- Research article
- Open Access
Increased expression and local accumulation of the Prion Protein, Alzheimer Aβ peptides, superoxide dismutase 1, and Nitric oxide synthases 1 & 2 in muscle in a rabbit model of diabetes
© Bitel et al; licensee BioMed Central Ltd. 2010
- Received: 25 January 2010
- Accepted: 6 September 2010
- Published: 6 September 2010
Muscle disease associated with different etiologies has been shown to produce localized accumulations of amyloid and oxidative stress-related proteins that are more commonly associated with neurodegeneration in the brain. In this study we examined changes in muscle tissue in a classic model of diabetes and hyperglycemia in rabbits to determine if similar dysregulation of Alzheimer Aβ peptides, the prion protein (PrP), and superoxide dismutase 1 (SOD1), as well as nitric oxide synthases is produced in muscle in diabetic animals. This wild-type rabbit model includes systemic physiological expression of human-like Alzheimer precursor proteins and Aβ peptides that are considered key in Alzheimer protein studies.
Diabetes was produced in rabbits by injection of the toxic glucose analogue alloxan, which selectively enters pancreatic beta cells and irreversibly decreases insulin production, similar to streptozotocin. Quadriceps muscle from rabbits 16 wks after onset of diabetes and hyperglycemia were analyzed with biochemical and in situ methods. Immunoblots of whole muscle protein samples demonstrated increased PrP, SOD1, as well as neuronal and inducible Nitric oxide synthases (NOS1 and NOS2) in diabetic muscle. In contrast, we detected little change in Alzheimer Aβ precursor protein expression, or BACE1 and Presenilin 1 levels. However, Aβ peptides measured by ELISA increased several fold in diabetic muscle, suggesting a key role for Aβ cleavage in muscle similar to Alzheimer neurodegeneration in this diabetes model. Histological changes in diabetic muscle included localized accumulations of PrP, Aβ, NOS1 and 2, and SOD1, and evidence of increased central nuclei and cell infiltration.
The present study provides evidence that several classic amyloid and oxidative stress-related disease proteins coordinately increase in overall expression and form localized accumulations in diabetic muscle. The present study highlights the capacity of this wild-type animal model to produce an array of hallmark pathological features that have also been described in other muscle diseases.
- Diabetic Animal
- Inclusion Body Myositis
- Localize Accumulation
- Diabetic Rabbit
- Diabetic Muscle
Muscle disease has been linked with aging as well as metabolic conditions, which prominently includes diabetes [1–4]. In diabetes, weakness, wasting, and pain have been cited which commonly occur in quadriceps muscles. Muscle disease has been studied in a variety of conditions including animal models of high dietary cholesterol , pathological response to the drug chloroquine [6, 7], and inclusion body myositis . Each of these muscle conditions has been shown to produce localized accumulations of PrP and Aβ peptides, as well as superoxide dismutase 1 (SOD1) and Nitric oxide synthases 1 and 2 (NOS1: neuronal nNOS; and NOS2: inducible iNOS) [9, 10]. These proteins are more often thought of in the context of neurodegenerative diseases (PrP, mad cow disease; Aβ, Alzheimer disease (AD); and SOD1, Amyotrophic lateral sclerosis (ALS)/Lou Gehrig's disease). However, these proteins have also been linked with diabetes. For example, strong associations between AD and diabetes has led to use of the term 'Type III diabetes' for AD . More recently, extensive epidemiological data linking AD and diabetes are now supported by direct mechanistic links between Aβ peptide action and insulin receptor dysfunction in cells. Aβ peptides form small diffusible oligomers that can interact directly with insulin receptors (IR) on cell surfaces. This can lead to coordinate endocytosis of Aβ/IR complexes, and intracellular co-localization, which has been shown in cultured cells. Moreover, this process has also been linked with insulin resistance [12, 13]. Evidence for a role for these amyloid disease proteins in muscle disease also comes from transgenic models, where muscle-specific expression of PrP, Aβ or SOD1 also produced localized accumulation. In addition, these muscle disease models also showed evidence of central nuclei and cell infiltration [14–19].
Deleterious activities attributed to these disease proteins is linked with an ability to produce oxidative stress, and also to form oligomers and aggregates in brain, muscle, and lens, as well as pancreas during onset and progression of Type II diabetes [20–25]. Diabetes and hyperglycemia increase systemic and tissue-specific oxidative stress loads. Consistent with this, increases in glucose oxidation products have been measured in muscle as well as in the circulatory system in diabetic animals [26, 27]. Classic oxidative stress responses include stimulation of stress signaling pathways and activation of genes linked with stress and also cell proliferation, in part due to the activation of AP1 and NFκB stress-responsive transcription factors [28–30]. Previously, our laboratory also demonstrated PrP and Alzheimer Aβ Precursor Protein (AβPP) gene expression increase significantly during a response to oxidative stress [31–33]. Stress in tissues that include muscle can be aggravated by diabetes and high glucose that contributes to increased amyloid and oxidative stress-related protein expression and formation of protein deposits as well as producing further oxidative stress. In addition, stress signaling can affect normal cell migration and trophic responses [31, 34].
In the present study we examined expression of PrP, AβPP and Aβ, SOD1, NOS1 and NOS2 in muscle in 4 month-old wild-type (wt) rabbits induced to become diabetic and hyperglycemic with alloxan. This model has been used to model diabetic complications in >500 studies over the past 50 yrs. Unlike mice and rats, wt rabbits produce Aβ peptides with the same sequence as humans. Mouse and rat Aβ has lower metal affinity that limits its ability to form oligomers and also to produce oxidative stress [20–23]. Like streptozotocin, alloxan is a toxic glucose analogue that selectively enters pancreatic β-cells via Glut2 glucose transporters, which are not expressed in muscle [35–37]. Alloxan forms toxic reactive oxygen species in pancreatic β-cells, and irreversibly decreases insulin production. Consistent with these activities, alloxan has a short half-life (~1.5 min), and is cleared quickly. Here, we examined quadriceps from diabetic and normal control rabbits 16 weeks after onset of diabetes and hyperglycemia. Studies of diabetic complications in other organs using this model indicated a time frame of 4-6 mos produced substantial effects [38, 39]. We identified substantial increases in PrP, SOD1, NOS1, and NOS2 expression on immunoblots of total muscle protein samples from diabetic animals, and ELISA assays measured several fold increases in Aβ peptides produced in diabetic muscle. Consistent with those findings, in situ examination of diabetic and control muscle identified localized accumulations of each of these proteins in muscle sections from diseased animals, and also identified muscle fibers with central nuclei and evidence of cell infiltration.
Production of diabetes and hyperglycemia in rabbits
New Zealand white rabbits (Covance) were used in accordance with NIH guidelines and approved protocols. All rabbits were males to limit hormonal effects at this stage of our studies. 3-4 month-old rabbits were housed at RT° with a 12 hr light/12 hr dark cycle, and fed 260 gm/day of a standard pellet diet with free access to dH2O. Seven rabbits were given 150 mg/kg alloxan (Sigma) in a single injection through a catheter in an ear vein and six untreated rabbits were used as normal controls. During the initial 24 hrs after alloxan, 10% glucose in dH2O was given to reduce adverse effects. After one week, rabbits exhibiting a consistent elevation in blood glucose (> 350 mg/dl) remained in the study. Normal blood glucose in control rabbits was ~100 mg/dl, and blood glucose was monitored prior to feeding each morning. At the start of this study, rabbits weighed ~2.5 kg. After 16 wks, rabbits were taken for analysis. Diabetic rabbits gained an average of 225 gm (s.d. 180 gm) and control rabbits gained on average 500 gm (s.d. 50 gm), with no rabbits losing weight.
Immunohistochemistry and Immunofluorescence
Paraffin sections were prepared from buffered 4% paraformaldehyde fixed muscle tissues. Sections were de-waxed in xylenes and graded alcohol washes, and blocked in PBS with 10% serum corresponding to the 2° antibody used. For immunofluorescence detection, fluor-conjugated 2° antibodies (Invitrogen) were used to visualize complexes. Immunohistochemical staining used horseradish peroxidase Vectastain kits (Vector labs). Antibodies included: mouse mAb anti-PrP (Cayman Chemical Co.), rabbit mAb anti-PrP (Epitomics), 6E10 and 4G8 mAb anti-Aβ (Covance), rabbit anti-AβPP (Sigma), sheep polyclonal anti-SOD1 (CalBiochem) and mouse mAb anti-SOD1 (Thermo), mouse mAb anti-NOS1 and anti-NOS2 (BD Biosciences).
Immunoblot detection of proteins
Samples of total protein from quadriceps muscle from diabetic and normal control animals were homogenized in SDS sample buffer with reducing agent and protease inhibitors (Calbiochem), for electrophoresis on Bis-Tris gels (Invitrogen). Proteins resolved by molecular weight were blotted to PVDF filters, and blocked in 5% non-fat milk in PBS pH 7.4. Filters were probed overnight with antibodies diluted in PBS according to the supplier. HRP conjugated 2° antibodies (Jackson Labs) were used to visualize complexes with chemiluminescence kits on films (Amersham).
To quantify Aβ peptide levels in muscle tissue, ELISA kits (Covance) specific for Aβ peptides ending at amino acid 42 or amino acid 40 were used (x-42; x-40). These standard sandwich ELISAs used a primary antibody that recognized the Aβ peptides' C-terminus and distinguished Aβ40 from Aβ42, and the secondary antibody recognized an internal peptide epitope. Controls and standard curves were prepared as directed by the supplier. 150 mg of muscle tissue from experimental and control animals was solubilized in 5 M Guanidine buffer, and colorimetric quantification of HRP reaction product linked to antibody-antigen complexes was measured with a standard spectrometer plate reader. ELISA assays were performed three times for x-40 and x-42 Aβ peptides. A statistical power analysis indicated that three rabbits are theoretically required to provide sufficient power for this study, and this was also true when accounting for several fold differences we measured in our assays http://www.dssresearch.com/toolkit/sscalc/size.asp. For the ELISAs, the p-values were calculated using a 2-tailed ANOVA statistical test.
PrP, Aβ, SOD1, NOS1 and NOS2 overall expression increases in total muscle protein samples from diabetic rabbits
Deleterious effects of nitric oxide in disease are thought to involve reactive NO species that can form via NO interactions with molecular oxygen or superoxide radicals . In addition, deleterious increases in the level of NO also induce nitrosative stress and stimulate cellular pathways that contribute to protein S-nitrosylation and denitrosylation involving metalloproteins . Increased expression and accumulation of Nitric oxide synthases 1 and 2 has been observed in muscle and brain diseases that are also associated with these amyloid proteins which are capable of producing oxidative stress . When we examined changes in NOS1 and NOS2 protein levels in diabetic muscle on immunoblots, we identified a ~2-fold increase in NOS1 and NOS2 in total protein samples (Fig. 1B). NOS1 was detected more strongly in control muscle than NOS2, where NOS2 was barely detected in normal control muscle in our assays.
Local accumulations of amyloid and oxidative stress-related proteins as well as disorganized fibers, occur in muscle in diabetic animals
In the present study we demonstrated that several classic amyloid and oxidative stress-related disease proteins increase in overall expression and produce localized accumulations in quadriceps muscle in diabetic rabbits in our wt animal model. We also identified histopathology that included the presence of central nuclei in muscle fibers and increased cell infiltration, also described in other muscle diseases and models. Our results indicate that stress produced during the onset and progression of diabetes and hyperglycemia induced in mature animals stimulates the expression of these proteins throughout the muscle. However, future studies are needed to determine the factors and processes involved in producing focal accumulations of these proteins in muscle fibers in diabetic animals. Our study determined that significant pathology was produced at 16 weeks in unmanaged diabetes and hyperglycemic animals in our model, and further studies can determine the relationship and onset of pathology associated with each of these proteins.
Our experiments that analyzed Aβ peptides used several antibodies that each identified increased production of Aβ in diabetic muscle. ELISA assays measured ~7-fold increases in Aβ peptides in total muscle protein samples. These assays used primary antibodies that recognized presenilin/γ-secretase cleavage sites at amino acid 40 or 42, and a common secondary antibody that recognized an epitope several amino acids from the Aβ C-terminus. As a result, these assays have the capability to measure a variety of peptide lengths that are cleaved at a γ-secretase site at one end. Antibodies used in our in situ Aβ analysis detected epitopes close to the N-terminus, and also identified increased Aβ in deposits in diabetic muscle. Although these antibodies can potentially detect the AβPP parent protein, we did not observe increased AβPP expression in vitro or in muscle sections with AβPP specific antibodies. Together, these findings indicate increased Aβ in diabetic muscle is largely the result of increased proteolytic Aβ cleavage. These observations are consistent with studies on Aβ production in the brain, where Aβ production in that organ has not been shown to correspond with significant changes in AβPP levels either. In addition, these observations in muscle are supported by findings in transgenic mice that showed transgenic co-expression of presenilin with AβPP in muscle also leads to enhanced Aβ production.
Each of the proteins examined here is linked with oxidative stress as well as with protein misfolding disease mechanisms. Studies of amyloid protein structure in neurodegenerative disease indicated these proteins can act synergistically to produce insoluble aggregates. For example, pathological changes in PrP structure can contribute to misfolding of other PrP proteins, and can also influence folding of nearby Aβ peptides in neurons . The present finding of overlapping protein accumulations in diabetic muscle suggests similar interactions may also contribute to protein deposits containing multiple proteins in diabetic muscle. In addition, examination of the relative order and rate of production for each of these disease-related proteins at earlier stages after onset of diabetes and hyperglycemia in this model can also help sort out relative contributions of each protein in the formation of deposits in muscle fibers.
The present findings demonstrating a similar set of proteins accumulate in muscle fibers in this diabetes model as in other muscle disease conditions discussed above, is also supported by gene array studies that examined global gene expression changes in different models of muscle disease. Microarray experiments comparing expression profiles in muscle disuse, cachexia, repetitive stress, and diabetes in streptozotocin treated animals, found common changes in overall expression patterns and specific pathways in these disease models [47, 48]. These observations also indicate similar pathways are triggered in a spectrum of muscle conditions. However, we speculate increased expression that produces substantial localized accumulations of Aβ, SOD1, PrP and NOS1 and NOS2 in a number of muscle disease conditions, suggests these proteins have a prominent and early role that is shared in muscle conditions linked with different modes of physiological stress. Increased NOS expression and NO production is linked with nitrative and nitrosative stress. Together with reactive oxygen species produced in non-enzymatic glycation reactions in diabetes, increased NO can react with superoxides to form peroxynitrite which is also a highly reactive oxidant and the increased intracellular production of NO and peroxynitrites can become cytotoxic [49–55]. The close relationship these proteins have with oxidative stress disease mechanisms suggests further that oxidative stress is also a common and early factor in these conditions. In summary, the present study demonstrates for the first time that pathophysiology resulting from diabetes and hyperglycemia substantially increases the overall expression of PrP, Aβ, SOD1 and NOS1 & 2 proteins in diabetic muscle, and produces localized accumulations of each of these proteins in muscle fibers.
The present findings identify this well-characterized model of diabetes and hyperglycemia in wild-type rabbits as a new and potentially important venue for simultaneously reproducing a range of hallmark pathological features seen in a variety of muscle disease conditions linked with different etiologies. The production of diabetes and hyperglycemia in otherwise normal rabbits allows for normal physiological contributions by potentially synergistic disease mechanisms associated with amyloid and oxidative stress-related disease proteins analyzed here. Our demonstration of increased expression and localized accumulations of these proteins in diseased muscle that are more often associated with neurodegenerative disease also has the potential to inform about shared disease processes and potential therapeutics that can affect brain as well as muscle.
We thank Paula Pierce (Excalibur Pathology, Moore OK) for preparation and advice for analysis of histological sections and discussions regarding pathology observed, and Dr. Annie Beuve (UMDNJ) for use of an additional fluorescence microscope during this study. We also thank Dr. Xavier Fioramonti for critical reading of our manuscript and Dr. Bruce Scharf, Head of the UMDNJ animal facility resources, for advice and discussion on our animal model throughout this study.
- Barcelo A, Rajpathak S: Incidence and prevalence of diabetes mellitus in the Americas. Rev Panam Salud Publica. 2001, 10 (5): 300-308.View ArticlePubMedGoogle Scholar
- Idiculla J, Shirazi N, Opacka-Juffry J, Ganapathi : Diabetic amyotrophy: a brief review. Natl Med J India. 2004, 17 (4): 200-202.PubMedGoogle Scholar
- Sun Z LL, Liu N, Liu Y: Muscular response and adaptation to diabetes mellitus. Front Biosci. 2008, 13: 4765-4794. 10.2741/3038.View ArticlePubMedGoogle Scholar
- Yildirim Donmez FFF: Muscle compromise in diabetes. Acta Radiol. 2008, 49: 673-679. 10.1080/02841850802105269.View ArticlePubMedGoogle Scholar
- Chen X GO, Geiger JD: Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis. Am J Physiol Regul Integr Comp Physiol. 2008, 294: R829-835.View ArticlePubMedGoogle Scholar
- Furukawa H, Doh-ura K, Sasaki K, Iwaki T: Accumulation of prion protein in muscle fibers of experimental chloroquine myopathy: in vivo model for deposition of prion protein in non-neuronal tissues. Lab Invest. 2004, 84 (7): 828-835. 10.1038/labinvest.3700111.View ArticlePubMedGoogle Scholar
- Tsuzuki K, Fukatsu R, Takamaru Y, Yoshida T, Hayashi Y, Yamaguchi H, Fujii N, Takahata N: Amyloid beta protein in rat soleus muscle in chloroquine-induced myopathy using end-specific antibodies for A beta 40 and A beta 42: immunohistochemical evidence for amyloid beta protein. Neurosci Lett. 1995, 202 (1-2): 77-80. 10.1016/0304-3940(95)12205-2.View ArticlePubMedGoogle Scholar
- Askanas V, Engel WK: Inclusion-body myositis and myopathies: different etiologies, possibly similar pathogenic mechanisms. Curr Opin Neurol. 2002, 15 (5): 525-531. 10.1097/00019052-200210000-00002.View ArticlePubMedGoogle Scholar
- Tsuruta Y, Furuta A, Taniguchi N, Yamada T, Kira J, Iwaki T: Increased expression of manganese superoxide dismutase is associated with that of nitrotyrosine in myopathies with rimmed vacuoles. Acta Neuropathol. 2002, 103 (1): 59-65. 10.1007/s004010100428.View ArticlePubMedGoogle Scholar
- Yang CC, Alvarez RB, Engel WK, Heller SL, Askanas V: Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies. Brain. 1998, 121 (Pt 6): 1089-1097. 10.1093/brain/121.6.1089.View ArticlePubMedGoogle Scholar
- Pilcher H: Alzheimer's disease could be "type 3 diabetes". Lancet Neurol. 2006, 5 (5): 388-389. 10.1016/S1474-4422(06)70434-3.View ArticlePubMedGoogle Scholar
- De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL: Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA. 2009, 106 (6): 1971-1976. 10.1073/pnas.0809158106.PubMed CentralView ArticlePubMedGoogle Scholar
- Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL: Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008, 22 (1): 246-260. 10.1096/fj.06-7703com.View ArticlePubMedGoogle Scholar
- Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, Belia S, Wannenes F, Nicoletti C, Del Prete Z, Rosenthal N, Molinaro M, Protasi F, Fanò G, Sandri M, Musarò A: Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 2008, 8 (5): 425-436. 10.1016/j.cmet.2008.09.002.View ArticlePubMedGoogle Scholar
- Huang S, Liang J, Zheng M, Li X, Wang M, Wang P, Vanegas D, Wu D, Chakraborty B, Hays AP, Chen K, Chen SG, Booth S, Cohen M, Gambetti P, Kong Q: Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice. Proc Natl Acad Sci USA. 2007, 104 (16): 6800-6805. 10.1073/pnas.0608885104.PubMed CentralView ArticlePubMedGoogle Scholar
- Jin LW, Hearn MG, Ogburn CE, Dang N, Nochlin D, Ladiges WC, Martin GM: Transgenic mice over-expressing the C-99 fragment of betaPP with an alpha-secretase site mutation develop a myopathy similar to human inclusion body myositis. Am J Pathol. 1998, 153 (6): 1679-1686.PubMed CentralView ArticlePubMedGoogle Scholar
- Kitazawa M, Green KN, Caccamo A, LaFerla FM: Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion body myositis-like pathology and motor deficits in transgenic mice. Am J Pathol. 2006, 168 (6): 1986-1997. 10.2353/ajpath.2006.051232.PubMed CentralView ArticlePubMedGoogle Scholar
- Moussa CE, Fu Q, Kumar P, Shtifman A, Lopez JR, Allen PD, LaFerla F, Weinberg D, Magrane J, Aprahamian T, Walsh K, Rosen KM, Querfurth HW: Transgenic expression of beta-APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology. FASEB J. 2006, 20 (12): 2165-2167. 10.1096/fj.06-5763fje.View ArticlePubMedGoogle Scholar
- Sugarman MC, Kitazawa M, Baker M, Caiozzo VJ, Querfurth HW, LaFerla FM: Pathogenic accumulation of APP in fast twitch muscle of IBM patients and a transgenic model. Neurobiol Aging. 2006, 27 (3): 423-432. 10.1016/j.neurobiolaging.2005.02.011.View ArticlePubMedGoogle Scholar
- Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI: Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42. J Neurochem. 2000, 75 (3): 1219-1233. 10.1046/j.1471-4159.2000.0751219.x.View ArticlePubMedGoogle Scholar
- Brown DR, Wong BS, Hafiz F, Clive C, Haswell SJ, Jones IM: Normal prion protein has an activity like that of superoxide dismutase. Biochem J. 1999, 344 (Pt 1): 1-5. 10.1042/0264-6021:3440001.PubMed CentralView ArticlePubMedGoogle Scholar
- Bush AI: Metals and neuroscience. Curr Opin Chem Biol. 2000, 4 (2): 184-191. 10.1016/S1367-5931(99)00073-3.View ArticlePubMedGoogle Scholar
- Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI: Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem. 2002, 277 (43): 40302-40308. 10.1074/jbc.M206428200.View ArticlePubMedGoogle Scholar
- Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, Laszlo F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian N, McGeer PL: Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging. 2008, 31: 1503-1515. 10.1016/j.neurobiolaging.2008.08.019.PubMed CentralView ArticlePubMedGoogle Scholar
- Frederikse PH, Farnsworth P, Zigler JS: Thiamine deficiency in vivo produces fiber cell degeneration in mouse lenses. Biochem Biophys Res Commun. 1999, 258 (3): 703-707. 10.1006/bbrc.1999.0560.View ArticlePubMedGoogle Scholar
- Maiese K, Chong ZZ, Shang YC: Mechanistic insights into diabetes mellitus and oxidative stress. Curr Med Chem. 2007, 14 (16): 1729-1738. 10.2174/092986707781058968.PubMed CentralView ArticlePubMedGoogle Scholar
- Unoki H, Yamagishi S: Advanced glycation end products and insulin resistance. Curr Pharm Des. 2008, 14 (10): 987-989. 10.2174/138161208784139747.View ArticlePubMedGoogle Scholar
- Karin M: Role for IKK2 in muscle: waste not, want not. J Clin Invest. 2006, 116 (11): 2866-2868. 10.1172/JCI30268.PubMed CentralView ArticlePubMedGoogle Scholar
- Kefaloyianni E, Gaitanaki C, Beis I: ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF-kappaB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 2006, 18 (12): 2238-2251. 10.1016/j.cellsig.2006.05.004.View ArticlePubMedGoogle Scholar
- Kramer HF, Goodyear LJ: Exercise, MAPK, and NF-kappaB signaling in skeletal muscle. J Appl Physiol. 2007, 103 (1): 388-395. 10.1152/japplphysiol.00085.2007.View ArticlePubMedGoogle Scholar
- Frederikse PH, Garland D, Zigler JS, Piatigorsky J: Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. J Biol Chem. 1996, 271 (17): 10169-10174. 10.1074/jbc.271.17.10169.View ArticlePubMedGoogle Scholar
- Frederikse PH, Zigler SJ, Farnsworth PN, Carper DA: Prion protein expression in mammalian lenses. Curr Eye Res. 2000, 20 (2): 137-143.View ArticlePubMedGoogle Scholar
- Trejo J, Massamiri T, Deng T, Dewji NN, Bayney RM, Brown JH: A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. J Biol Chem. 1994, 269 (34): 21682-21690.PubMedGoogle Scholar
- Standridge JB: Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease. Curr Alzheimer Res. 2006, 3 (2): 95-108. 10.2174/156720506776383068.View ArticlePubMedGoogle Scholar
- Lenzen S: The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia. 2008, 51 (2): 216-226. 10.1007/s00125-007-0886-7.View ArticlePubMedGoogle Scholar
- Munday R, Ludwig K, Lenzen S: The relationship between the physicochemical properties and the biological effects of alloxan and several N-alkyl substituted alloxan derivatives. J Endocrinol. 1993, 139 (1): 153-163. 10.1677/joe.0.1390153.View ArticlePubMedGoogle Scholar
- Szkudelski T: The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001, 50 (6): 537-546.PubMedGoogle Scholar
- Arnqvist HJ: Effect of alloxan-diabetes on the metabolism of rabbit colon smooth muscle. Acta Physiol Scand. 1975, 93 (4): 500-504. 10.1111/j.1748-1716.1975.tb05841.x.View ArticlePubMedGoogle Scholar
- Von Sallmann L CL, Grimes P, Collins EM: Morphological study on alloxan-induced cataract. AMA Arch Ophthalmol. 1958, 59: 55-67.View ArticlePubMedGoogle Scholar
- Haraguchi T, Fisher S, Olofsson S, Endo T, Groth D, Tarentino A, Borchelt DR, Teplow D, Hood L, Burlingame A, Lycke E, Prusiner SB: Asparagine-linked glycosylation of the scrapie and cellular prion proteins. Arch Biochem Biophys. 1989, 274 (1): 1-13. 10.1016/0003-9861(89)90409-8.View ArticlePubMedGoogle Scholar
- Sandbrink R, Monning U, Masters CL, Beyreuther K: Expression of the APP gene family in brain cells, brain development and aging. Gerontology. 1997, 43 (1-2): 119-131. 10.1159/000213840.View ArticlePubMedGoogle Scholar
- Wink DA, Mitchell JB: Chemical biology of nitric oxide: Insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med. 1998, 25 (4-5): 434-456. 10.1016/S0891-5849(98)00092-6.View ArticlePubMedGoogle Scholar
- Foster MW, Liu L, Zeng M, Hess DT, Stamler JS: A genetic analysis of nitrosative stress. Biochemistry. 2009, 48 (4): 792-799. 10.1021/bi801813n.View ArticlePubMedGoogle Scholar
- Duncan AJ, Heales SJ: Nitric oxide and neurological disorders. Mol Aspects Med. 2005, 26 (1-2): 67-96. 10.1016/j.mam.2004.09.004.View ArticlePubMedGoogle Scholar
- Li H, Wolfe MS, Selkoe DJ: Toward structural elucidation of the gamma-secretase complex. Structure. 2009, 17 (3): 326-334. 10.1016/j.str.2009.01.007.PubMed CentralView ArticlePubMedGoogle Scholar
- Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM: Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature. 2009, 457 (7233): 1128-1132. 10.1038/nature07761.PubMed CentralView ArticlePubMedGoogle Scholar
- Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL: Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004, 18 (1): 39-51. 10.1096/fj.03-0610com.View ArticlePubMedGoogle Scholar
- Sacheck JM, Hyatt JP, Raffaello A, Jagoe RT, Roy RR, Edgerton VR, Lecker SH, Goldberg AL: Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J. 2007, 21 (1): 140-155. 10.1096/fj.06-6604com.View ArticlePubMedGoogle Scholar
- Tamir S, Burney S, Tannenbaum SR: DNA damage by nitric oxide. Chem Res Toxicol. 1996, 9 (5): 821-827. 10.1021/tx9600311.View ArticlePubMedGoogle Scholar
- Tamir S, deRojas-Walker T, Wishnok JS, Tannenbaum SR: DNA damage and genotoxicity by nitric oxide. Methods Enzymol. 1996, 269: 230-243. full_text.View ArticlePubMedGoogle Scholar
- Szabo C, Ohshima H: DNA damage induced by peroxynitrite: subsequent biological effects. Nitric Oxide. 1997, 1 (5): 373-385. 10.1006/niox.1997.0143.View ArticlePubMedGoogle Scholar
- Burney S, Caulfield JL, Niles JC, Wishnok JS, Tannenbaum SR: The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res. 1999, 424 (1-2): 37-49.View ArticlePubMedGoogle Scholar
- Goldstein IM, Ostwald P, Roth S: Nitric oxide: a review of its role in retinal function and disease. Vision Res. 1996, 36 (18): 2979-2994. 10.1016/0042-6989(96)00017-X.View ArticlePubMedGoogle Scholar
- Pieper AA, Verma A, Zhang J, Snyder SH: Poly (ADP-ribose) polymerase, nitric oxide and cell death. Trends Pharmacol Sci. 1999, 20 (4): 171-181. 10.1016/S0165-6147(99)01292-4.View ArticlePubMedGoogle Scholar
- Du Y, Smith MA, Miller CM, Kern TS: Diabetes-induced nitrative stress in the retina, and correction by aminoguanidine. J Neurochem. 2002, 80 (5): 771-779. 10.1046/j.0022-3042.2001.00737.x.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.