacológico , Fitoterapia , Trigonella , Animales , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Isoleucina/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Síndrome Metabólico/metabolismo , Preparaciones de Plantas/uso terapéuticoRESUMEN
Neuropeptide Y (NPY) is present in the hypothalamus, where it is believed to play a key role in the control of food intake. Evidence for this assertion has come from studies demonstrating that acute administration of NPY into the hypothalamus or into the brain ventricles leads to increased food intake. In the case of chronic administration, the hyperphagic effects of NPY are prolonged leading to the development of an obese state. NPY levels in the hypothalamus are temporally correlated with food intake and are markedly elevated in response to energy depletion. However, attempts to demonstrate an important role for NPY in the control of food intake using NPY knockout mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies has produced equivocal results. Despite this many pharmaceutical companies have moved ahead with the search for agonists and antagonists of NPY receptor subtypes as anti-obesity agents. Antagonists of the NPY Y(1) and NPY Y(5) receptor subtype initially looked promising since analogs of NPY with high selectivity for these receptors strongly stimulated food intake. However, attempts to inhibit the signaling of NPY through the NPY Y(1) and NPY Y(5) receptors has produced equivocal effects on food intake. Recent observations that the gut derived peptide PYY(3-36) suppresses appetite by stimulating both peripherally and centrally located NPY Y(2) receptors remain controversial in animals but the effects look promising in human studies. Whether this will be the long awaited therapy based on manipulation of NPY receptors will await further studies of long term efficacy and more importantly a favorable side effect profile.
Asunto(s)
Peso Corporal/fisiología , Sistemas de Liberación de Medicamentos/métodos , Receptores de Neuropéptido/fisiología , Animales , Peso Corporal/efectos de los fármacos , Humanos , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/antagonistas & inhibidoresRESUMEN
This study was designed to determine the effect of pteridines, R- and S-tetrahydrobiopterin, sepiapterin, and dihydrobiopterin on endothelium-dependent contractions to acetylcholine in isolated aortas from spontaneously hypertensive rat and normotensive Wistar-Kyoto rat. The noncumulative addition of redox-active pteridines R- and S-tetrahydrobiopterin (but not the oxidized analogues sepiapterin and dihydrobiopterin) produced a concentration-dependent transient contraction in isolated aortic rings from both normotensive and hypertensive rats. R- and S-tetrahydrobiopterin (but not sepiapterin or dihydrobiopterin) potentiated the endothelium-dependent contractions to acetylcholine but only in aortas from hypertensive rats and in the presence of N(G)-nitro-L-arginine. In these aortas, the generation of oxygen-derived free radicals by the combination of xanthine plus xanthine oxidase also potentiated the endothelium-dependent contractions to acetylcholine. The presence of R-tetrahydrobiopterin did not alter the characteristics of the endothelium-dependent contractions because they were inhibited by valeryl salicylate, an inhibitor of cyclooxygenase-1, by S18886, a TP-receptor antagonist or by Tiron, a cell permeable superoxide anion scavenger. However, the contractions to acetylcholine, which are unaffected by the combination of superoxide dismutase and catalase, become significantly inhibited by these two scavengers in the presence of R-tetrahydrobiopterin. In the presence of N(G)-nitro-L-arginine, R-tetrahydrobiopterin did not affect the contractions to phenylephrine, U 46619, or to oxygen-derived free radicals generated by xanthine plus xanthine oxidase. These results indicate that the production of superoxide by the autoxidation of tetrahydrobiopterin selectively enhances endothelium-dependent contractions in the spontaneously hypertensive rat when nitric oxide synthase is inhibited.
Asunto(s)
Biopterinas/análogos & derivados , Biopterinas/farmacología , Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Vasoconstricción , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Aorta/fisiopatología , Técnicas de Cultivo , Ditiotreitol/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Inhibidores Enzimáticos/farmacología , Hipertensión/enzimología , Hipertensión/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Pteridinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reductoras/farmacología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
A modified bioassay system was designed to demonstrate the diffusible nature of endothelium-derived contracting factor(s) released by acetylcholine in the aorta of spontaneously hypertensive rat. In "sandwich"-like layered preparation, isometric tension was recorded from a bioassay strip (without endothelium) in the presence of N(G)-nitro-L-arginine and tetrahydrobiopterin to selectively potentiate endothelium-dependent contractions. A donor strip (with or without endothelium) was stitched on the bioassay tissue so that it did not directly contribute to the recorded contractions. Acetylcholine induced contractions that occurred only when the donor strip was with endothelium. Superoxide dismutase did not affect but catalase and the combination of superoxide dismutase plus catalase significantly decreased the endothelium-dependent contraction. The contractions in the layered preparations were abolished when the donor strip with endothelium was treated previously with valeryl salicylate, an irreversible cyclooxygenase-1 inhibitor, but remained unaffected when the bioassay strip was treated with the compound. Previous treatment of the bioassay strip alone with S 18886 abolished the contractile response, whereas treatment of the donor strip with endothelium by the selective TP receptor antagonist only produced a moderate inhibition. These results indicate that in the aorta of spontaneously hypertensive rats, endothelium-dependent contractions to acetylcholine involve a diffusible substance(s) released by the endothelium. The production of this contracting factor(s) requires the activation of endothelial cyclooxygenase-1, and its action the activation of TP receptors on the vascular smooth muscle cells.
Asunto(s)
Aorta/fisiopatología , Biopterinas/análogos & derivados , Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Vasoconstricción , Vasoconstrictores/farmacología , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Bioensayo/métodos , Biopterinas/farmacología , Ciclooxigenasa 1 , Difusión , Endotelio Vascular/química , Endotelio Vascular/enzimología , Hipertensión/enzimología , Hipertensión/metabolismo , Isoenzimas/análisis , Isoenzimas/fisiología , Masculino , Proteínas de la Membrana , Músculo Liso Vascular/química , Prostaglandina-Endoperóxido Sintasas/análisis , Prostaglandina-Endoperóxido Sintasas/fisiología , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Receptores de Tromboxanos/análisis , Receptores de Tromboxanos/fisiología , Vasoconstrictores/análisisRESUMEN
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, with a major role in stimulation of feeding behavior in mammals. MCH signals in the brain occur via two seven-transmembrane G protein-coupled receptors, namely MCH1 (SLC-1, MCH(1), MCH-R1, or MCH-1R) and MCH2 (SLT, MCH(2), MCH-R2, or MCH-2R). In this study, we demonstrate that the pro-MCH(131-165) peptide neuropeptide-glutamic acid-isoleucine (NEI)-MCH is more potent than MCH in stimulating feeding in the rat. Using rat MCH1-expressed human embryonic kidney 293 cells, we show that NEI-MCH exhibits 5-fold less affinity in a binding assay and 2-fold less potency in a cAMP assay than MCH. A similar 7- to 8-fold shift in potency was observed in a Ca(2+)(i) assay using rat MCH1 or human MCH2-transfected Chinese hamster ovary cell models. This demonstrates that NEI-MCH is not a better agonist than MCH at either of the MCH receptors. Then, we compared the proteolysis resistance of MCH and NEI-MCH to rat brain membrane homogenates and purified proteases. Kinetics of peptide degradation using brain extracts indicated a t(1/2) of 34.8 min for MCH and 78.5 min for NEI-MCH with a specific pattern of cleavage of MCH but not NEI-MCH by exo- and endo-proteases. Furthermore, MCH was found highly susceptible to degradation by aminopeptidase M and endopeptidase 24.11, whereas NEI-MCH was fully resistant to proteolysis by these enzymes. Therefore, our results strongly suggest that reduced susceptibility to proteases of NEI-MCH compared with MCH account for its enhanced activity in feeding behavior. NEI-MCH represents therefore the first MCH natural functional "superagonist" so far described.
Asunto(s)
Estimulantes del Apetito/farmacología , Ventrículos Cerebrales/fisiología , Conducta Alimentaria/efectos de los fármacos , Hormonas Hipotalámicas/farmacología , Fragmentos de Péptidos/farmacología , Precursores de Proteínas/farmacología , Secuencia de Aminoácidos , Animales , Estimulantes del Apetito/administración & dosificación , Células CHO , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Línea Celular , Ventrículos Cerebrales/efectos de los fármacos , Cricetinae , AMP Cíclico/farmacología , Humanos , Hormonas Hipotalámicas/administración & dosificación , Hormonas Hipotalámicas/química , Inyecciones Intraventriculares , Riñón , Cinética , Masculino , Datos de Secuencia Molecular , Fragmentos de Péptidos/administración & dosificación , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/química , Ratas , Ratas Wistar , TransfecciónRESUMEN
The mitochondrial uncoupling protein of brown adipose tissue (UCP1) was expressed in skeletal muscle and heart of transgenic mice at levels comparable with the amount found in brown adipose tissue mitochondria. These transgenic mice have a lower body weight, and when related to body weight, food intake and energy expenditure are increased. A specific reduction of muscle mass was observed but varied according to the contractile activity of muscles. Heart and soleus muscle are unaffected, indicating that muscles undergoing regular contractions, and therefore with a continuous mitochondrial ATP production, are protected. In contrast, the gastrocnemius and plantaris muscles showed a severely reduced mass and a fast to slow shift in fiber types promoting mainly IIa and IIx fibers at the expense of fastest and glycolytic type IIb fibers. These observations are interpreted as a consequence of the strong potential dependence of the UCP1 protonophoric activity, which ensures a negligible proton leak at the membrane potential observed when mitochondrial ATP production is intense. Therefore UCP1 is not deleterious for an intense mitochondrial ATP production and this explains the tolerance of the heart to a high expression level of UCP1. In muscles at rest, where ATP production is low, the rise in membrane potential enhances UCP1 activity. The proton return through UCP1 mimics the effect of a sustained ATP production, permanently lowering mitochondrial membrane potential. This very likely constitutes the origin of the signal leading to the transition in fiber types at rest.