Philip J Atherton

McMaster University, Hamilton, Ontario, Canada

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Publications (61)284.15 Total impact

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    ABSTRACT: Background: The anabolic response of skeletal muscle to essential amino acids (EAAs) is dose dependent, maximal at modest doses, and short lived, even with continued EAA availability, a phenomenon termed “muscle-full.” However, the effect of EAA ingestion profile on muscle metabolism remains undefined. Objective: We determined the effect of Bolus vs. Spread EAA feeding in young men and hypothesized that muscle-full is regulated by a dose-, not delivery profile–, dependent mechanism. Methods: We provided 16 young healthy men with 15 g mixed-EAA, either as a single dose (“Bolus” n = 8) or in 4 fractions at 45-min intervals (“Spread” n = 8). Plasma insulin and EAA concentrations were assayed by ELISA and ion-exchange chromatography, respectively. Limb blood flow by was determined by Doppler ultrasound, muscle microvascular flow by Sonovue (Bracco) contrast-enhanced ultrasound, and phosphorylation of mammalian target of rapamycin complex 1 substrates by immunoblotting. Intermittent muscle biopsies were taken to quantify myofibrillar-bound 13C6-phenylalanine to determine muscle protein synthesis (MPS). Results: Bolus feeding achieved rapid insulinemia (13.6 μIU ⋅ mL−1, 25 min after commencement of feeding), aminoacidemia (∼2500 μM at 45 min), and capillary recruitment (+45% at 45 min), whereas Spread feeding achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (peak: ∼1500 μM at 135 min), and no detectable capillary recruitment (all P < 0.01 vs. Bolus). Despite these differences, identical anabolic responses were observed; fasting fractional synthetic rates of 0.054% ⋅ h−1 (Bolus) and 0.066% ⋅ h−1 (Spread) increased to 0.095% and 0.104% ⋅ h−1 (no difference in increment or final values between regimens). With both Spread and Bolus feeding strategies, a latency of at least 90 min was observed before an upswing in MPS was evident. Similarly with both feeding strategies, MPS returned to fasting rates by 180 min despite elevated circulating EAAs. Conclusion: These data do not support EAA delivery profile as an important determinant of anabolism in young men at rest, nor rapid aminoacidemia/leucinemia as being a key factor in maximizing MPS. This trial was registered at clinicaltrials.gov as NCT01735539.
    Journal of Nutrition 01/2015; · 4.23 Impact Factor
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    ABSTRACT: Aging is associated with a gradual loss of muscle mass termed sarcopenia, which has significant impact on quality-of-life. Because oxidative stress is proposed to negatively impact upon musculoskeletal aging, we investigated links between human aging and markers of oxidative stress, and relationships to muscle mass and strength in young and old nonsarcopenic and sarcopenic adults. Sixteen young and 16 old males (further subdivided into "old" and "old sarcopenic") were studied. The abundance of protein carbonyl adducts within skeletal muscle sarcoplasmic, myofibrillar, and mitochondrial protein subfractions from musculus vastus lateralis biopsies were determined using Oxyblot immunoblotting techniques. In addition, concentrations of recognized cytoprotective proteins (eg, heat shock proteins [HSP], αβ-crystallin) were also assayed. Aging was associated with increased mitochondrial (but not myofibrillar or sarcoplasmic) protein carbonyl adducts, independently of (stage-I) sarcopenia. Correlation analyses of all subjects revealed that mitochondrial protein carbonyl abundance negatively correlated with muscle strength ([1-repetition maximum], p = .02, r (2) = -.16), but not muscle mass (p = .13, r (2) = -.08). Abundance of cytoprotective proteins, including various HSPs (HSP 27 and 70), were unaffected by aging/sarcopenia. To conclude, these data reveal that mitochondrial protein carbonylation increases moderately with age, and that this increase may impact upon skeletal muscle function, but is not a hallmark of (stage-I) sarcopenia, per se.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2014; · 4.31 Impact Factor
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    ABSTRACT: Muscle hypertrophy following resistance training (RT) involves activation of myofibrillar protein synthesis (MPS) to expand the myofibrillar protein pool. The degree of hypertrophy following RT is, however, highly variable and thus we sought to determine the relationship between the acute activation of MPS and RT-induced hypertrophy. We measured MPS and signalling protein activation after the first session of resistance exercise (RE) in untrained men (n = 23) and then examined the relation between MPS with magnetic resonance image determined hypertrophy. To measure MPS, young men (24±1 yr; body mass index = 26.4±0.9 kg•m(2)) underwent a primed constant infusion of L-[ring-(13)C6] phenylalanine to measure MPS at rest, and acutely following their first bout of RE prior to 16 wk of RT. Rates of MPS were increased 235±38% (P<0.001) above rest 60-180 min post-exercise and 184±28% (P = 0.037) 180-360 min post exercise. Quadriceps volume increased 7.9±1.6% (-1.9-24.7%) (P<0.001) after training. There was no correlation between changes in quadriceps muscle volume and acute rates of MPS measured over 1-3 h (r = 0.02), 3-6 h (r = 0.16) or the aggregate 1-6 h post-exercise period (r = 0.10). Hypertrophy after chronic RT was correlated (r = 0.42, P = 0.05) with phosphorylation of 4E-BP1(Thr37/46) at 1 hour post RE. We conclude that acute measures of MPS following an initial exposure to RE in novices are not correlated with muscle hypertrophy following chronic RT.
    PLoS ONE 02/2014; 9(2):e89431. · 3.53 Impact Factor
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    ABSTRACT: We investigated architectural, functional, and molecular responses of human skeletal muscle to concentric (CON) or eccentric (ECC) resistance training (RT). Twelve young males performed 10 weeks of concentric (CON) or eccentric (ECC) resistance training (RT) (n = 6 CON, 6 ECC). An additional 14 males were recruited to evaluate acute muscle fascicle behaviour and molecular signalling in biopsies collected from vastus lateralis (VL) after 30 min of single bouts of CON or ECC exercise. VL volume was measured by magnetic resonance imaging. Muscle architecture (fascicle length, Lf; pennation angle, PA) was evaluated by ultrasonography. Muscle remodelling signals to CON or ECC loading (MAPK/AKT-mammalian target of rapamycin (mTOR) signalling) and inflammatory pathway (TNFα/Murf-1-MAFbx) were evaluated by immunoblotting. Despite the ~1.2 fold greater load of the ECC group, similar increases in muscle volume (+8% CON and +6% ECC) and in maximal voluntary isometric contraction (+9% CON and +11% ECC) were found after RT. However, increases in Lf were greater after ECC than CON (+12 vs. +5%) while increases in PA were greater in CON than ECC (+30 vs. +5%). Distinct architectural adaptations were associated with preferential growth in the distal regions of VL for ECC (+ECC +8% vs. +CON +2) and mid-belly for CON (ECC +7 vs. CON +11%). While MAPK activation (p38MAPK, ERK1/2, p90RSK) was specific to ECC, neither mode affected AKT-mTOR or inflammatory signalling 30 min after exercise. Muscle growth with CON and ECC RT occurs with different morphological adaptations reflecting distinct fibre fascicle behaviour and molecular responses. This article is protected by copyright. All rights reserved.
    Acta Physiologica 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Quantification of muscle protein synthesis (MPS) remains a cornerstone to understanding the control of muscle mass. Traditional (13)C-amino-acid tracer methodologies necessitate sustained bed-rest and intravenous cannulation(s), restricting studies to ~12h, and thus cannot holistically inform on diurnal MPS. This limits insight into the regulation of habitual muscle metabolism in health, ageing and disease while querying the utility of tracer-techniques to predict the long-term efficacy of anabolic/anti-catabolic interventions. We tested the efficacy of the D2O tracer for quantifying MPS over a period not feasible with (13)C tracers and too short to quantify changes in mass. Eight men (22±3.5y) undertook one-legged resistance-exercise over 8-d (4×8-10 repetitions: 80%-1RM every second-day, to yield 'non-exercised' vs. 'exercise' leg-comparisons) with Vastus Lateralis biopsies taken bi-laterally: 0, 2, 4 and 8-days. After day-0 biopsies, participants consumed a D2O bolus (150ml; 70-Atom%); saliva was collected daily. Fractional synthetic rates (FSR) of myofibrillar (MyoPS), sarcoplasmic (SPS) and collagen (CPS) protein-fractions were measured by GC-Pyrolysis-IRMS and TC/EA-IRMS. Body-water initially enriched at 0.16-0.24 APE, decayed at ~0.009%.d-1. In the non-exercised-leg, MyoPS was: 1.45±0.10%.d-1, 1.47±0.06%.d(-1), 1.35±0.07%.d-1 at 0-2, 0-4 and 0-8d respectively (~0.05-0.06%.h-1). MyoPS was greater in the exercised-leg (0-2d 1.97±0.13%.d(-1), 0-4d 1.96±0.15%.d-1; P<0.01, 0-8d 1.79±0.12%.d(-1); P<0.05). CPS was slower than MyoPS, but followed a similar pattern, with the exercised-leg tending to yield greater FSR's (0-2d; 1.14±0.13%.d-1 vs. 1.45±0.15%.d(-1), 0-4d; 1.13±0.07%.d(-1) vs. 1.47±0.18%.d(-1), 0-8d; 1.03±0.09%.d(-1) vs. 1.40±0.11%.d(-1)). SPS remained unchanged. Therefore, D2O has unrivaled utility to quantify day-to-day MPS in humans and inform on short-term changes in anabolism, and presumably, catabolism alike.
    AJP Endocrinology and Metabolism 12/2013; · 4.51 Impact Factor
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    ABSTRACT: Skeletal muscle anabolism associated with postprandial plasma aminoacidaemia and insulinaemia is contingent upon amino acids (AA) and insulin crossing the microcirculation-myocyte interface. In this study, we hypothesised that increasing muscle microvascular blood volume [flow] would enhance fed-state anabolic responses in muscle protein turnover. We studied 10 young men (23.2±2.1 y) under postabsorptive and fed (I.V Glamin® (~10 g AA), glucose ~7.5 mmol·l(-1))) conditions. Methacholine was infused into the femoral artery of one-leg to determine, via bilateral comparison, the effects of feeding alone versus feeding plus pharmacological vasodilation. We measured leg blood flow (LBF) [femoral artery] by Doppler-ultrasound, muscle microvascular blood volume (MBV) by contrast-enhanced ultrasound (CEUS), muscle protein synthesis (MPS) and breakdown (MPB; A-V balance modelling) and net protein balance (NPB) using [1,2-(13)C2] leucine and [D5] phenylalanine tracers via gas chromatography-mass spectrometry (GC-MS). Indices of anabolic-signalling/endothelial activation (e.g. Akt/mTORC1/NOS) were assessed using immunoblotting techniques. Under fed conditions, LBF (+12±5%, P<0.05), MBV (+25±10%, P<0.05) and MPS (+129±33%, P<0.05) increased. Infusion of methacholine further enhanced LBF (+126±12%, P<0.05) and MBV (+79±30%, P<0.05). In-spite of these radically different blood flow conditions, neither increases in MPS in response to feeding (0.04±0.004 vs. 0.08±0.01%·h(-1), P<0.05) nor improvements in NPB (-9.7±4.8 vs. 34.2±14.1 nmol·min(-1), P<0.05) were affected by methacholine infusion (MPS 0.07±0.01%·h(-1); NPB 50.6±15.5 nmol·min(-1)), whereas MPB was unaltered by either feeding or infusion of methacholine. Thus, enhancing LBF/MBV above that occurring naturally with feeding alone, does not improve muscle anabolism.
    AJP Endocrinology and Metabolism 11/2013; · 4.51 Impact Factor
  • P J Atherton, B E Phillips
    The Journal of Physiology 11/2013; 591(Pt 21):5267-8. · 4.38 Impact Factor
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    ABSTRACT: Compromised limb blood flow in aging may contribute to the development of sarcopenia, frailty, and the metabolic syndrome. We developed a novel contrast-enhanced ultrasound technique using Sonovue™ to characterize muscle microvasculature responses to an oral feeding stimulus (15 g essential amino acids) in young (∼20 years) and older (∼70 years) men. Intensity-time replenishment curves were made via an ultrasound probe "fixed" over the quadriceps, with intermittent high mechanical index destruction of microbubbles within muscle vasculature. This permitted real-time measures of microvascular blood volume (MBV), microvascular flow velocity (MFV) and their product, microvascular blood flow (MBF). Leg blood flow (LBF) was measured by Doppler and insulin by enzyme-linked immunosorbent assay. Steady-state contrast concentrations needed for comparison between different physiological states were achieved <150 sec from commencing Sonovue™ infusion, and MFV and MBV measurements were completed <120 sec thereafter. Interindividual coefficients of variation in MBV and MFV were 35-40%, (N = 36). Younger men (N = 6) exhibited biphasic vascular responses to feeding with early increases in MBV (+36%, P < 0.008 45 min post feed) reflecting capillary recruitment, and late increases in MFV (+77%, P < 0.008) and MBF (+130%, P < 0.007 195 min post feed) reflecting more proximal vessel dilatation. Early MBV responses were synchronized with peak insulin but not increased LBF, while later changes in MFV and MBF occurred with insulin at post absorptive values but alongside increased LBF. All circulatory responses were absent in old men (N = 7). Thus, impaired postprandial circulation could impact age-related declines in muscle glucose disposal, protein anabolism, and muscle mass.
    Physiological reports. 10/2013; 1(5):e00119.
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    ABSTRACT: Focal adhesion kinase (FAK) is an attachment complex protein associated with the regulation of muscle mass, through as of yet unclear mechanisms. We tested whether FAK is functionally important for muscle hypertrophy, with the hypothesis that FAK knockdown (FAK-KD) would impede cell growth associated with a trophic stimulus. C2C12 skeletal muscle cells harbouring FAK targeted (FAK-KD) or scrambled (SCR) shRNA were created using lentiviral transfection techniques. Both FAK-KD and SCR myotubes were incubated for 24 h with IGF-1 (10 ng.ml(-1)) and additional SCR cells (± IGF-1) were incubated with a FAK-kinase inhibitor before assay of cell growth. Muscle protein synthesis (MPS) and putative FAK signalling mechanisms (immunoblotting and co-immunoprecipitation) were assessed. IGF-1-induced increases in myotube width (+41±7% vs. non-IGF-1-treated) and total protein (+44±6%) were, after 24 h, attenuated in FAK-KD cells while MPS was suppressed in FAK-KD vs. SCR after 4 h. These blunted responses were associated with attenuated IGF-1-induced FAK Tyr397 phosphorylation, and markedly suppressed phosphorylation of tuberous sclerosis complex 2 (TSC2) and critical downstream mTOR signalling (ribosomal S6 kinase, eIF4F assembly) in FAK shRNA cells (all P<0.05 vs. IGF-1-treated SCR cells). However, binding of FAK to TSC2 or its phosphatase Shp-2 was not affected by IGF-1 or cell phenotype. Finally, FAK-KD mediated suppression of cell growth was recapitulated by direct inhibition of FAK kinase activity in SCR cells. We conclude that FAK is required for IGF-1-induced muscle hypertrophy, through a TSC2-mTOR-S6K1-dependent pathway via means requiring the kinase activity of FAK, but not altered FAK-TSC2 or FAK-Shp-2 binding.
    AJP Endocrinology and Metabolism 05/2013; · 4.51 Impact Factor
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    ABSTRACT: Skeletal muscle structure and function are markedly affected by chronic disuse. With unloading, muscle mass is lost at rate of about 0.4 %/day but little is known about the recovery of muscle mass and strength following disuse. Here we report an extensive data set describing in detail skeletal muscle adaptations in structure and function in response to both disuse and retraining. Eight young men (23 ± 2.2 years) underwent 3 weeks of unilateral lower limb suspension (ULLS) followed by a 3-week resistance training recovery program. Knee extensor isometric torque, voluntary activation, quadriceps femoris (QF) muscle volume (QFvol), fascicle length (Lf) and pennation angle (θ), physiological cross-sectional area (PCSA) of all four heads of the QF muscle, were measured before, after ULLS, and post-ULLS-resistance training. Needle biopsies were taken from the vastus lateralis muscle of a subgroup (n = 6) of the same subjects and cross sectional area of individual muscle s and myosin content of muscle samples were determined. Following 3 weeks of ULLS, isometric torque decreased by 26 %, PCSA by 3 %, QFvol by 10 %. Lf and θ of all four heads of QF significantly decreased (p ≤ 0.05). Following the 3-week retraining period, isometric torque, PCSA, QFvol, Lf and θ of all four heads of QF were all fully restored to pre ULLS values. CSA of individual muscle fibres and myosin content of muscle samples decreased by 26 and 35 % respectively (post-ULLS) and recovered to almost pre-ULLS values following retraining. There were no significant changes in voluntary activation of the quadriceps muscles in response to either ULLS or subsequent retraining. These results indicate that: (1) the loss of muscle force with 3-week unloading in humans is mostly explained by muscle atrophy and by a decrease in myosin content and, (2) all the neuromuscular changes induced by this model of disuse can be fully restored after a resistance training intervention of equal duration.
    Biogerontology 05/2013; · 3.01 Impact Factor
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    ABSTRACT: Background:Alterations in muscle protein metabolism underlie age-related muscle atrophy. During periods of muscle disuse, muscle protein synthesis is blunted and muscle atrophy occurs in young and old. The impact of a short reduction in physical activity on muscle protein metabolism in older adults is unknown.Purpose:To investigate the impact of 14 days of reduced daily steps on fasted and fed-state rates of myofibrillar protein synthesis (MPS) to provide insight into the mechanisms for changes in muscle mass and markers of metabolic health.Methods:Prior to and following 14 d of reduced daily step-count, ten, healthy older adults (72±1 yr) underwent measures of insulin sensitivity, muscle strength, physical function and body composition. Using a primed constant infusion of L-[ring-(13)C6] phenylalanine with serial muscle biopsies, basal, postabsorptive and postprandial rates of MPS were determined before and after the 14 d intervention.Results:Daily step-count was reduced by ∼76% to 1413±110 steps/d. Leg fat-free mass was reduced by ∼3.9% (P < 0.001). Postabsorptive insulin resistance was increased by ∼12% and postprandial insulin sensitivity reduced by ∼43% following step-reduction (P < 0.005). Concentrations of TNF-α and CRP were increased by ∼12 and 25%, respectively, following step-reduction (P < 0.05). Postprandial rates of MPS were reduced by ∼26% following the intervention (P = 0.028) with no difference in postabsorptive rates.Conclusion:The present study demonstrates that 14 days of reduced steps in older adults induces small but measurable reductions in muscle mass that appear to be underpinned by reductions in post-prandial MPS and are accompanied by impairments in insulin sensitivity and systemic inflammatory markers and postprandial MPS.
    The Journal of Clinical Endocrinology and Metabolism 04/2013; · 6.31 Impact Factor
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    ABSTRACT: Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. Of all nutrients, the single amino acid Leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is "sensed" have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-13C2]Leu and [2H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by A-V dilution). Orally consumed 3.42g free-acid (FA-HMB) HMB (providing 2.42g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42g Leu, stimulated MPS (HMB: +70% vs. Leu: +110 %). While HMB and Leu both increased anabolic signaling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e., p70S6K1 signaling ≤90 min vs. ≤30 min for HMB). HMB consumption also attenuated MPB (-57 %) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.
    The Journal of Physiology 04/2013; · 4.38 Impact Factor
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    ABSTRACT: [This corrects the article on p. e1003389 in vol. 9.].
    PLoS Genetics 04/2013; 9(4). · 8.17 Impact Factor
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    ABSTRACT: Physical activity and molecular ageing presumably interact to precipitate musculoskeletal decline in humans with age. Herein, we have delineated molecular networks for these two major components of sarcopenic risk using multiple independent clinical cohorts. We generated genome-wide transcript profiles from individuals (n = 44) who then undertook 20 weeks of supervised resistance-exercise training (RET). Expectedly, our subjects exhibited a marked range of hypertrophic responses (3% to +28%), and when applying Ingenuity Pathway Analysis (IPA) up-stream analysis to ∼580 genes that co-varied with gain in lean mass, we identified rapamycin (mTOR) signaling associating with growth (P = 1.4×10(-30)). Paradoxically, those displaying most hypertrophy exhibited an inhibited mTOR activation signature, including the striking down-regulation of 70 rRNAs. Differential analysis found networks mimicking developmental processes (activated all-trans-retinoic acid (ATRA, Z-score = 4.5; P = 6×10(-13)) and inhibited aryl-hydrocarbon receptor signaling (AhR, Z-score = -2.3; P = 3×10(-7))) with RET. Intriguingly, as ATRA and AhR gene-sets were also a feature of endurance exercise training (EET), they appear to represent "generic" physical activity responsive gene-networks. For age, we found that differential gene-expression methods do not produce consistent molecular differences between young versus old individuals. Instead, utilizing two independent cohorts (n = 45 and n = 52), with a continuum of subject ages (18-78 y), the first reproducible set of age-related transcripts in human muscle was identified. This analysis identified ∼500 genes highly enriched in post-transcriptional processes (P = 1×10(-6)) and with negligible links to the aforementioned generic exercise regulated gene-sets and some overlap with ribosomal genes. The RNA signatures from multiple compounds all targeting serotonin, DNA topoisomerase antagonism, and RXR activation were significantly related to the muscle age-related genes. Finally, a number of specific chromosomal loci, including 1q12 and 13q21, contributed by more than chance to the age-related gene list (P = 0.01-0.005), implying possible epigenetic events. We conclude that human muscle age-related molecular processes appear distinct from the processes regulated by those of physical activity.
    PLoS Genetics 03/2013; 9(3):e1003389. · 8.17 Impact Factor
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    ABSTRACT: Cachexia is a consequence of tumor burden caused by ill-defined catabolic alterations in muscle protein turnover. We aimed to explore the effect of tumor burden and resection on muscle protein turnover in patients with nonmetastatic colorectal cancer (CRC), which is a surgically curable tumor that induces cachexia. We recruited the following 2 groups: patients with CRC [n = 13; mean ± SEM age: 66 ± 3 y; BMI (in kg/m(2)): 27.6 ± 1.1] and matched healthy controls (n = 8; age: 71 ± 2 y; BMI: 26.2 ± 1). Control subjects underwent a single study, whereas CRC patients were studied twice before and ∼6 wk after surgical resection to assess muscle protein synthesis (MPS), muscle protein breakdown (MPB), and muscle mass by using dual-energy X-ray absorptiometry. Leg muscle mass was lower in CRC patients than in control subjects (6290 ± 456 compared with 7839 ± 617 g; P < 0.05) and had an additional decline after surgery (5840 ± 456 g; P < 0.001). Although postabsorptive MPS was unaffected, catabolic changes with tumor burden included the complete blunting of postprandial MPS (0.038 ± 0.004%/h in the CRC group compared with 0.065 ± 0.006%/h in the control group; P < 0.01) and a trend toward increased MPB under postabsorptive conditions (P = 0.09). Although surgical resection exacerbated muscle atrophy (-7.2%), catabolic changes in protein metabolism had normalized 6 wk after surgery. The recovery in postprandial MPS after surgery was inversely related to the degree of muscle atrophy (r = 0.65, P < 0.01). CRC patients display reduced postprandial MPS and a trend toward increased MPB, and tumor resection reverses these derangements. With no effective treatment of cancer cachexia, future therapies directed at preserving muscle mass should concentrate on alleviating proteolysis and enhancing anabolic responses to nutrition before surgery while augmenting muscle anabolism after resection.
    American Journal of Clinical Nutrition 10/2012; 96(5):1064-70. · 6.50 Impact Factor
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    Nature 08/2012; 488(7413):E9-10; discussion E10-1. · 42.35 Impact Factor
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    ABSTRACT: We explored the relationships between resistance exercise volume/intensity and muscle myofibrillar protein synthetic (MPS) responses in young and older men. In a crossover design, four groups of six young (24±6 years) and older (70±5 years) men performed two volumes of resistance exercise: either 40% one repetition maximum (1RM) (3 × 14, then 6 × 14 repetitions) or 75% 1RM (3 × 8, then 6 × 8 repetitions), such that at the same volume, work was identical between intensities. Muscle biopsies were taken 0, 1, 2, and 4hours after exercise to measure MPS via myofibrillar bound [1,2-(13)C(2)]leucine and indices of mammalian target of rapamycin signaling by immunoblotting. In younger men, doubling exercise volume produced limited added effects, whereas in older men, it resulted in greater MPS and p70S6 kinase (p70S6K(Thr389)) phosphorylation at both intensities, that is, MPS area under the curve: 75% (1× volume: 0.07±0.01 vs 2× volume: 0.14% ± 0.02% protein synthesized/4hours (p < .001). Doubling exercise volume is a valid strategy to maximize postexercise MPS in ageing.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2012; 67(11):1170-7. · 4.31 Impact Factor
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    ABSTRACT: BACKGROUND: Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes. METHODS: We followed age-matched healthy controls and CC patients without distant metastasis on radiological imaging before and 6 weeks after hemi-colectomy surgery. Body composition was analysed using dual energy X-ray absorptiometry. Mitochondrial enzyme activity and protein concentrations were analysed in vastus lateralis muscle biopsies. RESULTS: In pre-surgery, there were no differences in lean mass between CC patients and age-matched controls (46.1 + 32.5 vs. 46.1 + 37.3 kg). Post-resection lean mass was reduced in CC patients (43.8 + 30.3 kg, P < 0.01). When comparing markers of mitochondrial function, the following were observed: pyruvate dehydrogenase (PDH) activity was lower in CC patients pre-surgery (P < 0.001) but normalized post-resection and cytochrome c oxidase and pyruvate dehydrogenase E2 subunit protein expression were lower in CC patients pre-surgery and not restored to control values post-resection (P < 0.001). Nuclear factor kappa-B, an inflammatory marker, was higher in CC patients pre-surgery compared to controls (P < 0.01), returning to control levels post-resection. CONCLUSION: Muscle mass was affected by surgery rather than cancer per se. PDH activity was however lower in cancer patients, suggesting that muscle mass and mitochondrial enzyme activity are not inextricably linked. This reduction in mitochondrial enzyme activity may well contribute to the significant risks of major surgery to which CC patients are exposed.
    Journal of cachexia, sarcopenia and muscle. 05/2012;

Publication Stats

2k Citations
284.15 Total Impact Points

Institutions

  • 2008–2013
    • McMaster University
      • Department of Kinesiology
      Hamilton, Ontario, Canada
  • 2007–2013
    • University of Nottingham
      • School of Graduate Entry Medicine and Health
      Nottigham, England, United Kingdom
  • 2012
    • University of London
      Londinium, England, United Kingdom
  • 2009–2011
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 2008–2011
    • Washington University in St. Louis
      • Center for Human Nutrition
      Saint Louis, MO, United States
  • 2004–2006
    • University of Central Lancashire
      Preston, England, United Kingdom
  • 2005
    • University of Dundee
      Dundee, Scotland, United Kingdom