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Biomedical subjects

M A Tarnopolsky

Publications and source records attributed to M A Tarnopolsky.

At least 19 recordsLinked to original sources
PubMed2005

Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise.

To search for novel transcriptional pathways that are activated in skeletal muscle after endurance exercise, we used cDNA microarrays to measure global mRNA expression after an exhaustive bout of high-intensity cycling (approximately 75 min). Healthy, young, sedentary males performed the cycling bout, and skeletal muscle biopsies were taken from the vastus lateralis before, and at 3 and 48 h after exercise. We examined mRNA expression in individual muscle samples from four subjects using cDNA microarrays, used repeated-measures significance analysis of microarray (SAM) to determine statistically significant expression changes, and confirmed selected results using real-time RT-PCR. In total, the expression of 118 genes significantly increased 3 h postcycling and 8 decreased. At 48 h, the expression of 29 genes significantly increased and 5 decreased. Many of these are potentially important novel genes involved in exercise recovery and adaptation, including several involved in 1) metabolism and mitochondrial biogenesis (FOXO1, PPARdelta, PPARgamma, nuclear receptor binding protein 2, IL-6 receptor, ribosomal protein L2, aminolevulinate delta-synthase 2); 2) the oxidant stress response (metalothioneins 1B, 1F, 1G, 1H, 1L, 2A, 3, interferon regulatory factor 1); and 3) electrolyte transport across membranes [Na+-K+-ATPase (beta3), SERCA3, chloride channel 4]. Others include genes involved in cell stress, proteolysis, apoptosis, growth, differentiation, and transcriptional activation, as well as all three nuclear receptor subfamily 4A family members (Nur77, Nurr1, and Nor1). This study is the first to characterize global mRNA expression during recovery from endurance exercise, and the results provide potential insight into 1) the transcriptional contributions to homeostatic recovery in human skeletal muscle after endurance exercise, and 2) the transcriptional contributions from a single bout of endurance exercise to the adaptive processes that occur after a period of endurance exercise training.

Adult↗
PubMed2004

Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy.

OBJECTIVE: To determine whether creatine monohydrate (CrM) supplementation increases strength and fat-free mass (FFM) in boys with Duchenne muscular dystrophy (DD). METHODS: Thirty boys with DD (50% were taking corticosteroids) completed a double-blind, randomized, cross-over trial with 4 months of CrM (about 0.10 g/kg/day), 6-week wash-out, and 4 months of placebo. Measurements were completed of pulmonary function, compound manual muscle and handgrip strength, functional tasks, activity of daily living, body composition, serum creatine kinase and gamma-glutamyl transferase activity and creatinine, urinary markers of myofibrillar protein breakdown (3-methylhistidine), DNA oxidative stress (8-hydroxy-2-deoxyguanosine [8-OH-2-dG]), and bone degradation (N-telopeptides). RESULTS: During the CrM treatment phase, there was an increase in handgrip strength in the dominant hand and FFM (p < 0.05), with a trend toward a loss of global muscle strength (p = 0.056) only for the placebo phase, with no improvements in functional tasks or activities of daily living. Corticosteroid use, but not CrM treatment, was associated with a lower 8-OH-2-dG/creatinine (p < 0.05), and CrM treatment was associated with a reduction in N-telopeptides (p < 0.05). CONCLUSIONS: Four months of CrM supplementation led to increases in FFM and handgrip strength in the dominant hand and a reduction in a marker of bone breakdown and was well tolerated in children with DD.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Na+,K+-ATPase concentration and fiber type distribution after spinal cord injury.

Complete spinal cord injury (SCI) is characterized, in part, by reduced fatigue-resistance of the paralyzed skeletal muscle during stimulated contractions, but the underlying mechanisms are not fully understood. The effects of complete SCI on skeletal muscle Na(+),K(+)-adenosine triphosphatase (ATPase) concentration, and fiber type distribution were therefore investigated. Six individuals (aged 32.0 +/- 5.3 years) with complete paraplegia (T4-T10; 1-19 years since injury) participated. There was a significantly lower Na(+),K(+)-ATPase concentration in the paralyzed vastus lateralis (VL) when compared to either the subjects' own unaffected deltoid or literature values (from our laboratory, utilizing the same methodology) of VL Na(+),K(+)-ATPase concentration for the healthy able-bodied (141.6 +/- 50.0, 213.4 +/- 23.9, 339 +/- 16 pmol/g wet wt., respectively; P < 0.05). There was also a significant negative correlation between the Na(+),K(+)-ATPase concentration in the paralyzed VL and years since injury (r = -0.75, P < 0.05). These findings are clinically relevant as they suggest that reductions in Na(+),K(+)-ATPase contribute to the fatigability of paralyzed muscle after SCI. Unexpectedly, the VL muscles of our subjects had a higher proportion of their area represented by type I fibers compared to literature values for the VL of the healthy able-bodied (52.6 +/- 25.3% vs. 36 +/- 11.3%, respectively; P < 0.05). As all our subjects had upper motor neuron injuries and, therefore, experienced muscle spasticity, our findings warrant further investigation into the relationship between muscle spasticity and fiber type expression after SCI.

Adult↗
PubMed2004

Pathology of skeletal muscle in mitochondrial disorders.

Muscle histology is an essential component of the diagnostic work-up for mitochondrial cytopathies and is very important in both ruling in disease as well as ruling out the disease (i.e., alternate diagnoses). A muscle biopsy method must provide tissue for histology, electron microscopy, enzymes and DNA and this can be obtained with a suction-modified 5 mm needle. Proper embedding and processing is important for optimal diagnostic yield. The essential stains for mitochondrial histology remain the modified Gomori trichrome, cytochrome oxidase, succinate dehydrogenase, and NADH. Electron microscopy can be helpful in selected cases, however, the decision to perform this on all samples remains a contentious issue. Some cases of mitochondrial cytopathy may show no abnormalities on histology or electron microscopy (i.e., LHON), whereas, other conditions can mimic mitochondrial disease through secondary mitochondrial changes (i.e., inclusion body myositis). Athletes show evidence of increased mitochondrial numbers but do not normally develop ragged red fibers or paracrystalline inclusions. Aging is associated with an accumulation of mitochondrial abnormalities and is an important factor to consider in the interpretation of the sample. For example, biopsies in young children with mitochondrial disease may be normal at the histological level and otherwise healthy older adults can show mitochondrial changes such as ragged red and COX-negative fibers.

Journal Article↗
PubMed2003

Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice.

This study investigated the effects of riluzole (Ril), creatine (Cr) and a combination of these treatments on the onset and progression of clinical signs and neuropathology in an animal model of familial amyotrophic lateral sclerosis, the G93A transgenic mouse (n=13-17 per group). The onset of clinical signs was delayed (P<0.05) by about 12 days in all treatment groups compared with control; however, no differences occurred between treatments. All animals were killed at 199 days of age. At the end of the experimental period the severity of clinical signs was less (P<0.05) with all treatments compared with control. Again no differences between treatments were observed. The treatments had no effect on the number of neurons in ventral horns of the lumbar region of the spinal cord. Transgenic mice ingesting Cr displayed elevated (P<0.05) total Cr levels in cerebral hemispheres (5%) and spinal cord (8%), but not skeletal muscles. These data demonstrate that treatment with Ril and Cr were both effective in delaying disease onset and clinical disability. To the age of killing, no additional benefit was conferred by co-administration of Ril and Cr.

Age of Onset↗
PubMed2003

Interaction of fibre type, potentiation and fatigue in human knee extensor muscles.

AIM: To examine the effect of fibre type on potentiation and fatigue. METHODS: Young men (n = 4 per group) with a predominance of type I [61.4 +/- 6.9% (SD), group I (GI)] or type II [71.8 +/- 9.2%, group II (GII)] fibres in vastus lateralis, performed a fatigue protocol of sixteen 5-s maximal voluntary isometric contractions (MVCs) of the right knee extensors. Maximal twitches and corresponding muscle action potentials (M-waves) were evoked before the first MVC, during the 3-s rest period after each MVC and at intervals during the 5-min recovery period after the last MVC. RESULTS: Group II [49.3 +/- 2.6% (SE)] had a greater decrease in MVC force than GI (22.8 +/- 6.2%) during the fatigue protocol. Group II (126.4 +/- 13.6%) showed greater twitch force potentiation early in the fatigue protocol than GI (38.2 +/- 2.3%), but greater depression at the end (33.7 +/- 13.7% vs.17.4 +/- 3.4%). Twitch time-to-peak torque (TPT) and half relaxation time (HRT) initially decreased but then increased as the fatigue protocol progressed; GII had a greater increase in HRT. During a 5-min recovery period twitch force increased above the prefatigue level and remained so until the end of the recovery period; the pattern was similar in GI and GII. Twitch TPT and HRT remained elevated during recovery. M-wave area increased throughout the fatigue protocol and the first part of recovery before returning to baseline values in GII, whereas there were no significant changes in GI. The interaction between potentiation and fatigue was amplified in GII early in the fatigue protocol with concurrently greater twitch and M-wave potentiation, and greater MVC force decrease and HRT increase. Late in the protocol, GII had a greater decrease in twitch and MVC force combined with greater M-wave potentiation. CONCLUSION: It is concluded that fibre type distribution influences potentiation and fatigue of the twitch, and potentiation of the M-wave during fatiguing exercise.

Action Potentials↗
PubMed2003

Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats.

Creatine monohydrate (CrM) supplementation appears to be relatively safe based on data from short-term and intermediate-term human studies and results from several therapeutic trials. The purpose of the current study was to characterize pathological changes after intermediate-term and long-term CrM supplementation in mice [healthy control and SOD1 (G93A) transgenic] and rats (prednisolone and nonprednisolone treated). Histological assessment (18-20 organs/tissues) was performed on G93A mice after 159 days, and in Sprague-Dawley rats after 365 days, of CrM supplementation (2% wt/wt) compared with control feed. Liver histology was also evaluated in CD-1 mice after 300 days of low-dose CrM supplementation (0.025 and 0.05 g x kg-1x day-1) and in Sprague-Dawley rats after 52 days of CrM supplementation (2% wt/wt) with and without prednisolone. Areas of hepatitis were observed in the livers of the CrM-supplemented G93A mice (P < 0.05), with no significant inflammatory lesions in any of the other 18-20 tissues/organs that were evaluated. The CD-1 mice also showed significant hepatic inflammatory lesions (P < 0.05), yet there was no negative effect of CrM on liver histology in the Sprague-Dawley rats after intermediate-term or long-term supplementation nor was inflammation seen in any other tissues/organs (P = not significant). Dietary CrM supplementation can induce inflammatory changes in the liver of mice, but not rats. The observed inflammatory changes in the murine liver must be considered in the evaluation of hepatic metabolism in CrM-supplemented mice. Species differences must be considered in the evaluation of toxicological and physiological studies.

Animals↗
PubMed2003

Adaptations in human muscle sarcoplasmic reticulum to prolonged submaximal training.

In this study, we employed single-leg submaximal cycle training, conducted over a 10-wk period, to investigate adaptations in sarcoplasmic reticulum (SR) Ca(2+)-regulatory proteins and processes of the vastus lateralis. During the final weeks, the untrained volunteers (age 21.4 +/- 0.3 yr; means +/- SE, n = 10) were exercising 5 times/wk and for 60 min/session. Analyses were performed on tissue extracted by needle biopsy approximately 4 days after the last training session. Compared with the control leg, the trained leg displayed a 19% reduction (P < 0.05) in homogenate maximal Ca(2+)-ATPase activity (192 +/- 11 vs. 156 +/- 18 micromol. g protein(-1). min(-1)), a 4.3% increase (P < 0.05) in pCa(50), defined as the Ca(2+) concentration at half-maximal activity (6.01 +/- 0.05 vs. 6.26 +/- 0.07), and no change in the Hill coefficient (1.75 +/- 0.15 vs. 1.76 +/- 0.21). Western blot analysis using monoclonal antibodies (7E6 and A52) revealed a 13% lower (P < 0.05) sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) 1 in trained vs. control in the absence of differences in SERCA2a. Training also resulted in an 18% lower (P < 0.05) SR Ca(2+) uptake and a 26% lower (P < 0.05) Ca(2+) release. It is concluded that a downregulation in SR Ca(2+) cycling in vastus lateralis occurs with aerobic-based training, which at least in the case of Ca(2+) uptake can be explained by reduction in Ca(2+)-ATPase activity and SERCA1 protein levels.

Adaptation, Physiological↗
PubMed2002

Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy.

OBJECTIVE: To evaluate the potential of modafinil in reducing excessive daytime somnolence (EDS) and enhancing indexes of quality of life and mood in patients with myotonic dystrophy (DM). METHODS: Forty patients with DM were randomized to receive modafinil and placebo for 14 days each, using a double-blind, cross-over design. Before and after each trial, subjects completed handgrip strength testing, spirometry, and quality-of-life measures (RAND). On days 7 and 14, each subject completed the Epworth Sleepiness Scale (ESS), the Stanford Sleepiness Scale (SSS), and the Profile of Mood States (POMS). RESULTS: ESS scores were lower while taking modafinil (mean 248 mm; 95% confidence limit 220 to 276 mm) as compared with placebo (309 mm; 281 to 336 mm) (p < 0.001). Mean SSS scores were also lower during the modafinil trial (3.05; 2.77 to 3.33) than during the placebo trial (3.45; 3.18 to 3.71) (p < 0.05). The POMS indicated that modafinil decreased fatigue-inertia (p < 0.001) and increased vigor-activity and tension-anxiety (p < 0.001) indexes. The total mood disturbance score was also decreased during the modafinil trial as compared with placebo (p < 0.05). The RAND quality-of-life measures of energy (p < 0.001) and health change (p < 0.05) were both significantly enhanced during the modafinil treatment phase. No changes in maximal grip strength or forced expired volume in 1 second were detected over the course of the study. Headache was the most frequently reported adverse event. Four patients withdrew from the study, three because of side effects (two during modafinil ingestion and one during placebo ingestion). CONCLUSION: Modafinil reduces somnolence and improves mood in patients with DM.

Activities of Daily Living↗
PubMed2002

Post exercise hypotension is not mediated by the serotonergic system in borderline hypertensive individuals.

Recent evidence from our laboratory and others have suggested that the mechanism for a decrease in resting blood pressure after an acute bout of exercise is a centrally mediated decrease in total peripheral resistance. This study examined the effect of the central serotonergic system on post exercise hypotension (PEH) in 11 borderline hypertensive individuals (nine male, two female) aged 24.5 +/- 5.1 years. Each subject completed two, 30-min cycling bouts at 70% of VO2peak while under placebo or a selective serotonin re-uptake inhibitor (SSRI) treatment. Blood pressure was recorded directly from the radial artery, and treatments were randomised, double blinded and separated by at least 14 days. Baseline blood pressure was 145/72 mm Hg for systolic (SBP) and diastolic (DBP) respectively. Peripheral measures of serotonin (5-HT) were lower under SSRI treatment, whereas the major 5-HT metabolite, 5-hydroxyindoleacetic acid, was not significantly changed, indicating elevated central 5-HT levels. There was no difference in any of the haemodynamic variables between trials. Despite an increased heart rate for the initial 75 min post exercise, SBP was decreased as much as 23 mm Hg during the initial 60 min post exercise, after which it had returned to normal. DBP was unchanged after exercise. Circulating adrenaline (0.60 +/- 0.14 ng/mL to 1.3 +/- 1.6 ng/ml) and noradrenaline (0.27 +/- 0.31 ng/ml to 4.5 +/- 2.1 ng/ml) were significantly elevated during exercise. Both returned to pre-exercise levels within 15 min post exercise. Unexpectedly, oxygen uptake was slightly (5%), but significantly increased over the entire duration of the SSRI trial. We conclude that the central serotonergic system is not responsible for PEH in our borderline hypertensive population.

Adult↗
PubMed2002

Substrate turnover and oxidation during moderate-intensity exercise following acute plasma volume expansion.

In previous work using prolonged, light cycle exercise, we were unable to demonstrate an effect of acute plasma volume (PV) expansion on glucose kinetics or substrate oxidation, despite a decline in whole-body lipolysis (Phillips et al., 1997). However, PV is known to decrease arterial O2 content. The purpose of this study was to examine whether substrate turnover and oxidation would be altered with heavier exercise where the challenge to O2 delivery is increased. Eight untrained males (VO2max = 3.52 +/- 0.12 l/min) twice performed 90 min of cycle ergometry at 62 % VO2peak, both prior to (CON) and following induced plasma volume expansion (Dextran [6 %] or Pentaspan [10 %]) (6.7 ml/kg) (PVX). Glucose and glycerol kinetics were determined with primed constant infusions of [6.6-(2)H2] glucose and [(2)H5] glycerol, respectively. PVX resulted in a 15.8 +/- 2.2 % increase (p < 0.05) in PV. Glucose and glycerol appearance (Ra) and utilization (Rd), although increasing progressively (p < 0.05) with exercise, were not different between conditions. Similarly, no differences in substrate oxidation, either fat or carbohydrate, were observed between the two conditions. Prolonged exercise resulted in an increase (p < 0.05) in plasma glucagon and a decrease (p < 0.05) in plasma insulin during both conditions. With PVX, the exercise-induced increase in glucagon was diminished (p < 0.05). We conclude that impairment in O2 content mediated by an elevated PV does not alter glucose, and glycerol kinetics or substrate oxidation even at moderate exercise intensity.

Adult↗
PubMed2001

Myoadenylate deaminase deficiency does not affect muscle anaplerosis during exhaustive exercise in humans.

1. Myoadenylate deaminase (AMPD) deficiency is present in 1--2 % of the population. In theory, this deficiency may alter exercise energy metabolism by impairing the purine nucleotide cycle (PNC) and reducing tricarboxylic acid (TCA) cycle anaplerosis. The role of the PNC in TCA cycle anaplerosis is still a debated issue in physiology. Using patients with the AMPD1 mutation will allow a human 'knockout' approach to answering this question. 2. Muscle AMPD activity and genotype (whole blood AMPD1 analysis) was used to classify participants into three groups: n = 3 with absence of AMPD activity and -/- AMPD1 genotype (homozygous); n = 4 with less than 50 % normal AMPD activity and +/- genotype (heterozygous) and n = 12 with normal AMPD activity and +/+ genotype (control). Biopsies were taken from the vastus lateralis muscle before and after incremental cycle ergometry exercise to exhaustion. The muscle biopsies were analysed for AMPD activity, purine nucleotides/nucleosides and bases, creatine, phosphocreatine, amino acids, and the TCA cycle intermediates malate, citrate and fumarate. 3. Time to exhaustion on the cycle ergometer was not different between groups. Muscle adenosine monophosphate increased significantly with exercise for homozygous subjects as compared with the other groups (P < 0.05). Inosine monophosphate increased significantly after exercise for control (P < 0.05) but not for the homozygous subjects. There were no other between-group differences for any other measured variables. 4. In summary, complete and partial muscle AMPD deficiency did not affect TCA cycle anaplerosis, phosphocreatine hydrolysis, energy charge or exercise performance.

AMP Deaminase↗
PubMed2001

Expression of MCT1 and MCT4 in a patient with mitochondrial myopathy.

Mitochondrial myopathies (MM) are characterized by alterations in oxidative phosphorylation. The resultant increase in glycolytic flux produces a variable lactic acidosis. Intracellular acidification can induce both metabolic and, in the case of skeletal muscle, contractile dysfunction. Skeletal muscle lactate transporters have recently been identified which include both monocarboxylate transporter 1 (MCT1) and 4 (MCT4). Lactate import into oxidative skeletal muscle appears to be catalyzed by MCT1, whereas its extrusion from glycolytic fibers may be mediated by MCT4. We describe the expression of these isoforms in a patient with MM as compared to controls (n = 5). MCT4 content was 86% (>3 SD) higher in the patient with MM, whereas MCT1 content was less markedly elevated (47%), as compared to controls. These findings support previous work suggesting that the major role of MCT4 is to defend intracellular pH by extruding lactate and H(+) to the interstitium. The role of MCT1 in MM is less clear.

Aged↗
PubMed2001

Creatine transporter and mitochondrial creatine kinase protein content in myopathies.

Total creatine or phosphocreatine, or both, are reduced in the skeletal muscle of patients with inflammatory myopathy, mitochondrial myopathy, and muscular dystrophy/congenital myopathy. We used Western blotting techniques to measure skeletal muscle creatine transporter protein and sarcomeric mitochondrial creatine kinase (mtCK) protein content in patients with inflammatory myopathy (N = 8), mitochondrial myopathy (N = 5), muscular dystrophy (N = 7), and congenital myopathy (N = 3), as compared to a control group without a neuromuscular diagnosis (N = 8). Creatine transporter protein content was lower for all groups compared to control subjects (P < 0.05; P < 0.01 for congenital myopathy). Mitochondrial CK (mtCK) was lower for inflammatory myopathy (P < 0.05), higher for mitochondrial myopathy (P < 0.05), not different for muscular dystrophy, and markedly lower for the congenital myopathy group (P < 0.01), compared to control subjects. Together, these data suggest that the reduction in total creatine or phosphocreatine in patients with certain myopathies is correlated with creatine transporter and not mtCK protein content. This further supports the belief that creatine monohydrate supplementation may benefit patients with low muscle creatine stores, although the reduction in creatine transporter protein may have implications for dosing.

Adult↗
PubMed2001

An acute oral dose of caffeine does not alter glucose kinetics during prolonged dynamic exercise in trained endurance athletes.

This study investigated the possible influence of oral caffeine administration on endogenous glucose production and energy substrate metabolism during prolonged endurance exercise. Twelve trained endurance athletes [seven male, five female; peak oxygen consumption (VO2peak) = 65.5 ml.kg-1.min-1] performed 60 min of cycle ergometry at 65% VO2peak twice, once after oral caffeine administration (6 mg.kg-1) (CAF) and once following consumption of a placebo (PLA). CAF and PLA were administered in a randomized double-blind manner 75 min prior to exercise. Plasma glucose kinetics were determined with a primed-continuous infusion of [6,6-2H]glucose. No differences in oxygen consumption (VO2), and carbon dioxide production (VCO2) were observed between CAF and PLA, at rest or during exercise. Blood glucose concentrations were similar between the two conditions at rest and also during exercise. Exercise did lead to an increase in serum free fatty acid (FFA) concentrations for both conditions; however, no differences were observed between CAF and PLA. Both the plasma glucose rate of appearance (Ra) and disappearance (Rd) increased at the onset of exercise (P < 0.05), but were not affected by CAF, as compared to PLA. CAF did lead to a higher plasma lactate concentration during exercise (P < 0.05). It was concluded that an acute oral dose of caffeine does not influence plasma glucose kinetics or energy substrate oxidation during prolonged exercise in trained endurance athletes. However, CAF did lead to elevated plasma lactate concentrations. The exact mechanism of the increase in plasma lactate concentrations remains to be determined.

Administration, Oral↗
PubMed2001

Post exercise hypotension is sustained during subsequent bouts of mild exercise and simulated activities of daily living.

Our purpose was to examine whether the transient suppression of blood pressure that occurs during the hours following acute exercise (termed post exercise hypotension) persists throughout an active period of subsequent mild exercise and simulated activities of daily living (ADL) using direct measurements of arterial pressure. Eight recreationally active participants, with low borderline systolic hypertension completed 30 min of cycle ergometry at 70% VO(2Peak) and 30 min of quiet seated rest on separate days (randomised order). Following exercise and rest, subjects completed a 70-min protocol of mild exercise and simulated ADL. Blood pressure was monitored throughout by catheterisation of the radial artery. Exercise resulted in lower systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) throughout the post exercise ADL period compared to control measurements taken without prior exercise. The maximal difference in SBP, DBP and MAP between trials was 26, 7 and 13 mm Hg respectively. Average differences in SBP, DBP and MAP between trials were 16, 5 and 8 mm Hg respectively. This relative hypotension occurred in spite of higher heart rates during the ADL measurement period following the prior exercise. Furthermore, many of the blood pressure measurements during the post exercise period were significantly lower than the pre-exercise values during the same trial. We conclude that post exercise hypotension persists during mild exercise and simulated ADL. Although the duration of this relative hypotension needs to be determined, acute exercise may serve as a non-pharmacological aid in the treatment of hypertension.

Activities of Daily Living↗