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1.
Skelet Muscle ; 10(1): 12, 2020 04 27.
Article in English | MEDLINE | ID: mdl-32340625

ABSTRACT

BACKGROUND: Pulmonary hypertension leads to right ventricular heart failure and ultimately to cardiac cachexia. Cardiac cachexia induces skeletal muscles atrophy and contractile dysfunction. MAFbx and MuRF1 are two key proteins that have been implicated in chronic muscle atrophy of several wasting states. METHODS: Monocrotaline (MCT) was injected over eight weeks into mice to establish pulmonary hypertension as a murine model for cardiac cachexia. The effects on skeletal muscle atrophy, myofiber force, and selected muscle proteins were evaluated in wild-type (WT), MuRF1, and MuRF2-KO mice by determining muscle weights, in vitro muscle force and enzyme activities in soleus and tibialis anterior (TA) muscle. RESULTS: In WT, MCT treatment induced wasting of soleus and TA mass, loss of myofiber force, and depletion of citrate synthase (CS), creatine kinase (CK), and malate dehydrogenase (MDH) (all key metabolic enzymes). This suggests that the murine MCT model is useful to mimic peripheral myopathies as found in human cardiac cachexia. In MuRF1 and MuRF2-KO mice, soleus and TA muscles were protected from atrophy, contractile dysfunction, while metabolic enzymes were not lowered in MuRF1 or MuRF2-KO mice. Furthermore, MuRF2 expression was lower in MuRF1KO mice when compared to C57BL/6 mice. CONCLUSIONS: In addition to MuRF1, inactivation of MuRF2 also provides a potent protection from peripheral myopathy in cardiac cachexia. The protection of metabolic enzymes in both MuRF1KO and MuRF2KO mice as well as the dependence of MuRF2 expression on MuRF1 suggests intimate relationships between MuRF1 and MuRF2 during muscle atrophy signaling.


Subject(s)
Hypertension, Pulmonary/metabolism , Muscle Proteins/genetics , Muscle, Skeletal/metabolism , Muscular Atrophy/metabolism , Tripartite Motif Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Animals , Citrate (si)-Synthase/blood , Creatine Kinase/blood , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/pathology , Malate Dehydrogenase/blood , Mice , Mice, Inbred C57BL , Muscle Contraction , Muscle Proteins/metabolism , Muscle Strength , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Atrophy/etiology , Muscular Atrophy/pathology , Tripartite Motif Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism
2.
Sci Rep ; 9(1): 17616, 2019 11 26.
Article in English | MEDLINE | ID: mdl-31772390

ABSTRACT

The high metabolic activity associated with endurance flights and intense fuelling of migrant birds may produce large quantities of reactive oxygen species, which cause oxidative damage. Yet it remains unknown how long-lived birds prepare for oxidative challenges prior to extreme flights. We combined blood measurements of oxidative status and enzyme and fat metabolism in Hudsonian godwits (Limosa haemastica, a long-lived shorebird) before they embarked on non-stop flights longer than 10,000 km during their northbound migrations. We found that godwits increased total antioxidant capacity (TAC) and reduced oxidative damage (TBARS) as the pre-migratory season progressed, despite higher basal metabolic rates before departure. Elevations in plasma ß-hydroxybutyrate and uric acid suggest that lipid and protein breakdown supports energetic requirements prior to migration. Significant associations between blood mitochondrial cytochrome-c oxidase and plasma TAC (negative) and TBARS (positive) during winter indicate that greater enzyme activity can result in greater oxidative damage and antioxidant responses. However enzyme activity remained unchanged between winter and premigratory stages, so birds may be unable to adjust metabolic enzyme activity in anticipation of future demands. These results indicate that godwits enhance their oxidative status during migratory preparation, which might represent an adaptation to diminish the physiological costs of long-distance migration.


Subject(s)
Animal Migration/physiology , Charadriiformes/metabolism , Flight, Animal/physiology , Oxidative Stress , 3-Hydroxybutyric Acid/blood , Adiposity , Animals , Antioxidants/analysis , Basal Metabolism , Citrate (si)-Synthase/blood , Electron Transport Complex IV/blood , Energy Metabolism , Erythrocytes/chemistry , Female , Lipid Peroxidation , Longevity , Male , Seasons , Thiobarbituric Acid Reactive Substances/analysis , Triglycerides/blood , Uric Acid/blood
3.
Indian J Med Res ; 147(2): 189-194, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29806608

ABSTRACT

BACKGROUND & OBJECTIVES: : Bartonella henselae causes infections which closely resemble febrile illness and chronic diseases such as tuberculosis and haematological malignancies. There are not many studies on Bartonella infections from India. The present study was undertaken to diagnose B. henselae infection in diverse clinical conditions in a tertiary care hospital in north India. METHODS: A total of 145 patients including those with fever and lymphadenopathy, infective endocarditis and neuroretinitis were enrolled in the study. Whole blood, serum and lymph node aspirate and valvular vegetations if available, were obtained. Samples were plated on chocolate agar and brain-heart infusion agar containing five per cent fresh rabbit blood and were incubated at 35°C for at least four weeks in five per cent CO2with high humidity. Immunofluorescent antibody assay (IFA) was done for the detection of IgM antibodies in the serum using a commercial kit. Whole blood was used to perform polymerase chain reaction (PCR) for the citrate synthase gene (gltA). RESULTS: IFA was positive in 11 of 140 (7.85%) patients and PCR was positive in 3 of 140 (2.14%) patients. Culture was negative in all the cases. A higher incidence of Bartonella infection was seen in patients with fever and lymphadenopathy (n=30), seven of whom were children. In ophthalmological conditions, four cases were IFA positive. INTERPRETATION & CONCLUSIONS: The present study shows that the threat of Bartonella infection is a reality in India. It is also an important treatable cause of fever and lymphadenopathy in children. Serology and PCR are useful tests for its diagnosis. Clinicians should consider. BARTONELLA: infection in the differential diagnosis of febrile illnesses and chronic diseases.


Subject(s)
Bartonella Infections/blood , Bartonella henselae/isolation & purification , Citrate (si)-Synthase/blood , Lymphadenopathy/blood , Zoonoses/blood , Adolescent , Adult , Animals , Antibodies, Bacterial/blood , Bartonella Infections/microbiology , Bartonella Infections/transmission , Bartonella henselae/pathogenicity , Cat-Scratch Disease/epidemiology , Cat-Scratch Disease/transmission , Cats , Child , Disease Reservoirs , Female , Humans , India/epidemiology , Lymphadenopathy/microbiology , Lymphadenopathy/pathology , Male , Middle Aged , Rabbits , Rats , Tertiary Care Centers , Young Adult , Zoonoses/epidemiology , Zoonoses/microbiology , Zoonoses/pathology
4.
J Physiol ; 592(8): 1873-86, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24514907

ABSTRACT

The aim was to investigate the metabolic and anti-inflammatory effects of resveratrol alone and when combined with exercise training in skeletal muscle of aged human subjects. Healthy, physically inactive men (60-72 years old) were randomized to either 8 weeks of daily intake of 250 mg resveratrol or placebo or to 8 weeks of high-intensity exercise training with 250 mg resveratrol or placebo. Before and after the interventions, resting blood samples and muscle biopsies were obtained and a one-legged knee-extensor endurance exercise test was performed. Exercise training increased skeletal muscle peroxisome proliferator-activated receptor-γ co-activator-1α mRNA ~1.5-fold, cytochrome c protein ~1.3-fold, cytochrome c oxidase I protein ~1.5-fold, citrate synthase activity ~1.3-fold, 3-hydroxyacyl-CoA dehydrogenase activity ~1.3-fold, inhibitor of κB-α and inhibitor of κB-ß protein content ~1.3-fold and time to exhaustion in the one-legged knee-extensor endurance exercise test by ∼1.2-fold, with no significant additive or adverse effects of resveratrol on these parameters. Despite an overall ~25% reduction in total acetylation level in skeletal muscle with resveratrol, no exclusive resveratrol-mediated metabolic effects were observed on the investigated parameters. Notably, however, resveratrol blunted an exercise training-induced decrease (~20%) in protein carbonylation and decrease (~40%) in tumour necrosis factor α mRNA content in skeletal muscle. In conclusion, resveratrol did not elicit metabolic improvements in healthy aged subjects; in fact, resveratrol even impaired the observed exercise training-induced improvements in markers of oxidative stress and inflammation in skeletal muscle. Collectively, this highlights the metabolic efficacy of exercise training in aged subjects and does not support the contention that resveratrol is a potential exercise mimetic in healthy aged subjects.


Subject(s)
Exercise , Muscle, Skeletal/drug effects , Stilbenes/pharmacology , Aged , Citrate (si)-Synthase/blood , Cyclooxygenase 1/blood , Double-Blind Method , Glyceraldehyde-3-Phosphate Dehydrogenases/blood , Humans , I-kappa B Proteins/blood , Male , Muscle, Skeletal/growth & development , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Resveratrol , Transcription Factors/blood , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
5.
Hypertension ; 53(5): 782-9, 2009 May.
Article in English | MEDLINE | ID: mdl-19349555

ABSTRACT

Exercise is known to reduce cardiovascular risk. However, its role on atherosclerotic plaque stabilization is unknown. Apolipoprotein E(-/-) mice with vulnerable (2-kidney, 1-clip: angiotensin [Ang] II-dependent hypertension model) or stable atherosclerotic plaques (1-kidney, 1-clip: Ang II-independent hypertension model and normotensive shams) were used for experiments. Mice swam regularly for 5 weeks and were compared with sedentary controls. Exercised 2-kidney, 1-clip mice developed significantly more stable plaques (thinner fibrous cap, decreased media degeneration, layering, macrophage content, and increased smooth muscle cells) than sedentary controls. Exercise did not affect blood pressure. Conversely, swimming significantly reduced aortic Ang II type 1 receptor mRNA levels, whereas Ang II type 2 receptor expression remained unaffected. Sympathetic tone also significantly diminished in exercised 2-kidney, 1-clip mice compared with sedentary ones; renin and aldosterone levels tended to increase. Ang II type 1 downregulation was not accompanied by improved endothelial function, and no difference in balance among T-helper 1, T-helper 2, and T regulatory cells was observed between sedentary and exercised mice. These results show for the first time, in a mouse model of Ang II-mediated vulnerable plaques, that swimming prevents atherosclerosis progression and plaque vulnerability. This benefit is likely mediated by downregulating aortic Ang II type 1 receptor expression independent from any hemodynamic change. Ang II type 1 downregulation may protect the vessel wall from the Ang II proatherogenic effects. Moreover, data presented herein further emphasize the pivotal and blood pressure-independent role of Ang II in atherogenesis.


Subject(s)
Atherosclerosis/prevention & control , Blood Pressure , Heart Rate , Hypertension/complications , Receptor, Angiotensin, Type 1/genetics , Swimming , Aldosterone/blood , Animals , Apolipoproteins E/physiology , Cholesterol/blood , Citrate (si)-Synthase/blood , Hypertension/physiopathology , Interleukin-6/blood , Mice , Mice, Inbred C57BL , Nitric Oxide Synthase Type III/genetics , Norepinephrine/blood , RNA, Messenger/analysis , Renin/blood
6.
Med Sci Sports Exerc ; 41(5): 1155-63, 2009 May.
Article in English | MEDLINE | ID: mdl-19346970

ABSTRACT

PURPOSE: Development of an endurance training-overtraining protocol for Wistar rats that includes increased workload and is characterized by analyses of performance and biomarkers. METHODS: The running protocol lasted 11 wk: 8 wk of daily exercise sessions followed by 3 wk of increasing training frequency (two, three, and four times), with decreasing recovery time between sessions (4, 3, and 2 h) to cause an imbalance between overload and recovery. The performance tests were made before training (T1) and after the 4th (T2), 8th (T3), 9th (T4), 10th (T5), and 11th (T6) training weeks. All rats showed significantly increased performance at T4, at which time eight rats, termed the trained group (Tr), were sacrificed for blood and muscle assays. After T6, two groups were distinguishable by differences in the slope (alpha) of a line fitted to the individual performances at T4, T5, and T6: nonfunctional overreaching (NFOR; alpha < -15.05 kg x m) and functional overreaching (FOR; alpha >or= -15.05 kg x m). RESULTS: Data were presented as mean +/- SD. FOR maintained the performance at T6 similar to Tr at T4 (530.6 +/- 85.3 and 487.5 +/- 61.4 kg x m, respectively). The FOR and the Tr groups showed higher muscle citrate synthase activity (approximately 40%) and plasma glutamine/glutamate ratio (Gm/Ga; 4.5 +/- 1.7 and 4.5 +/- 0.9, respectively) than the sedentary control (CO) group (2.8 +/- 0.5). The NFOR group lost the performance acquired at T4 (407.3 +/- 88.2 kg x m) after T6 (280.5 +/- 93.1 kg x m) and exhibited sustained leukocytosis. NFOR's Gm/Ga (3.1 +/- 0.2) and muscle citrate synthase activity were similar to CO values. CONCLUSIONS: The decline in performance in the NFOR group could be related to the decrease in muscle oxidative capacity. We observed a trend in the Gm/Ga and leukocytosis that is similar to what has been sometimes observed in overtrained humans. This controlled training-overtraining animal model may be useful for seeking causative mechanisms of performance decline.


Subject(s)
Models, Animal , Physical Conditioning, Animal/physiology , Animals , Citrate (si)-Synthase/biosynthesis , Citrate (si)-Synthase/blood , Glutamine/biosynthesis , Glutamine/blood , Leukocytes , Male , Rats , Rats, Wistar
7.
Appl Physiol Nutr Metab ; 33(1): 93-101, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18347658

ABSTRACT

A chronic increase in physical activity and (or) endurance training can improve insulin sensitivity in insulin-resistant skeletal muscle. Cellular mechanisms responsible for the development of insulin resistance are unclear, though one proposed mechanism is that nutrient overload chronically increases available energy, over-activating the mammalian target of rapamycin (mTOR) and ribosomal S6 kinase 1 (S6K1) signaling pathway leading to increased phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1). The objective of this study was to determine if increased physical activity would inhibit mTOR/S6K1 signaling and reduce IRS-1 serine phosphorylation in rat skeletal muscle. Soleus muscle was collected from fed male Sprague-Dawley sedentary rats (Inactive) and rats with free access to running wheels for 9 weeks (Active). Immunoblotting methods were used to measure phosphorylation status of mTOR, S6K1, IRS-1, and PKB/Akt (protein kinase B/AKT), and total abundance of proteins associated with the mTOR pathway. Muscle citrate synthase activity and plasma insulin and glucose concentrations were measured. Phosphorylation of mTOR (Ser2448), S6K1 (Thr389), and IRS-1 (Ser636-639) was reduced in Active rats (p<0.05). Total protein abundance of mTOR, S6K1, IRS-1, 4E-BP1, eEF2, PKB/Akt and AMPKalpha, and phosphorylation of PKB/Akt were unaffected (p>0.05). Total SKAR protein, a downstream target of S6K1, and citrate synthase activity increased in Active rats (p<0.05), though plasma insulin and glucose levels were unchanged (p>0.05). Reduced mTOR/S6K1 signaling during chronic increases in physical activity may play an important regulatory role in the serine phosphorylation of IRS-1, which should be examined as a potential mechanism for attenuation of insulin resistance associated with increased IRS-1 serine phosphorylation.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Muscle, Skeletal/physiology , Physical Conditioning, Animal/physiology , Protein Kinases/metabolism , Ribosomal Protein S6 Kinases/metabolism , Animals , Blood Glucose , Blotting, Western , Citrate (si)-Synthase/blood , Insulin/blood , Insulin Receptor Substrate Proteins , Insulin Resistance/physiology , Lactic Acid/blood , Male , Phosphorylation , Rats , Rats, Sprague-Dawley , STAT1 Transcription Factor/physiology , Serine/metabolism , TOR Serine-Threonine Kinases
8.
Eur J Appl Physiol ; 98(5): 497-506, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17006714

ABSTRACT

The aim of the present study was to examine the differences in fat oxidation between endurance trained (ET) and untrained (UT) women. Eight ET and nine UT women performed a progressive cycle ergometer test until exhaustion. The rate of fat oxidation was similar at low work rates (

Subject(s)
Lipid Metabolism/physiology , Physical Endurance/physiology , Physical Fitness/physiology , Acyl-CoA Dehydrogenases/blood , Adult , Body Composition/physiology , Citrate (si)-Synthase/blood , Exercise Test , Female , Glycogen/metabolism , Humans , Kinetics , Lipase/blood , Muscle Fibers, Skeletal/physiology , Muscle, Skeletal/cytology , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiology , Oxidation-Reduction , Oxygen Consumption/physiology , Pulmonary Gas Exchange/physiology
9.
J Inherit Metab Dis ; 25(8): 673-9, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12705497

ABSTRACT

Coenzyme Q10 (CoQ10) serves as an electron carrier within the mitochondrial respiratory chain (MRC), where it is integrally involved in oxidative phosphorylation and consequently ATP production. It has recently been suggested that phenylketonuria (PKU) patients may be susceptible to a CoQ10 deficiency as a consequence of their phenylalanine-restricted diet, which avoids foods rich in CoQ10 and its precursors. Furthermore, the high phenylalanine level in PKU patients not on dietary restriction may also result in impaired endogenous CoQ10 production, as previous studies have suggested an inhibitory effect of phenylalanine on HMG-CoA reductase, the rate-controlling enzyme in CoQ10 biosynthesis. We investigated the effect of both dietary restriction and elevated plasma phenylalanine concentration on blood mononuclear cell CoQ10 concentration and the activity of MRC complex II + III (succinate:cytochrome-c reductase; an enzyme that relies on endogenous CoQ10) in a PKU patient population. The concentrations of CoQ10 and MRC complex II + III activity were not found to be significantly different between the PKU patients on dietary restriction, PKU patients off dietary restriction and the control group, although plasma phenylalanine levels were markedly different. The results from this investigation suggest that dietary restriction and the elevated plasma phenylalanine levels of PKU patients do not effect mononuclear cell CoQ10 concentration and consequently the activity of complex II + III of the MRC.


Subject(s)
Mitochondrial Diseases/enzymology , Monocytes/enzymology , Phenylketonurias/enzymology , Succinate Cytochrome c Oxidoreductase/blood , Ubiquinone/analogs & derivatives , Ubiquinone/blood , Adolescent , Adult , Chromatography, High Pressure Liquid , Citrate (si)-Synthase/blood , Coenzymes , Female , Humans , Hydroxymethylglutaryl CoA Reductases/metabolism , Male , Middle Aged , Mitochondrial Diseases/blood , Mitochondrial Diseases/diet therapy , Phenylalanine/blood , Phenylalanine/metabolism , Phenylketonurias/blood
10.
J Exp Biol ; 203(Pt 6): 1039-45, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10683163

ABSTRACT

The effects of cell age on metabolism in the nucleated red blood cells of rainbow trout (Oncorhynchus mykiss) were examined. Red blood cells were separated according to age using fixed-angle centrifugation. The mean erythrocyte haemoglobin concentration in old red blood cells was found to be 120 % of that in young red blood cells. In young red blood cells, the activities of the mitochondrial enzymes citrate synthase and cytochrome oxidase were 135-200 %, respectively, of those measured in old red blood cells. The activity of the glycolytic enzyme lactate dehydrogenase in young red blood cells was 170 % of that in old red blood cells, whereas the activity of the glycolytic enzyme pyruvate kinase was not significantly affected by cell age. In addition, young red blood cells consumed over twice as much O(2) and devoted 50 % more O(2) to protein synthesis and the activity of Na(+)/K(+)-ATPase than old red blood cells. Red blood cell age did not significantly affect the rate of lactate production. This study shows that ageing in rainbow trout nucleated red blood cells is accompanied by a significant decline in aerobic energy production and the processes it supports, as well as a corresponding increase in the glycolytic contribution to metabolism.


Subject(s)
Erythrocyte Aging/physiology , Erythrocytes/metabolism , Oncorhynchus mykiss/blood , Animals , Citrate (si)-Synthase/blood , Electron Transport Complex IV/blood , Erythrocytes/ultrastructure , Glycolysis , Hemoglobins/analysis , L-Lactate Dehydrogenase/blood , Mitochondria/enzymology , Oxygen/blood , Oxygen Consumption , Pyruvate Kinase/blood , Sodium-Potassium-Exchanging ATPase/blood
11.
Equine Vet J Suppl ; (30): 521-7, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10659311

ABSTRACT

This experiment was undertaken to determine whether there were differences in cardiorespiratory, haematological and muscular responses in horses trained at either low or moderate intensities. Ten Thoroughbred horses previously rested in paddocks for 4 months were trained 5 days/week for 9 weeks. Horses were allocated randomly into fast or slow groups and exercised the same distance each day. Training distances were 1600 m in Weeks 0 and 1 up to 4000 m in Week 9. The fast group were trained at an intensity inducing a post training blood lactate of 4-8 mmol/l. This intensity was determined for each horse each week. The slow group trained at half the speed of the fast group (blood lactate < 2 mmol/l). Horses performed a standardised exercise test prior to (Week 0) and on Weeks 1, 2, 3, 4, 7 and 9 of training. HR, VO2, VCO2 and blood lactate concentration were recorded during the last 15 s of each step. Blood samples were collected at the end of each test for determination of red cell and plasma volume. Muscle biopsies were collected from the middle gluteal muscle before training and after 4 and 9 weeks training. Training intensity had few effects on the majority of variables measured and results for both groups are combined unless otherwise stated. Bodyweight was unaffected by training. Economy of locomotion decreased from 12.0 +/- 0.4 ml/kg bwt/m prior to training to 13.8 +/- 0.6 ml/kg bwt/m at the end of training in the fast group. Run time to fatigue was not affected by training intensity. VO2max increased from 120.3 +/- 4.8 to 144.7 +/- 3.5 ml/kg bwt/min with a significant correlation between run time and VO2max. Peak HR was 221.4 +/- 2.5 beats/min prior to training and 226.5 +/- 1.7 beats/min after the first 4 weeks of training. V200 and VLa4 increased in response to training. Similarly, VLa4 increased from 7.0 +/- 0.5 to 9.2 +/- 0.2 m/s with VLa4 correlated to VO2max. Plasma volume decreased from 29.1 +/- 1.7 to 25.8 +/- 0.9 l during the last 3 weeks of training. Blood volume, red cell volume and/or red cell volume/kg were unaffected by intensity or duration of training. The activity of CS in muscle increased in the first 5 weeks of training whereas HAD activity was not affected by intensity or duration of training.


Subject(s)
Energy Metabolism , Horses/physiology , Physical Conditioning, Animal , 3-Hydroxyacyl CoA Dehydrogenases/blood , Animals , Blood Volume , Body Weight , Citrate (si)-Synthase/blood , Heart Rate , Lactic Acid/blood , Oxygen Consumption
12.
Neurology ; 50(3): 793-5, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9521279

ABSTRACT

We report a pilot study of three oral doses of coenzyme Q10 (CoQ10) (200 mg administered two, three, or four times per day for 1 month) in 15 subjects with Parkinson's disease. Oral CoQ10 caused a substantial increase in the plasma CoQ10 level. It was well tolerated, but at the highest dose (200 mg four times per day) mild, transient changes in the urine were noted. CoQ10 did not change the mean score on the motor portion of the Unified Parkinson's Disease Rating Scale. There was a trend toward an increase in complex I activity in the subjects.


Subject(s)
Mitochondria/enzymology , Parkinson Disease, Secondary/drug therapy , Ubiquinone/analogs & derivatives , Absorption , Administration, Oral , Aged , Citrate (si)-Synthase/blood , Coenzymes , Dose-Response Relationship, Drug , Drug Carriers , Female , Humans , Male , Middle Aged , Mitochondria/drug effects , NAD(P)H Dehydrogenase (Quinone)/blood , Parkinson Disease, Secondary/physiopathology , Pilot Projects , Severity of Illness Index , Ubiquinone/adverse effects , Ubiquinone/pharmacokinetics , Ubiquinone/therapeutic use , Vitamin E
13.
Mov Disord ; 12(1): 3-8, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8990047

ABSTRACT

Reports on mitochondrial respiratory chain (MRC) complex I (CI) dysfunction in the substantia nigra in Parkinson's disease (PD) support the oxidative stress hypothesis in the neuropathogenesis of PD. Studies in peripheral tissue have found variable decreased CI and occasionally other complex activity suggestive of systemic impairment of MRC function in PD; however, MRC activity may be influenced by numerous variables. We conducted spectrophotometric measurements of MRC function in platelet mitochondrial preparations in 13 individuals with PD and 9 age-matched controls (CON) and have identified additional variables that may affect MRC activity. Mean CI, CIII, CIV, and citrate synthase (CS) activities were similar between PD and CON. CIII and CIV, specific and CS-corrected, activities were significantly positively correlated with CI in combined and individual group data, with the exception of CIII CS-corrected and CIV specific activities in CON and PD, respectively. CIII and CS specific activities were negatively correlated with age in CON, but varied randomly in PD. In PD, CIII specific activity was 1.4-fold higher in those with a history of environmental risk factors for PD and CIV specific activity was lower in those with a positive family history of PD [8.34 +/- 0.74 (n = 4) vs. 12.4 +/- 1.1 (SEM) min-1 mg-1; p = 0.046]. Group heterogeneity, variables affecting enzyme activity, and intrinsic properties of cells may thus contribute to conflicting data in studies of MRC function in platelets and other tissues.


Subject(s)
Blood Platelets/enzymology , Electron Transport/physiology , Mitochondria/enzymology , Parkinson Disease/blood , Adult , Aged , Citrate (si)-Synthase/blood , Electron Transport Complex III/blood , Electron Transport Complex IV/blood , Female , Humans , Male , Middle Aged , NAD(P)H Dehydrogenase (Quinone)/blood , Reference Values
14.
Biochem Biophys Res Commun ; 215(3): 1001-5, 1995 Oct 24.
Article in English | MEDLINE | ID: mdl-7488023

ABSTRACT

The electron transfer activity of Complex I of the respiratory chain and Complex I-linked ATP synthesis were investigated in leukocytes of four males affected by Leber hereditary optic neuropathy and a mutation in the ND6 gene at nucleotide position 14,484 of mtDNA. The electron transfer activity in leukocytes of the patients was about 35% of that in control leukocytes, whereas the Complex I-linked ATP synthesis showed a decrease of only about 20%. This demonstrates that all three mtDNA mutations that are clearly associated with Leber hereditary optic neuropathy result in deficiency of Complex I. However, the relationship between these mtDNA mutations, the function of Complex I and the phenotypic profile remains elusive.


Subject(s)
DNA, Mitochondrial/genetics , Genetic Carrier Screening , NAD(P)H Dehydrogenase (Quinone)/deficiency , NAD(P)H Dehydrogenase (Quinone)/genetics , Optic Atrophies, Hereditary/genetics , Point Mutation , Adenosine Triphosphate/blood , Citrate (si)-Synthase/blood , Humans , Kinetics , Leukocytes/metabolism , Male , NAD(P)H Dehydrogenase (Quinone)/blood , Optic Atrophies, Hereditary/enzymology , Phenotype , Reference Values
15.
Neurology ; 45(2): 344-8, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7854537

ABSTRACT

Previous studies have demonstrated impaired complex I activity in platelets from Parkinson's disease (PD) patients who were receiving levodopa and other medications for their disease. Eleven patients with early PD underwent three sequential plateletphereses: while on no medication, after receiving carbidopa/levodopa for 1 month, and after receiving carbidopa/levodopa plus selegiline for 1 additional month. As expected, carbidopa/levodopa and selegiline significantly improved motor function in these patients. Treatment with carbidopa/levodopa alone and carbidopa/levodopa plus selegiline did not affect the activities of complexes I, II/III, and IV and citrate synthetase. These observations support the hypothesis that impaired complex I activity in PD patients is a characteristic of the disease and not due to medications.


Subject(s)
Blood Platelets/enzymology , Carbidopa/therapeutic use , Levodopa/therapeutic use , Mitochondria/enzymology , Parkinson Disease/blood , Parkinson Disease/drug therapy , Selegiline/therapeutic use , Adult , Aged , Analysis of Variance , Blood Platelets/drug effects , Citrate (si)-Synthase/blood , Electron Transport , Electron Transport Complex II , Electron Transport Complex III/blood , Female , Humans , Male , Middle Aged , Mitochondria/drug effects , Multienzyme Complexes/blood , NAD(P)H Dehydrogenase (Quinone)/blood , Oxidoreductases/blood , Plateletpheresis , Succinate Dehydrogenase/blood
16.
J Appl Physiol (1985) ; 78(1): 76-81, 1995 Jan.
Article in English | MEDLINE | ID: mdl-7713847

ABSTRACT

The purpose of this study was to determine the interactive effects of 10-12 wk of streptozotocin-induced diabetes (65 mg/kg) and moderate-intensity exercise training on total myocardial GLUT-4 and GLUT-1 proteins. Sprague-Dawley rats (n = 52) were randomly divided into sedentary control (SC), exercise-trained control (ETC), sedentary diabetic (SD), and exercise-trained control (ETD) groups. Diabetes (SD), and exercise-trained diabetic (ETD) groups. Diabetes resulted in a 70% reduction in myocardial GLUT-4 (28.3+/- 3.1 and 94.6 +/- 3.4% for SD and SC, respectively; P < 0.0001) and an 18.5% decrease in GLUT-1 (62.5 +/- 4.7 and 76.8 +/- 4.5% for SD and SC, respectively; P = 0.06). Exercise training increased citrate synthase activity in the medial and long heads of the triceps brachii in both groups (P < 0.001). Fasting blood glucose improved with training in diabetic animals (348 +/- 27 and 569 +/- 28 mg/dl for ETD and SD, respectively; P < 0.05). The diabetes-induced reduction in GLUT-4 was attenuated with exercise training (46.8 +/- 9.3% for ETD; P < 0.02 compared with SD). In contrast, training resulted in a further 25% decrease compared with SD in GLUT-1 in ETD (46.8 +/- 9.3%; P < 0.03 compared with SD). Exercise training had no effect on either GLUT-4 (87.2 +/- 4.0%) or GLUT-1 (75.4 +/- 5.1%) in ETC. GLUT-4 inversely correlated (r = -0.81; P < or = 0.001) with fasting blood glucose. In conclusion, diabetes resulted in a 70% reduction in myocardial GLUT-4 and an 18% decrease in GLUT-1.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Monosaccharide Transport Proteins/metabolism , Myocardium/metabolism , Physical Conditioning, Animal , Animals , Blood Glucose/metabolism , Citrate (si)-Synthase/blood , Diabetes Mellitus, Experimental/enzymology , Female , Glucose Transporter Type 1 , Glucose Transporter Type 4 , Insulin/blood , Muscle Proteins/metabolism , Myocardium/enzymology , Rats , Rats, Sprague-Dawley
17.
J Neurol Sci ; 122(1): 80-3, 1994 Mar.
Article in English | MEDLINE | ID: mdl-8195807

ABSTRACT

We report the effect of the 11,778 and 3460 base pair mitochondrial DNA mutations, found in Leber's hereditary optic neuropathy (LHON), on platelet mitochondrial respiratory chain enzyme activity. We measured respiratory chain enzyme activities in platelets from 4 patients with the 3460 mutation, 17 patients with the 11,778 mutation and compared them with those of 41 healthy age-matched controls. We observed a 67% (P < 0.001) reduction in the mean NADH CoQ1 reductase (complex I) activity of the 3460 group compared to the control group. It has been shown previously that platelet mitochondrial biochemistry is affected by cigarette smoking. A significant reduction (25%, P < 0.03) in the mean complex I activity of the 11,778 group was only observed when the non-smokers within that group were compared to the non-smoking controls. The effect of smoking observed in this study may explain why previous workers have not observed a decrease in complex I activity associated with the 11,778 mutation. There was no significant change in the activity of complexes II/III or IV with either of these mutations. There was a significant increase (26%, P < 0.008) in citrate synthase (CS) activity with the non-smoking 11,778 group compared to the non-smoking control group, rising to 40% (P < 0.002) in those with this mutation who smoked. This reflects an increase in mitochondrial mass with the 11,778 mutation. This effect was not observed with the 3460 mutation even though the complex deficiency was much more severe.


Subject(s)
Blood Platelets/enzymology , Mitochondria/enzymology , Optic Atrophies, Hereditary/blood , Blood Platelets/ultrastructure , Citrate (si)-Synthase/blood , DNA, Mitochondrial/metabolism , Electron Transport Complex I , Electron Transport Complex IV/blood , Humans , Mutation , NADH, NADPH Oxidoreductases/blood , Optic Atrophies, Hereditary/enzymology , Smoking/blood , Succinate Cytochrome c Oxidoreductase/blood
18.
Cephalalgia ; 14(1): 21-3, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8200018

ABSTRACT

To investigate energy metabolism in migraine, we determined platelet mitochondrial enzyme activities in 40 patients with migraine with aura and in 40 patients with migraine without aura during attack-free intervals and in 24 healthy control subjects. NADH-dehydrogenase, citrate synthase and cytochrome-c-oxidase activities in both patient groups were significantly lower than in controls (p < 0.01), while NADH-cytochrome-c-reductase activity was reduced only in migraine with aura (p < 0.01). No alteration in succinate-dehydrogenase was observed. Monoamine-oxidase activity differed between sexes (p < 0.05) but within each sex group no difference was observed between patients and controls. We hypothesize that the defect in mitochondrial enzymes observed indicates a systemic impairment of mitochondrial function in migraine patients.


Subject(s)
Blood Platelets/physiology , Citrate (si)-Synthase/deficiency , Cytochrome-c Oxidase Deficiency , Electron Transport , Migraine Disorders/blood , Mitochondria/physiology , NADH Dehydrogenase/deficiency , Adolescent , Adult , Aged , Blood Platelets/enzymology , Citrate (si)-Synthase/blood , Electron Transport Complex IV/blood , Energy Metabolism , Female , Humans , Male , Middle Aged , Migraine Disorders/classification , Mitochondria/enzymology , Monoamine Oxidase/blood , NADH Dehydrogenase/blood , Succinate Dehydrogenase/blood
19.
Q J Med ; 86(10): 657-60, 1993 Oct.
Article in English | MEDLINE | ID: mdl-8255963

ABSTRACT

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity. We measured mitochondrial respiratory chain enzyme activities in platelets from 18 normal healthy non-smoking controls and compared them with those from 23 similarly healthy cigarette smoking individuals. A 24% decrease (p < 0.02) was observed in the mean NADH CoQ1 reductase (complex I) activity of the smoking group compared with that of the non-smoking group. There was no significant change in the activity of any of the other respiratory chain enzymes. This is the first demonstration in vivo of mitochondrial inhibition by a common environmental agent. The results offer a novel mechanism of action for the cellular toxicity, or even mutagenicity, associated with cigarette smoking. In addition, these data have important implications for the interpretation of platelet mitochondrial complex I activities in disease states. They are particularly relevant to our interpretation and understanding of the complex I deficiency in Parkinson's disease platelets.


Subject(s)
Mitochondria/enzymology , Smoking/adverse effects , Blood Platelets/enzymology , Citrate (si)-Synthase/blood , Electron Transport , Electron Transport Complex I , Electron Transport Complex IV/blood , Female , Humans , Male , NADH, NADPH Oxidoreductases/blood , Succinate Cytochrome c Oxidoreductase/blood
20.
Neurology ; 42(6): 1246-7, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1318523

ABSTRACT

We measured cytochrome oxidase activity in thrombocytes from patients with senile dementia of the Alzheimer type. We found no decrease in enzyme activity in Alzheimer's disease patients when compared with patients with multi-infarct dementia, with young control donors, and with age-matched control donors.


Subject(s)
Alzheimer Disease/blood , Blood Platelets/enzymology , Electron Transport Complex IV/blood , Adult , Citrate (si)-Synthase/blood , Dementia, Multi-Infarct/blood , Humans
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