ORCID Profile
0000-0003-3860-4136
Current Organisation
Centenary Institute of Cancer Medicine and Cell Biology
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Publisher: American Physiological Society
Date: 12-2019
DOI: 10.1152/AJPCELL.00209.2019
Abstract: Skeletal muscle mass, a strong predictor of longevity and health in humans, is determined by the balance of two cellular processes, muscle protein synthesis (MPS) and muscle protein breakdown. MPS seems to be particularly sensitive to changes in mechanical load and/or nutritional status therefore, much research has focused on understanding the molecular mechanisms that underpin this cellular process. Furthermore, older in iduals display an attenuated MPS response to anabolic stimuli, termed anabolic resistance, which has a negative impact on muscle mass and function, as well as quality of life. Therefore, an understanding of which, if any, molecular mechanisms contribute to anabolic resistance of MPS is of vital importance in formulation of therapeutic interventions for such populations. This review summarizes the current knowledge of the mechanisms that underpin MPS, which are broadly ided into mechanistic target of rapamycin complex 1 (mTORC1)-dependent, mTORC1-independent, and ribosomal biogenesis-related, and describes the evidence that shows how they are regulated by anabolic stimuli (exercise and/or nutrition) in healthy human skeletal muscle. This review also summarizes evidence regarding which of these mechanisms may be implicated in age-related skeletal muscle anabolic resistance and provides recommendations for future avenues of research that can expand our knowledge of this area.
Publisher: Wiley
Date: 03-2018
DOI: 10.14814/PHY2.13628
Publisher: Cold Spring Harbor Laboratory
Date: 11-12-2019
DOI: 10.1101/872127
Abstract: Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity, however, the mechanistic basis of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH) 2 D 3 ) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH) 2 D 3 to the regulation of skeletal muscle mitochondrial function in vitro , however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we utilised lentiviral mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared to shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P 0.001). VDR-KD myoblasts displayed a 30%, 30% and 36% reduction in basal, coupled and maximal respiration respectively ( P 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33% and 48% reduction in basal, coupled and maximal respiration ( P 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATP ox ) was reduced by 20% suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content as well as markers of fusion and fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro , providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
Publisher: American Physiological Society
Date: 08-2010
DOI: 10.1152/AJPCELL.00438.2009
Abstract: Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)-independent manner. The present study examined the effect of 72-h treatment with sodium pyruvate (5–50 mM) or sodium chloride (50 mM) as an osmotic control on the regulation of mitochondrial substrate metabolism and biogenesis in C2C12 myotubes. Pyruvate (50 mM) increased the levels of fatty acid oxidation enzymes (CD36, 61%, and β-oxidative enzyme 3-hydroxyacyl-CoA dehydrogenase, 54%) and the expression of cytochrome- c oxidase subunit I (220%) and cytochrome c (228%), consistent with its previous described role as a promoter of mitochondrial biogenesis. However, in contrast, pyruvate treatment reduced glucose transporter 4 (42%), phosphofructokinase (57%), and PGC1α (72%) protein content as well as PGC1α (48%) and PGC1β (122%) mRNA. The decrease in PGC1α was compensated for by an increase in the PGC1α-related coactivator (PRC 187%). Pyruvate treatment reduced basal and insulin-stimulated glucose uptake (41% and 31%, respectively) and palmitate uptake and oxidation (24% and 31%, respectively). The addition of the pyruvate dehydrogenase activator dichloroacetate (DCA) and the TCA precursor glutamine increased PGC1α expression (368%) and returned PRC expression to basal. Glucose uptake increased by 4.2-fold with DCA and glutamine and palmitate uptake increased by 18%. Coupled to this adaptation was an 80% increase in oxygen consumption. The data suggest that supraphysiological doses of pyruvate decrease mitochondrial function despite limited biogenesis and that anaplerotic agents can reverse this effect.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Wiley
Date: 24-04-2012
Publisher: American Society for Clinical Investigation
Date: 11-2011
DOI: 10.1172/JCI58554
Publisher: Wiley
Date: 05-2016
DOI: 10.14814/PHY2.12803
Publisher: Wiley
Date: 12-09-2014
DOI: 10.1111/ACEL.12150
Publisher: Georg Thieme Verlag KG
Date: 06-2008
Abstract: The present study examined the use of the maximal lactate steady state (MLSS) as an exercise training stimulus in moderately trained runners. Fourteen healthy in iduals (12 male, 2 female age 25 +/- 6 years, height 1.76 +/- 0.05 m, body mass 76 +/- 8 kg mean +/- SD) took part in the study. Following determination of the lactate threshold (LT), VO2max, running velocity at MLSS (vMLSS) and a control period of 4 weeks, participants were pair matched and split into two cohorts performing either continuous (CONT: 2 sessions/week at vMLSS) or intermittent treadmill running (INT: 2 sessions/week, 3-min repetitions 0.5 km . h (-1) above and below vMLSS). vMLSS increased in CONT by 8 % from 12.3 +/- 1.5 to 13.4 +/- 1.6 km . h (-1) (p < 0.05) and in INT by 5 % from 12.2 +/- 1.9 km . h (-1) to 12.9 +/- 1.9 km . h (-1) (p < 0.05). Running speed at the LT increased by 7 % in the CONT group (p < 0.05) and by 9 % in the INT group (p < 0.05). VO2max increased by 10 % in the CONT group (p < 0.05) and by 6 % in INT (p < 0.05). Two sessions per week at vMLSS are capable of eliciting improvements in the physiological responses at LT, MLSS, and VO2max in moderately trained runners.
Publisher: Frontiers Media SA
Date: 02-10-2020
Publisher: Wiley
Date: 20-02-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2010
Publisher: Springer Science and Business Media LLC
Date: 10-07-2017
DOI: 10.1038/S41598-017-05483-X
Abstract: The mechanistic target of rapamycin (mTOR) is a central mediator of protein synthesis in skeletal muscle. We utilized immunofluorescence approaches to study mTOR cellular distribution and protein-protein co-localisation in human skeletal muscle in the basal state as well as immediately, 1 and 3 h after an acute bout of resistance exercise in a fed (FED 20 g Protein/40 g carbohydrate/1 g fat) or energy-free control (CON) state. mTOR and the lysosomal protein LAMP2 were highly co-localised in basal s les. Resistance exercise resulted in rapid translocation of mTOR/LAMP2 towards the cell membrane. Concurrently, resistance exercise led to the dissociation of TSC2 from Rheb and increased in the co-localisation of mTOR and Rheb post exercise in both FED and CON. In addition, mTOR co-localised with Eukaryotic translation initiation factor 3 subunit F (eIF3F) at the cell membrane post-exercise in both groups, with the response significantly greater at 1 h of recovery in the FED compared to CON. Collectively our data demonstrate that cellular trafficking of mTOR occurs in human muscle in response to an anabolic stimulus, events that appear to be primarily influenced by muscle contraction. The translocation and association of mTOR with positive regulators (i.e. Rheb and eIF3F) is consistent with an enhanced mRNA translational capacity after resistance exercise.
Publisher: Wiley
Date: 22-03-2020
Publisher: Springer Science and Business Media LLC
Date: 19-04-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2013
Publisher: Bioscientifica
Date: 05-2021
DOI: 10.1530/JOE-20-0233
Abstract: Vitamin D deficiency is associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D-related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo , we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were either fed a control diet (2200 IU/kg i.e. vitamin D replete) or a vitamin D-deplete (0 IU/kg) diet for periods of 1, 2 and 3 months. Gastrocnemius muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3 months of diet-induced vitamin D deficiency, respiration supported via complex I + II (CI + II P ) and the electron transport chain (ETC) were 35 and 37% lower when compared to vitamin D-replete mice ( P 0.05). Despite functional alterations, citrate synthase activity, AMPK phosphorylation, mitofilin, OPA1 and ETC subunit protein content remained unchanged in response to dietary intervention ( P 0.05). In conclusion, we report that 3 months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial respiration in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggest that vitamin D-mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.
Publisher: Springer Science and Business Media LLC
Date: 06-2012
Publisher: American Physiological Society
Date: 06-2012
DOI: 10.1152/AJPENDO.00004.2012
Abstract: The glycogen content of muscle determines not only our capacity for exercise but also the signaling events that occur in response to exercise. The result of the shift in signaling is that frequent training in a low-glycogen state results in improved fat oxidation during steady-state submaximal exercise. This review will discuss how the amount or localization of glycogen particles can directly or indirectly result in this differential response to training. The key direct effect discussed is carbohydrate binding, whereas the indirect effects include the metabolic shift toward fat oxidation, the increase in catecholamines, and osmotic stress. Although our understanding of the role of glycogen in response to training has expanded exponentially over the past 5 years, there are still many questions remaining as to how stored carbohydrate affects the muscular adaptation to exercise.
Publisher: Elsevier BV
Date: 12-2020
Publisher: American Physiological Society
Date: 03-2012
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.SEMCDB.2022.03.022
Abstract: Endurance exercise is well established to increase mitochondrial content and function in skeletal muscle, a process termed mitochondrial biogenesis. Current understanding is that exercise initiates skeletal muscle mitochondrial remodeling via modulation of cellular nutrient, energetic and contractile stress pathways. These subtle changes in the cellular milieu are sensed by numerous transduction pathways that serve to initiate and coordinate an increase in mitochondrial gene transcription and translation. The result of these acute signaling events is the promotion of growth and assembly of mitochondria, coupled to a greater capacity for aerobic ATP provision in skeletal muscle. The aim of this review is to highlight the acute metabolic events induced by endurance exercise and the subsequent molecular pathways that sense this transient change in cellular homeostasis to drive mitochondrial adaptation and remodeling.
Publisher: Wiley
Date: 15-09-2015
DOI: 10.1113/JP271219
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.LFS.2011.03.020
Abstract: Cardiac function is modulated by the sympathetic nervous system through β-adrenergic receptor (β-AR) activity and this represents the main regulatory mechanism for cardiac performance. To date, however, the metabolic and molecular responses to β(2)-agonists are not well characterized. Therefore, we studied the inotropic effect and signaling response to selective β(2)-AR activation by tulobuterol. Strips of rat right ventricle were electrically stimulated (1Hz) in standard Tyrode solution (95% O(2), 5% CO(2)) in the presence of the β(1)-antagonist CGP-20712A (1μM). A cumulative dose-response curve for tulobuterol (0.1-10μM), in the presence or absence of the phosphodiesterase (PDE) inhibitor IBMX (30μM), or 10min incubation (1μM) with the β(2)-agonist tulobuterol was performed. β(2)-AR stimulation induced a positive inotropic effect (maximal effect=33±3.3%) and a decrease in the time required for half relaxation (from 45±0.6 to 31±1.8ms, -30%, p<0.001) after the inhibition of PDEs. After 10min of β(2)-AR stimulation, p-AMPKα(T172) (54%), p-PKB(T308) (38%), p-AS160(T642) (46%) and p-CREB(S133) (63%) increased, without any change in p-PKA(T197). These results suggest that the regulation of ventricular contractility is not the primary function of the β(2)-AR. Rather, β(2)-AR could function to activate PKB and AMPK signaling, thereby modulating muscle mass and energetic metabolism of rat ventricular muscle.
Publisher: Wiley
Date: 02-06-2016
DOI: 10.1113/EP085647
Publisher: Springer Science and Business Media LLC
Date: 08-11-2010
DOI: 10.1038/ONC.2010.497
Publisher: American Physiological Society
Date: 03-2020
DOI: 10.1152/AJPCELL.00568.2019
Abstract: Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity however, the mechanistic bases of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D 3 (1α,25(OH) 2 D 3 ) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH) 2 D 3 to the regulation of skeletal muscle mitochondrial function in vitro however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we used lentivirus-mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared with an shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes ( P 0.001). VDR-KD myoblasts displayed a 30%, 30%, and 36% reduction in basal, coupled, and maximal respiration, respectively ( P 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33%, and 48% reduction in basal, coupled, and maximal respiration ( P 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATP Ox ) was reduced by 20%, suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content, as well as markers of mitochondrial fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
Publisher: American Physiological Society
Date: 07-2021
DOI: 10.1152/JAPPLPHYSIOL.00811.2020
Abstract: The data presented here suggest that metabolic responses to steady-state aerobic exercise are somewhat resistant to short-term changes in dietary carbohydrate (CHO) intake within the 5–6.5 g CHO·kg −1 ·day −1 [46–61% energy intake (EI)] range. In contrast, reduction in short-term dietary CHO intake to ∼2.4 g CHO·kg −1 ·day −1 (21% EI) evoked clear changes indicative of increased fat and decreased CHO metabolism during exercise.
Publisher: MDPI AG
Date: 26-12-2017
DOI: 10.3390/NU10010023
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.EJPHAR.2012.11.001
Abstract: β-adrenoceptors are members of the G protein-coupled receptor superfamily which play a key role in the regulation of myocardial function. Their activation increases cardiac performance but can also induce deleterious effects such as cardiac arrhythmias or myocardial apoptosis. In fact, inhibition of β-adrenoceptors exerts a protective effect in patients with sympathetic over-stimulation during heart failure. Although β(2)-adrenoceptor is not the predominant subtype in the heart, it seems to importantly contribute to the cardiac effects of adrenergic stimulation however, the mechanism by which this occurs is not fully understood. This review summarizes the current knowledge on the role of β(2)-adrenoceptors in the regulation of cardiac contractility, metabolism, cardiomyocyte survival and cardiac arrhythmias. In addition, therapeutic considerations relating to stimulation of the β(2)-adrenoceptor such as an increase in cardiac contractility with low arrythmogenic effect, protection of the myocardium again apoptosis or positive regulation of heart metabolism are discussed.
Publisher: Wiley
Date: 06-12-2019
Publisher: Elsevier BV
Date: 05-2017
Publisher: The Company of Biologists
Date: 15-12-2005
DOI: 10.1242/JEB.01961
Abstract: Since its first documented observation in exhausted animal muscle in the early 19th century, the role of lactate (lactic acid) has fascinated muscle physiologists and biochemists. Initial interpretation was that lactate appeared as a waste product and was responsible in some way for exhaustion during exercise. Recent evidence, and new lines of investigation, now place lactate as an active metabolite, capable of moving between cells, tissues and organs, where it may be oxidised as a fuel or reconverted to form pyruvate or glucose. The questions now to be asked concern the effects of lactate at the systemic and cellular level on metabolic processes. Does lactate act as a metabolic signal to specific tissues, becoming a metabolite pseudo-hormone?Does lactate have a role in whole-body coordination of sympathetic arasympathetic nerve system control? And, finally, does lactate play a role in maintaining muscle excitability during intense muscle contraction? The concept of lactate acting as a signalling compound is a relatively new hypothesis stemming from a combination of comparative, cell and whole-organism investigations. It has been clearly demonstrated that lactate is capable of entering cells via the monocarboxylate transporter (MCT) protein shuttle system and that conversion of lactate to and from pyruvate is governed by specific lactate dehydrogenase isoforms, thereby forming a highly adaptable metabolic intermediate system. This review is structured in three sections,the first covering pertinent topics in lactate's history that led to the model of lactate as a waste product. The second section will discuss the potential of lactate as a signalling compound, and the third section will identify ways in which such a hypothesis might be investigated. In examining the history of lactate research, it appears that periods have occurred when advances in scientific techniques allowed investigation of this metabolite to expand. Similar to developments made first in the 1920s and then in the 1980s, contemporary advances in stable isotope, gene microarray and RNA interference technologies may allow the next stage of understanding of the role of this compound, so that, finally, the fundamental questions of lactate's role in whole-body and localised muscle function may be answered.
Publisher: Wiley
Date: 28-12-2016
DOI: 10.1096/FJ.15-281741
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JOCN.2019.06.029
Abstract: Isolated traumatic medial rectus palsies associated with closed head injury is rarely reported in literature. We report the case of a 48 year-old male with an isolated right medial rectus palsy following a mechanical fall with occipital headstrike. Bifrontal and bitemporal haemorrhagic contusions were seen on computed tomography (CT). Magnetic resonance imaging (MRI) revealed a T2 hyperintense lesion at the right paramedian dorsal midbrain, with changes on diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC), suggestive of ischaemic changes in the oculomotor nucleus. He was followed up at two- and six-weeks.
Publisher: Mary Ann Liebert Inc
Date: 08-2010
Publisher: Elsevier BV
Date: 12-2017
Publisher: Wiley
Date: 21-06-2016
DOI: 10.1111/APHA.12532
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
Publisher: Elsevier BV
Date: 02-2012
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.098087
Abstract: Vitamin D deficiency is known to be associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo , we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were fed either a control (2,200 IU/kg) or a vitamin D deplete (0 IU/kg) diet for periods of 1-, 2- and 3-months. Skeletal muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3-month of diet-induced vitamin D deficiency, respiration supported via CI+II P and ETC were 35% and 37% lower when compared to vitamin D replete mice ( P 0.05). Despite functional alterations, the protein expression of electron transfer chain subunits remained unchanged in response to dietary intervention ( P 0.05). In conclusion, we report that 3-months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial function in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggests that vitamin D mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.
Publisher: American Physiological Society
Date: 03-2022
DOI: 10.1152/AJPCELL.00388.2021
Abstract: As the principal energy-producing organelles of the cell, mitochondria support numerous biological processes related to metabolism, growth, and regeneration in skeletal muscle. Deterioration in skeletal muscle functional capacity with age is thought to be driven in part by a reduction in skeletal muscle oxidative capacity and reduced fatigue resistance. Underlying this maladaptive response is the development of mitochondrial dysfunction caused by alterations in mitochondrial quality control (MQC), a term encompassing processes of mitochondrial synthesis (biogenesis), remodeling (dynamics), and degradation (mitophagy). Knowledge regarding the role and regulation of MQC in skeletal muscle and the influence of aging in this process has rapidly advanced in the past decade. Given the emerging link between aging and MQC, therapeutic approaches to manipulate MQC to prevent mitochondrial dysfunction during aging hold tremendous therapeutic potential.
Publisher: Wiley
Date: 25-03-2018
DOI: 10.1002/JCP.26542
Abstract: Skeletal muscle fibers are giant multinucleated cells wherein in idual nuclei govern the protein synthesis in a finite volume of cytoplasm this is termed the myonuclear domain (MND). The factors that control MND size remain to be defined. In the present study, we studied the contribution of the NAD + ‐dependent deacetylase, sirtuin 1 (SIRT1), to the regulation of nuclear number and MND size. For this, we isolated myofibers from mice with tissue‐specific inactivation (mKO) or inducible overexpression (imOX) of SIRT1 and analyzed the 3D organisation of myonuclei. In imOX mice, the number of nuclei was increased whilst the average MND size was decreased as compared to littermate controls. Our findings were the opposite in mKO mice. Muscle stem cell (satellite cell) numbers were reduced in mKO muscles, a possible explanation for the lower density of myonuclei in these mice however, no change was observed in imOX mice, suggesting that other factors might also be involved, such as the functional regulation of stem cells/muscle precursors. Interestingly, however, the changes in the MND volume did not impact the force‐generating capacity of muscle fibers. Taken together, our results demonstrate that SIRT1 is a key regulator of MND sizes, although the underlying molecular mechanisms and the cause‐effect relationship between MND and muscle function remain to be fully defined.
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2019
DOI: 10.1101/742627
Abstract: Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness. We hypothesised that in men with overweight/obesity, acute exercise before versus after nutrient ingestion would increase whole-body and intramuscular lipid utilization, translating into greater increases in oral glucose insulin sensitivity over 6-weeks of training. We showed in men with overweight/obesity (mean±SD for BMI: 30.2±3.5 kg×m -2 for acute, crossover study, 30.9±4.5 kg×m -2 for randomized, controlled, training study) a single exercise bout before versus after nutrient provision increased lipid utilisation at the whole-body level, but also in both type I ( p 0.01) and type II muscle fibres ( p= 0.02). We then used a 6-week training intervention to show sustained, 2-fold increases in lipid utilisation with exercise before versus after nutrient provision ( p 0.01). Postprandial glycemia was not differentially affected by exercise training before vs after nutrient provision ( p 0.05), yet plasma was reduced with exercise training before, but not after nutrient provision ( p= 0.03), resulting in increased oral glucose insulin sensitivity when training was performed before versus after nutrient provision (25±38 vs −21±32 mL×min -1 ×m -2 p= 0.01) and this was associated with increased lipid utilisation during exercise ( r =0.50, p= 0.02). Regular exercise prior to nutrient provision augmented remodelling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 ( p 0.05). Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (i.e., in the fasted state) may exert beneficial effects on lipid utilisation and reduce postprandial insulinemia. Exercise in the fasted- versus fed-state increased intramuscular and whole-body lipid use, translating into increased muscle adaptation and insulin sensitivity when regularly performed over 6 weeks.
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 20-01-2016
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-05-2019
DOI: 10.1249/MSS.0000000000002034
Abstract: Across the lifespan, physical activity levels decrease and time spent sedentary typically increases. However, little is known about the impact that these behavioral changes have on skeletal muscle mass regulation. The primary aim of this study was to use a step reduction model to determine the impact of reduced physical activity and increased sedentary time on daily myofibrillar protein synthesis rates in healthy young men. Eleven men (22 ± 2 yr) completed 7 d of habitual physical activity (HPA) followed by 7 d of step reduction (SR). Myofibrillar protein synthesis rates were determined during HPA and SR using the deuterated water ( 2 H 2 O) method combined with the collection of skeletal muscle biopsies and daily saliva s les. Gene expression of selected proteins related to muscle mass regulation and oxidative metabolism were determined via real time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Daily step count was reduced by approximately 91% during SR (from 13,054 ± 2763 steps per day to 1192 ± 330 steps per day P 0.001) and this led to an increased contribution of sedentary time to daily activity (73% ± 6% to 90% ± 3% P 0.001). Daily myofibrillar protein synthesis decreased by approximately 27% from 1.39 ± 0.32%·d −1 during HPA to 1.01 ± 0.38%·d −1 during SR ( P 0.05). Muscle atrophy F-box and myostatin mRNA expression were upregulated, whereas mechanistic target of rapamycin, p53, and PDK4 mRNA expression were downregulated after SR ( P 0.05). One week of reduced physical activity and increased sedentary time substantially lowers daily myofibrillar protein synthesis rates in healthy young men.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 29-09-2011
Publisher: Wiley
Date: 21-12-2020
DOI: 10.1002/JCSM.12661
Publisher: Wiley
Date: 29-01-2021
DOI: 10.1113/JP280825
Publisher: Public Library of Science (PLoS)
Date: 17-10-2013
Publisher: Cold Spring Harbor Laboratory
Date: 16-11-2020
DOI: 10.1101/2020.11.16.384263
Abstract: Skeletal muscle wasting and dysfunction is a common characteristic of non-dialysis dependent chronic kidney disease (NDD-CKD). The mechanisms by which this occurs are not clearly understood and one reason for this is a lack of well controlled in-vitro methodologies to simulate NDD-CKD induced muscle wasting for mechanistic investigation at the cellular level. Here we sought to conduct the initial investigations into developing a CKD-induced skeletal muscle model for use as a mechanistic analysis tool as well as a test bed for potential novel therapeutics in this population. Human derived muscle cells (HDMCs) were isolated from n=5 NDD-CKD patients and n=3 matched healthy controls (HC) and taken through proliferation and differentiation phases in cell culture. Upon comparison of the 2 donor types, significantly greater mRNA expression of myogenic markers was noted in the NDD-CKD cultures in comparison to HC cultures, which was carried through to greater mRNA expression of myosin heavy chains (MyHCs) post differentiation. However, this was not carried over to protein expression where Pax7 and MyoD were seen to be expressed to a greater extent in HC cultures. mRNA expression markers of protein degradation were noted to be elevated in NDD-CKD cultures in comparison to HC cultures. In light of our findings, future work should seek to investigate the role of the ‘CKD environment’ as well as mechanisms implicated in transcription regulation to further advance the current model development as well as the mechanistic understanding of skeletal muscle wasting in CKD.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2020
DOI: 10.1038/S41467-020-16298-2
Abstract: Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic cl studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
Publisher: American Physiological Society
Date: 15-08-2014
DOI: 10.1152/AJPENDO.00674.2013
Abstract: The goal of the current work was to profile positive (mTORC1 activation, autocrine aracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1-IRS-1/2 signaling, BiP/CHOP/IRE1α, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of ∼4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser 501/503 and S6K1 Thr 389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser 473 phosphorylation was higher from 3–6 days, and this was associated with increased TSC2 Thr 939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr 1462 , was unchanged at 6 days. In agreement with the phosphorylation of Thr 1345 , SA led to activation of AMPKα1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1α levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1.
Publisher: Elsevier BV
Date: 06-2021
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2020
DOI: 10.1101/2020.10.26.350546
Abstract: Evidence is growing for a role of vitamin D in regulating skeletal muscle mass, strength and functional capacity. Given the role the kidneys play in activating total vitamin D, and the high prevalence of vitamin D deficiency in Chronic Kidney Disease (CKD), it is possible that deficiency contributes to the low levels of physical function and muscle mass in these patients. This is a secondary cross-sectional analysis of previously published interventional study, with ex vivo follow up work. 34 CKD patients at stages G3b-5 (eGFR 25.5 ± 8.3ml/min/1.73m2 age 61 ± 12 years) were recruited, with a sub-group (n=20) also donating a muscle biopsy. Vitamin D and associated metabolites were analysed in plasma by liquid chromatography tandem-mass spectroscopy and correlated to a range of physiological tests of muscle size, function, exercise capacity and body composition. The effects of 1α,25(OH) 2 D3 supplementation on myogenesis and myotube size was investigated in primary skeletal muscle cells from vitamin D deficient donors. In vivo , there was no association between total or active vitamin D and muscle size or strength, but a significant correlation with was seen with the total form. Ex vivo , 1α,25(OH) 2 D3 supplementation reduced IL-6 mRNA expression, but had no effect upon proliferation, differentiation or myotube diameter. This early preliminary work suggests that vitamin D deficiency is not a prominent factor driving the loss of muscle mass in CKD, but may play a role in reduced exercise capacity.
Publisher: Springer Berlin Heidelberg
Date: 2009
DOI: 10.1007/978-3-540-69357-4_3
Abstract: Muscle tissue bioreactors are devices which are employed to guide and monitor the development of engineered muscle tissue. These devices have a modern history that can be traced back more than a century, because the key elements of muscle tissue bioreactors have been studied for a very long time. These include barrier isolation and culture of cells, tissues and organs after isolation from a host organism the provision of various stimuli intended to promote growth and maintain the muscle, such as electrical and mechanical stimulation and the provision of a perfusate such as culture media or blood derived substances. An accurate appraisal of our current progress in the development of muscle bioreactors can only be made in the context of the history of this endeavor. Modern efforts tend to focus more upon the use of computer control and the application of mechanical strain as a stimulus, as well as substrate surface modifications to induce cellular organization at the early stages of culture of isolated muscle cells.
Publisher: American Diabetes Association
Date: 13-09-2012
DOI: 10.2337/DB11-1433
Abstract: Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α 55α 50α) are highly induced in AT from high-fat diet–fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT.
Publisher: Wiley
Date: 17-10-2020
DOI: 10.1113/EP088805
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2017
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2019
DOI: 10.1101/680462
Abstract: NAD + is modulated by conditions of metabolic stress and has been reported to decline with aging, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD + metabolome, and questioned if tissue NAD + levels are depressed with aging. We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD + metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways. NR also depressed levels of circulating inflammatory cytokines. In an additional study, 31 P magnetic resonance spectroscopy-based NAD + measurement in muscle and brain showed no difference between young and aged in iduals. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD + decline is not associated with chronological aging per se in human muscle or brain.
Publisher: American Physiological Society
Date: 11-2014
DOI: 10.1152/AJPENDO.00001.2014
Abstract: Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.
Publisher: Wiley
Date: 08-2011
Publisher: Canadian Science Publishing
Date: 06-2008
DOI: 10.1139/H08-028
Abstract: The purpose of this study was to examine the effects of acute protein ingestion on the recovery of muscle function and markers of muscle damage in the 72 h post eccentric-exercise. Nine recreationally active males recorded quadriceps maximum isometric voluntary contraction (MVC), peak 5 s power output (PPO), and perceived muscle soreness. Plasma creatine kinase (CK) and protein carbonyl (PC) content were measured prior to exercise. Delayed-onset muscle soreness (DOMS) was induced by a 30 min downhill run (–10°) at a target intensity of 75% age-predicted heart rate maximum, immediately followed by ingestion of 100 g protein (containing 40 g essential amino acids PRO) or placebo (CON) solution. The pre-exercise measures were re-taken in the subsequent 24, 48, and 72 h. CK, PC, and perceived muscle soreness increased significantly following exercise and with each supplement at 24 h. PC and muscle soreness remained elevated at 48 and 72 h (p 0.05), whereas CK returned to baseline values. No difference between conditions was observed for these measures. Peak MVC significantly declined in CON to –7.9% at 24 h, reaching a nadir of –10% at 48 h (p 0.05). In the PRO group, MVC remained within pre-exercise values at all time points. PPO followed a similar trend, reaching its nadir of –8.7% at 48 h in CON (p 0.05), but had recovered in the PRO trial. Ingestion of a single post-exercise protein mixture increases the rate of force and power restoration at 48 h, suggesting potential for protein as an ergogenic aid during the DOMS period.
Publisher: Wiley
Date: 24-12-2020
DOI: 10.1113/JP280652
Abstract: Reduced vitamin D receptor (VDR) expression prompts skeletal muscle atrophy. Atrophy occurs through catabolic processes, namely the induction of autophagy, while anabolism remains unchanged. In response to VDR‐knockdown mitochondrial function and related gene‐set expression is impaired. In vitro VDR knockdown induces myogenic dysregulation occurring through impaired differentiation. These results highlight the autonomous role the VDR has within skeletal muscle mass regulation. Vitamin D deficiency is estimated to affect ∼40% of the world's population and has been associated with impaired muscle maintenance. Vitamin D exerts its actions through the vitamin D receptor (VDR), the expression of which was recently confirmed in skeletal muscle, and its down‐regulation is linked to reduced muscle mass and functional decline. To identify potential mechanisms underlying muscle atrophy, we studied the impact of VDR knockdown (KD) on mature skeletal muscle in vivo , and myogenic regulation in vitro in C2C12 cells. Male Wistar rats underwent in vivo electrotransfer (IVE) to knock down the VDR in hind‐limb tibialis anterior (TA) muscle for 10 days. Comprehensive metabolic and physiological analysis was undertaken to define the influence loss of the VDR on muscle fibre composition, protein synthesis, anabolic and catabolic signalling, mitochondrial phenotype and gene expression. Finally, in vitro lentiviral transfection was used to induce sustained VDR‐KD in C2C12 cells to analyse myogenic regulation. Muscle VDR‐KD elicited atrophy through a reduction in total protein content, resulting in lower myofibre area. Activation of autophagic processes was observed, with no effect upon muscle protein synthesis or anabolic signalling. Furthermore, RNA‐sequencing analysis identified systematic down‐regulation of multiple mitochondrial respiration‐related protein and genesets. Finally, in vitro VDR‐knockdown impaired myogenesis (cell cycling, differentiation and myotube formation). Together, these data indicate a fundamental regulatory role of the VDR in the regulation of myogenesis and muscle mass, whereby it acts to maintain muscle mitochondrial function and limit autophagy.
Publisher: American Physiological Society
Date: 02-2018
DOI: 10.1152/AJPENDO.00311.2018
Abstract: Exercise performed in the fasted state acutely increases fatty acid availability and utilization. Furthermore, activation of energy-sensing pathways and fatty acid metabolic genes can be augmented by fasting and fasted exercise. However, whether a similar effect occurs at higher exercise intensities remains poorly understood. This study aimed to assess the effect of fed and fasted exercise upon postexercise signaling and mRNA responses during moderate- to high-intensity steady-state exercise. Eight male participants [age: 25 (SD 2) yr, V̇o 2peak : 47.9 (SD 3.8) ml·kg −1 ·min −1 ] performed 1 h of cycling at 70% W max in the fasted (FAST) state or 2 h following ingestion of a carbohydrate-rich mixed-macronutrient breakfast (FED). Muscle biopsies were collected pre-, immediately, and 3 h postexercise from the medial vastus lateralis, while venous blood s les were collected throughout the trial. Plasma, nonesterified fatty acid, and glycerol concentrations were elevated during FAST compared with FED, although substrate utilization during exercise was similar. AMPK Thr172 phosphorylation was ~2.5-fold elevated postexercise in both trials and was significantly augmented by ~30% during FAST. CREB Ser133 phosphorylation was elevated approximately twofold during FAST, although CREB Ser133 phosphorylation acutely decreased by ~50% immediately postexercise. mRNA expression of PDK4 was approximately three- to fourfold augmented by exercise and approximately twofold elevated throughout FAST, while expression of PPARGC1A mRNA was similarly activated (~10-fold) by exercise in both FED and FAST. In summary, performing moderate- to high-intensity steady-state exercise in the fasted state increases systemic lipid availability, elevates phosphorylation of AMPK Thr172 and CREB Ser133 , and augments PDK4 mRNA expression without corresponding increases in whole body fat oxidation and the mRNA expression of PPARGC1A.
Publisher: The Endocrine Society
Date: 15-05-2017
Publisher: American Physiological Society
Date: 02-2011
DOI: 10.1152/JAPPLPHYSIOL.00941.2010
Abstract: For over 10 years, we have known that the activation of the mammalian target of rapamycin complex 1 (mTORC1) has correlated with the increase in skeletal muscle size and strength that occurs following resistance exercise. Initial cell culture and rodent models of muscle growth demonstrated that the activation of mTORC1 is common to hypertrophy induced by growth factors and increased loading. The further observation that high loads increased the local production of growth factors led to the paradigm that resistance exercise stimulates the autocrine production of factors that act on membrane receptors to activate mTORC1, and this results in skeletal muscle hypertrophy. Over the last few years, there has been a paradigm shift. From both human and rodent studies, it has become clear that the phenotypic and molecular responses to resistance exercise occur in a growth factor-independent manner. Although the mechanism of load-induced mTORC1 activation remains to be determined, it is clear that it does not require classical growth factor signaling.
Publisher: Public Library of Science (PLoS)
Date: 17-06-2021
DOI: 10.1371/JOURNAL.PONE.0253269
Abstract: AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor. Activation of AMPK leads to a number of metabolic benefits, including improved mitochondrial function in skeletal muscle and lowering of serum glucose levels in type-2 diabetes models. However, direct activation of AMPK leads to cardiac enlargement, and an alternative strategy that activates AMPK without affecting the heart is needed. Inhibition of phosphodiesterase 4 (PDE4), which is poorly expressed in the human heart, activates AMPK in other tissues. In a screen to identify novel PDE4 inhibitors, we discovered compound CBU91, which is 5–10 fold more potent than rolipram, the best characterized PDE4 inhibitor. CBU91, like rolipram, is able to activate AMPK and Sirt1 and increase mitochondrial function in myotubes. These findings suggest that activation of AMPK in myotubes is a general property of PDE4 inhibition and that PDE4 inhibition may activate AMPK in metabolically relevant tissues without affecting the heart.
Publisher: Wiley
Date: 14-01-2022
DOI: 10.1002/JCSM.12802
Abstract: Skeletal muscle wasting and dysfunction are common characteristics noted in people who suffer from chronic kidney disease (CKD). The mechanisms by which this occurs are complex, and although progress has been made, the key underpinning mechanisms are not yet fully elucidated. With work to date primarily conducted in nephrectomy‐based animal models, translational capacity to our patient population has been challenging. This could be overcome if rationale developing work could be conducted in human based models with greater translational capacity. This could be achieved using cells derived from patient biopsies, if they retain phenotypic traits noted in vivo . Here, we performed a systematic characterization of CKD derived muscle cells (CKD n = 10 age: 54.40 ± 15.53 years eGFR: 22.25 ± 13.22 ml/min/1.73 m 2 ) in comparison with matched controls (CON n = 10 age: 58.66 ± 14.74 years eGFR: 85.81 ± 8.09 ml/min/1.73 m 2 ). Harvested human derived muscle cells (HDMCs) were taken through proliferative and differentiation phases and investigated in the context of myogenic progression, inflammation, protein synthesis, and protein breakdown. Follow up investigations exposed HDMC myotubes from each donor type to 0, 0.4, and 100 nM of IGF‐1 in order to investigate any differences in anabolic resistance. Harvested human derived muscle cells isolated from CKD patients displayed higher rates of protein degradation ( P = 0.044) alongside elevated expression of both TRIM63 (2.28‐fold higher, P = 0.054) and fbox32 (6.4‐fold higher, P 0.001) in comparison with CONs. No differences were noted in rates of protein synthesis under basal conditions ( P 0.05) however, CKD derived cells displayed a significant degree of anabolic resistance in response to IGF‐1 stimulation (both doses) in comparison with matched CONs (0.4 nm: P 0.001 100 nM: P 0.001). In summary, we report for the first time that HDMCs isolated from people suffering from CKD display key hallmarks of the well documented in vivo phenotype. Not only do these findings provide further mechanistic insight into CKD specific cachexia, but they also demonstrate this is a reliable and suitable model in which to perform targeted experiments to begin to develop novel therapeutic strategies targeting the CKD associated decline in skeletal muscle mass and function.
Publisher: American Physiological Society
Date: 12-2017
DOI: 10.1152/AJPCELL.00176.2017
Abstract: Mechanistic target of rapamycin (mTOR) resides as two complexes within skeletal muscle. mTOR complex 1 [mTORC1–regulatory associated protein of mTOR (Raptor) positive] regulates skeletal muscle growth, whereas mTORC2 [rapamycin-insensitive companion of mTOR (Rictor) positive] regulates insulin sensitivity. To examine the regulation of these complexes in human skeletal muscle, we utilized immunohistochemical analysis to study the localization of mTOR complexes before and following protein-carbohydrate feeding (FED) and resistance exercise plus protein-carbohydrate feeding (EXFED) in a unilateral exercise model. In basal s les, mTOR and the lysosomal marker lysosomal associated membrane protein 2 (LAMP2) were highly colocalized and remained so throughout. In the FED and EXFED states, mTOR/LAMP2 complexes were redistributed to the cell periphery [wheat germ agglutinin (WGA)-positive staining] (time effect P = 0.025), with 39% (FED) and 26% (EXFED) increases in mTOR/WGA association observed 1 h post-feeding/exercise. mTOR/WGA colocalization continued to increase in EXFED at 3 h (48% above baseline) whereas colocalization decreased in FED (21% above baseline). A significant effect of condition ( P = 0.05) was noted suggesting mTOR/WGA colocalization was greater during EXFED. This pattern was replicated in Raptor/WGA association, where a significant difference between EXFED and FED was noted at 3 h post-exercise/feeding ( P = 0.014). Rictor/WGA colocalization remained unaltered throughout the trial. Alterations in mTORC1 cellular location coincided with elevated S6K1 kinase activity, which rose to a greater extent in EXFED compared with FED at 1 h post-exercise/feeding ( P 0.001), and only remained elevated in EXFED at the 3 h time point ( P = 0.037). Collectively these data suggest that mTORC1 redistribution within the cell is a fundamental response to resistance exercise and feeding, whereas mTORC2 is predominantly situated at the sarcolemma and does not alter localization.
Publisher: American Physiological Society
Date: 10-2011
DOI: 10.1152/AJPREGU.00232.2011
Abstract: The transcriptional coactivator PGC-1α is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1α-related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 ± 0.3-fold and protein content by 108 ± 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 ± 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 ± 0.52%) and myosin heavy chain (15.4 ± 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some—COX4 (2.6 ± 0.18-fold), ATP5B (2.7 ± 0.34-fold) cytochrome c (5.1 ± 0.68-fold)—but not all, MTCO1 (0.61 ± 0.18-fold) and HAD (0.98 ± 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome– c (28.7 ± 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 ± 0.01-fold) and citrate synthase (2.1 ± 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 ± 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 ± 3.31%) and oxidation (31.1 ± 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 ± 0.22-fold) and protein (13.8 ± 2.08%) and CPT1 protein (28.9 ± 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 ± 0.3-fold vs. 4.4 ± 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC-1α. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.FREERADBIOMED.2016.01.016
Abstract: Despite over 50 years of research, the field of sports nutrition continues to grow at a rapid rate. Whilst the traditional research focus was one that centred on strategies to maximise competition performance, emerging data in the last decade has demonstrated how both macronutrient and micronutrient availability can play a prominent role in regulating those cell signalling pathways that modulate skeletal muscle adaptations to endurance and resistance training. Nonetheless, in the context of exercise performance, it is clear that carbohydrate (but not fat) still remains king and that carefully chosen ergogenic aids (e.g. caffeine, creatine, sodium bicarbonate, beta-alanine, nitrates) can all promote performance in the correct exercise setting. In relation to exercise training, however, it is now thought that strategic periods of reduced carbohydrate and elevated dietary protein intake may enhance training adaptations whereas high carbohydrate availability and antioxidant supplementation may actually attenuate training adaptation. Emerging evidence also suggests that vitamin D may play a regulatory role in muscle regeneration and subsequent hypertrophy following damaging forms of exercise. Finally, novel compounds (albeit largely examined in rodent models) such as epicatechins, nicotinamide riboside, resveratrol, β-hydroxy β-methylbutyrate, phosphatidic acid and ursolic acid may also promote or attenuate skeletal muscle adaptations to endurance and strength training. When taken together, it is clear that sports nutrition is very much at the heart of the Olympic motto, Citius, Altius, Fortius (faster, higher, stronger).
Publisher: Elsevier BV
Date: 11-2020
DOI: 10.1093/AJCN/NQAA229
Publisher: American Physiological Society
Date: 06-2017
DOI: 10.1152/AJPENDO.00438.2015
Abstract: In striated muscle, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on the metabolism of glucose and differential effects on the metabolism of protein. We have shown that, despite similar incorporation, treatment of C 2 C 12 myotubes (CM) with EPA but not DHA improves glucose uptake and protein accretion. We hypothesized that these differential effects of EPA and DHA may be due to ergent shifts in lipidomic profiles leading to altered proteomic profiles. We therefore carried out an assessment of the impact of treating CM with EPA and DHA on lipidomic and proteomic profiles. Fatty acid methyl esters (FAME) analysis revealed that both EPA and DHA led to similar but substantials changes in fatty acid profiles with the exception of arachidonic acid, which was decreased only by DHA, and docosapentanoic acid (DPA), which was increased only by EPA treatment. Global lipidomic analysis showed that EPA and DHA induced large alterations in the cellular lipid profiles and in particular, the phospholipid classes. Subsequent targeted analysis confirmed that the most differentially regulated species were phosphatidylcholines and phosphatidylethanolamines containing long-chain fatty acids with five (EPA treatment) or six (DHA treatment) double bonds. As these are typically membrane-associated lipid species we hypothesized that these treatments differentially altered the membrane-associated proteome. Stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics of the membrane fraction revealed significant ergence in the effects of EPA and DHA on the membrane-associated proteome. We conclude that the EPA-specific increase in polyunsaturated long-chain fatty acids in the phospholipid fraction is associated with an altered membrane-associated proteome and these may be critical events in the metabolic remodeling induced by EPA treatment.
Publisher: The Endocrine Society
Date: 27-03-2017
DOI: 10.1210/EN.2016-1722
Abstract: Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can lify circulating GC concentrations. Therefore, 11β-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11β-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11β-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 μg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11β-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11β-HSD1 KO mice to model lifetime GC exposure. BAT 11β-HSD1 expression and activity were elevated in response to GC excess and with aging. 11β-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11β-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11β-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2011
Publisher: American Physiological Society
Date: 09-2017
DOI: 10.1152/AJPCELL.00100.2017
Abstract: Although the signal pathways mediating muscle protein synthesis and degradation are well characterized, the transcriptional processes modulating skeletal muscle mass and adaptive growth are poorly understood. Recently, studies in mouse models of muscle wasting or acutely exercised human muscle have suggested a potential role for the transcription factor signal transducer and activator of transcription 3 (STAT3), in adaptive growth. Hence, in the present study we sought to define the contribution of STAT3 to skeletal muscle adaptive growth. In contrast to previous work, two different resistance exercise protocols did not change STAT3 phosphorylation in human skeletal muscle. To directly address the role of STAT3 in load-induced (i.e., adaptive) growth, we studied the anabolic effects of 14 days of synergist ablation (SA) in skeletal muscle-specific STAT3 knockout (mKO) mice and their floxed, wild-type (WT) littermates. Plantaris muscle weight and fiber area in the nonoperated leg (control CON) was comparable between genotypes. As expected, SA significantly increased plantaris weight, muscle fiber cross-sectional area, and anabolic signaling in WT mice, although interestingly, this induction was not impaired in STAT3 mKO mice. Collectively, these data demonstrate that STAT3 is not required for overload-mediated hypertrophy in mouse skeletal muscle.
Publisher: Wiley
Date: 06-01-2021
DOI: 10.1113/JP279411
Abstract: Mitochondria are dynamic organelles, intricately designed to meet cellular energy requirements. To accommodate alterations in energy demand, mitochondria have a high degree of plasticity, changing in response to transient activation of numerous stress‐related pathways. This adaptive response is particularly relevant in highly metabolic tissues such as skeletal muscle, where mitochondria support numerous biological processes related to metabolism, growth and regeneration. Aerobic exercise is a potent stimulus for skeletal muscle remodelling, leading to alterations in substrate utilisation, fibre‐type composition and performance. Underlying these physiological responses is a change in mitochondrial quality control (MQC), a term encompassing the co‐ordination of mitochondrial synthesis (biogenesis), remodelling (dynamics) and degradation (mitophagy) pathways. Understanding of MQC in skeletal muscle and the regulatory role of aerobic exercise of this process are rapidly advancing, as are the molecular techniques allowing the study of MQC in vivo . Given the emerging link between MQC and the onset of numerous non‐communicable diseases, understanding the molecular regulation of MQC, and the role of aerobic exercise in this process, will have substantial future impact on therapeutic approaches to manipulate MQC and maintain mitochondrial function across health span. image
Publisher: Springer Science and Business Media LLC
Date: 27-05-2010
Abstract: Myogenesis in C2C12 cells requires the activation of the PI3K/mTOR signaling pathways. Since mTOR signaling can feedback through S6K1 to inhibit the activation of PI3K, the aim of this work was to assess whether feedback from S6K1 played a role in myogenesis and determine whether siRNA mediated knockdown of S6K1 would lead to an increased rate of myotube formation. S6K1 activity increased in a linear fashion following plating and was more than 3-fold higher after Day 3 of differentiation (subconfluent = 11.09 ± 3.05, Day 3 = 29.34 ± 3.58). IRS-1 levels tended to increase upon serum withdrawal but decreased approximately 2-fold (subconfluent = 0.88 ± 0.10, Day 3 = 0.42 ± 0.06) 3 days following differentiation whereas IRS-2 protein remained stable. IRS-1 associated p85 was significantly reduced upon serum withdrawal (subconfluent = 0.86 ± 0.07, Day 0 = 0.31 ± 0.05), remaining low through day 1. IRS-2 associated p85 decreased following serum withdrawal (subconfluent = 0.96 ± 0.05, Day 1 = 0.56 ± 0.08) and remained suppressed up to Day 3 following differentiation (0.56 ± 0.05). Phospho-tyrosine associated p85 increased significantly from subconfluent to Day 0 and remained elevated throughout differentiation. siRNA directed against S6K1 and S6K2 did not result in changes in IRS-1 levels after either 48 or 96 hrs. Furthermore, neither 48 nor 96 hrs of S6K1 knockdown caused a change in myotube formation. Even though S6K1 activity increases throughout muscle cell differentiation and IRS-1 levels decrease over this period, siRNA suggests that S6K1 is not mediating the decrease in IRS-1. The decrease in IRS-1/2 associated p85 together with the increase in phospho-tyrosine associated p85 suggests that PI3K associates primarily with scaffolds other than IRS-1/2 during muscle cell differentiation.
Publisher: Elsevier BV
Date: 04-2019
Publisher: American Physiological Society
Date: 06-2012
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1038/S41598-017-14081-W
Abstract: Enhanced coverage and sensitivity of next-generation ‘omic’ platforms has allowed the characterization of gene, metabolite and protein responses in highly metabolic tissues, such as, skeletal muscle. A limitation, however, is the capability to determine interaction between dynamic biological networks. To address this limitation, we applied Weighted Analyte Correlation Network Analysis (WACNA) to RNA-seq and metabolomic datasets to identify correlated subnetworks of transcripts and metabolites in response to a high-fat diet (HFD)-induced obesity and/or exercise. HFD altered skeletal muscle lipid profiles and up-regulated genes involved in lipid catabolism, while decreasing 241 exercise-responsive genes related to skeletal muscle plasticity. WACNA identified the interplay between transcript and metabolite subnetworks linked to lipid metabolism, inflammation and glycerophospholipid metabolism that were associated with IL6, AMPK and PPAR signal pathways. Collectively, this novel experimental approach provides an integrative resource to study transcriptional and metabolic networks in skeletal muscle in the context of health and disease.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2022
DOI: 10.1007/S40279-022-01772-2
Abstract: Nicotinamide adenine dinucleotide (NAD + ) is a vital energy intermediate in skeletal muscle. The discovery of dietary-derived NAD + precursors has led to the rapid development of NAD + therapeutics designed to manipulate NAD + content in target tissues. Of those developed, nicotinamide riboside and nicotinamide mononucleotide have been reported to display health benefit in humans under clinical scenarios of NAD + deficiency. In contrast, relatively little is known regarding the potential benefit of nicotinamide riboside and nicotinamide mononucleotide supplementation in healthy in iduals, with questions remaining as to whether NAD + therapeutics can be used to support training adaptation or improve performance in athletic populations. Examining animal and human nicotinamide riboside supplementation studies, this review discusses current evidence suggesting that NAD + therapeutics do not alter skeletal muscle metabolism or improve athletic performance in healthy humans. Further, we will highlight potential reasons why nicotinamide riboside supplementation studies do not translate to healthy populations and discuss the futility of testing NAD + therapeutics outside of the clinical populations where NAD + deficiency is present.
Publisher: Elsevier BV
Date: 04-2017
Publisher: American Physiological Society
Date: 11-2014
DOI: 10.1152/AJPCELL.00399.2013
Abstract: It is well established that exercise elicits a finely tuned adaptive response in skeletal muscle, with contraction frequency, duration, and recovery shaping skeletal muscle plasticity. Given the power of physical activity to regulate metabolic health, numerous research groups have focused on the molecular mechanisms that sense, interpret, and translate this contractile signal into postexercise adaptation. While our current understanding is that contraction-sensitive allosteric factors (e.g., Ca 2+ , AMP, NAD + , and acetyl-CoA) initiate signaling changes, how the muscle translates changes in these factors into the appropriate adaptive response remains poorly understood. During the past decade, systems biology approaches, utilizing “omics” screening techniques, have allowed researchers to define global processes of regulation with incredible sensitivity and specificity. As a result, physiologists are now able to study substrate flux with stable isotope tracers in combination with metabolomic approaches and to coordinate these functional changes with proteomic and transcriptomic analysis. In this review, we highlight lysine acetylation as an important posttranslational modification in skeletal muscle. We discuss the evolution of acetylation research and detail how large proteomic screens in erse metabolic systems have led to the current hypothesis that acetylation may be a fundamental mechanism to fine-tune metabolic adaptation in skeletal muscle.
Publisher: Public Library of Science (PLoS)
Date: 16-07-2010
Publisher: Elsevier BV
Date: 09-2011
Publisher: American Physiological Society
Date: 07-2020
DOI: 10.1152/AJPCELL.00072.2020
Abstract: The role of dysregulated intracellular creatine (Cr) metabolism in disuse atrophy is unknown. In this study, skeletal muscle biopsy s les were obtained after 7 days of unilateral leg immobilization (IMMOB) and from the nonimmobilized control limb (CTRL) of 15 healthy men (23.1 ± 3.5 yr). S les were analyzed for fiber type cross-sectional area (CSA) and creatine transporter (CreaT) at the cell membrane periphery (MEM) or intracellular (INT) areas, via immunofluorescence microscopy. Creatine kinase (CK) and AMP-activated protein kinase (AMPK) were determined via immunoblot. Phosphocreatine (PCr), Cr, and ATP were measured via enzymatic analysis. Body composition and maximal isometric knee extensor strength were assessed before and after disuse. Leg strength and fat-free mass were reduced in IMMOB (~32% and 4%, respectively P 0.01 for both). Type II fiber CSA was smaller (~12% P = 0.028) and intramuscular PCr lower (~13% P = 0.015) in IMMOB vs. CTRL. CreaT protein was greater in type I fibers in both limbs ( P 0.01). CreaT was greater in IMMOB vs. CTRL ( P 0.01) and inversely associated with PCr concentration in both limbs ( P 0.05). MEM CreaT was greater than INT CreaT in type I and II fibers of both limbs (~14% for both P 0.01 for both). Type I fiber CreaT tended to be greater in IMMOB vs. CTRL ( P = 0.074). CK was greater and phospho-to-total AMPK Thr172 tended to be greater , in IMMOB vs. CTRL ( P = 0.013 and 0.051, respectively). These findings suggest that modulation of intracellular Cr metabolism is an adaptive response to immobilization in young healthy skeletal muscle.
Publisher: Wiley
Date: 07-09-2020
DOI: 10.1113/EP088795
Publisher: American Physiological Society
Date: 04-2006
DOI: 10.1152/JAPPLPHYSIOL.00822.2005
Abstract: We used three techniques of precooling to test the hypothesis that heat strain would be alleviated, muscle temperature (T mu ) would be reduced, and as a result there would be delayed decrements in peak power output (PPO) during exercise in hot, humid conditions. Twelve male team-sport players completed four cycling intermittent sprint protocols (CISP). Each CISP consisted of twenty 2-min periods, each including 10 s of passive rest, 5 s of maximal sprint against a resistance of 7.5% body mass, and 105 s of active recovery. The CISP, preceded by 20 min of no cooling (Control), precooling via an ice vest (Vest), cold water immersion (Water), and ice packs covering the upper legs (Packs), was performed in hot, humid conditions (mean ± SE 33.7 ± 0.3°C, 51.6 ± 2.2% relative humidity) in a randomized order. The rate of heat strain increase during the CISP was faster in Control than Water and Packs ( P 0.01), but it was similar to Vest. Packs and Water blunted the rise of T mu until minute 16 and for the duration of the CISP (40 min), respectively ( P 0.01). Reductions in PPO occurred from minute 32 onward in Control, and an increase in PPO by ∼4% due to Packs was observed (main effect P 0.05). The method of precooling determined the extent to which heat strain was reduced during intermittent sprint cycling, with leg precooling offering the greater ergogenic effect on PPO than either upper body or whole body cooling.
Publisher: Cold Spring Harbor Laboratory
Date: 26-06-2020
DOI: 10.1101/2020.06.23.143446
Abstract: Oral supplementation of the NAD + precursor Nicotinamide Riboside (NR) has been reported to increase Sirtuin (SIRT) signalling, mitochondrial biogenesis and endurance capacity in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study aimed to assess the effect of 7-day NR supplementation on exercise-induced transduction and transcriptional responses in skeletal muscle of young, healthy, recreationally active human volunteers. In a double-blinded, randomised, counter-balanced, crossover design, eight male participants (age: 23 ± 4 years, VO 2 peak: 46.5 ± 4.4 mL·kg -1 ·min -1 ) received one week of NR or cellulose placebo (PLA) supplementation (1000 mg·d -1 ) before performing one hour of cycling at 60% Wmax. Muscle biopsies were collected prior to supplementation and pre-, immediately and three-hours post-exercise from the medial vastus lateralis, whilst venous blood s les were collected throughout the trial. Global acetylation, auto-PARylation of PARP1, acetylation of p53 Lys382 and MnSOD Lys122 were unaffected by NR supplementation or exercise. Exercise led to an increase in AMPK Thr172 (1.6-fold), and ACC Ser79 (4-fold) phosphorylation, in addition to an increase in PGC-1α (∼5-fold) and PDK4 (∼10-fold) mRNA expression, however NR had no additional effect on this response. There was also no effect of NR supplementation on substrate utilisation at rest or during exercise or on skeletal muscle mitochondrial respiration. Finally, NR supplementation blunted the exercise induced activation of skeletal muscle NNMT mRNA expression, but had no effect on mRNA expression of NMRK1, NAMPT or NMNAT1, which were not significantly affected by NR supplementation or exercise. In summary, one week of NR supplementation does not augment skeletal muscle signal transduction pathways implicated in mitochondrial adaptation to endurance exercise.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2020
DOI: 10.1007/S00394-020-02247-8
Abstract: Red wine polyphenols (RWP) are plant-based molecules that have been extensively studied in relation to their protective effects on vascular health in both animals and humans. The aim of this review was to quantify and compare the efficacy of RWP and pure resveratrol on outcomes measures of vascular health and function in both animals and humans. Comprehensive database searches were carried out through PubMed, Web of Science and OVID for randomised, placebo-controlled studies in both animals and humans. Meta-analyses were carried out on acute and chronic studies of RWP in humans, alongside sub-group analysis where possible. Risk-of-bias assessment was carried out for all included studies based on randomisation, allocation, blinding, outcome data reporting, and other biases. 48 animal and 37 human studies were included in data extraction following screening. Significant improvements in measures of blood pressure and vascular function following RWP were seen in 84% and 100% of animal studies, respectively. Human studies indicated significant improvements in systolic blood pressure overall (− 2.6 mmHg, 95% CI: [− 4.8, − 0.4]), with a greater improvement in pure-resveratrol studies alone (− 3.7 mmHg, 95% CI: [− 7.3, − 0.0]). No significant effects of RWP were seen in diastolic blood pressure or flow-mediated dilation (FMD) of the brachial artery. RWP have the potential to improve vascular health in at risk human populations, particularly in regard to lowering systolic blood pressure however, such benefits are not as prevalent as those observed in animal models.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Frontiers Media SA
Date: 07-06-2017
Publisher: Cold Spring Harbor Laboratory
Date: 11-02-2020
DOI: 10.1101/2020.02.10.941054
Abstract: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell size and growth in response to nutrients, however, the mechanisms by which nutrient levels are sensed by mTORC1 in human skeletal muscle are yet to be fully elucidated. The Class III PI3Kinase Vps34 has recently been proposed as a sensor essential for mTORC1 activation following nutrient stimulation. We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (age – 21 ± 0.5yrs, mean ± SEM) ingested a PRO-CHO beverage containing 20/44/1g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1h and 3h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean±SEM) - 0.273±0.021, 1h - 0.347±0.022, Pearson’s Coefficient (r)) where it co-localized with mTOR (PRE – 0.312±0.018, 1h – 0.348±0.024, Pearson’s Coefficient (r))). These alterations occurred in parallel to an increase in S6K1 kinase activity – 941±164% of PRE at 1h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro . However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.
Publisher: Wiley
Date: 20-10-2020
DOI: 10.1111/SMS.13848
Publisher: American Society for Clinical Investigation
Date: 11-01-2022
Publisher: Proceedings of the National Academy of Sciences
Date: 24-02-2021
Abstract: Duchenne muscular dystrophy (DMD) is a fatal degenerative disease without a cure. Current standard pharmacological treatment is corticosteroids. Their prolonged use is associated with several undesirable side effects. Using Caenorhabditis elegans , we have identified pharmacological treatments that supplement hydrogen sulfide (H 2 S). One, sodium GYY4137, largely acts like prednisone to improve neuromuscular health the other, AP39, targets H 2 S delivery to mitochondria. As these are not steroids, they are unlikely to produce steroid-induced side effects. Additionally, as DMD mice show a decline in total sulfide, our results pave the way for evaluation of cellular and/or mitochondrial H 2 S in DMD pathology and warrant further investigation of selective H 2 S delivery approaches in mdx mice and/or higher animal models of DMD.
Publisher: Informa UK Limited
Date: 27-08-2014
DOI: 10.1080/17461391.2014.950345
Abstract: Concurrent training (the combination of endurance exercise to resistance training) is a common practice for athletes looking to maximise strength and endurance. Over 20 years ago, it was first observed that performing endurance exercise after resistance exercise could have detrimental effects on strength gains. At the cellular level, specific protein candidates have been suggested to mediate this training interference however, at present, the physiological reason(s) behind the concurrent training effect remain largely unknown. Even less is known regarding the optimal nutritional strategies to support concurrent training and whether unique nutritional approaches are needed to support endurance and resistance exercise during concurrent training approaches. In this review, we will discuss the importance of protein supplementation for both endurance and resistance training adaptation and highlight additional nutritional strategies that may support concurrent training. Finally, we will attempt to synergise current understanding of the interaction between physiological responses and nutritional approaches into practical recommendations for concurrent training.
Publisher: American Physiological Society
Date: 03-2014
DOI: 10.1152/JAPPLPHYSIOL.01072.2013
Abstract: AMPK (AMP-dependant protein kinase)-mTORC1 (mechanistic target of rapamycin in complex 1)-p70S6K1 (ribosomal protein S6 kinase 1 of 70 kDa) signaling plays a crucial role in muscle protein synthesis (MPS). Understanding this pathway has been advanced by the application of the Western blot (WB) technique. However, because many components of the mTORC1 pathway undergo numerous, multisite posttranslational modifications, solely studying the phosphorylation changes of mTORC1 and its substrates may not adequately represent the true metabolic signaling processes. The aim of this study was to develop and apply a quantitative in vitro [γ- 32 P] ATP kinase assay (KA) for p70S6K1 to assess kinase activity in human skeletal muscle to resistance exercise (RE) and protein feeding. In an initial series of experiments the assay was validated in tissue culture and in p70S6K1-knockout tissues. Following these experiments, the methodology was applied to assess p70S6K1 signaling responses to a physiologically relevant stimulus. Six men performed unilateral RE followed by the consumption of 20 g of protein. Muscle biopsies were obtained at pre-RE, and 1 and 3 h post-RE. In response to RE and protein consumption, p70S6K1 activity as assessed by the KA was significantly increased from pre-RE at 1 and 3 h post-RE. However, phosphorylated p70S6K1 thr389 was not significantly elevated. AMPK activity was suppressed from pre-RE at 3 h post-RE, whereas phosphorylated ACC ser79 was unchanged. Total protein kinase B activity also was unchanged after RE from pre-RE levels. Of the other markers we assessed by WB, 4EBP1 thr37/46 phosphorylation was the only significant responder, being elevated at 3 h post-RE from pre-RE. These data highlight the utility of the KA to study skeletal muscle plasticity.
Publisher: American Physiological Society
Date: 11-2010
DOI: 10.1152/AJPENDO.00038.2010
Abstract: High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and % carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1α, and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior ( P 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1α, and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors ( P 0.05). In C 2 C 12 muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 ( P 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity.
Publisher: Frontiers Media SA
Date: 04-12-2017
Publisher: American Physiological Society
Date: 06-2019
DOI: 10.1152/JAPPLPHYSIOL.00913.2018
Abstract: We examined the effects of graded muscle glycogen on exercise capacity and modulation of skeletal muscle signaling pathways associated with the regulation of mitochondrial biogenesis. In a repeated-measures design, eight men completed a sleep-low, train-low model comprising an evening glycogen-depleting cycling protocol followed by an exhaustive exercise capacity test [8 × 3 min at 80% peak power output (PPO), followed by 1-min efforts at 80% PPO until exhaustion] the subsequent morning. After glycogen-depleting exercise, subjects ingested a total of 0 g/kg (L-CHO), 3.6 g/kg (M-CHO), or 7.6 g/kg (H-CHO) of carbohydrate (CHO) during a 6-h period before sleeping, such that exercise was commenced the next morning with graded ( P 0.05) muscle glycogen concentrations (means ± SD: L-CHO: 88 ± 43, M-CHO: 185 ± 62, H-CHO: 278 ± 47 mmol/kg dry wt). Despite differences ( P 0.05) in exercise capacity at 80% PPO between trials (L-CHO: 18 ± 7, M-CHO: 36 ± 3, H-CHO: 44 ± 9 min), exercise induced comparable AMPK Thr172 phosphorylation (~4-fold) and PGC-1α mRNA expression (~5-fold) after exercise and 3 h after exercise, respectively. In contrast, neither exercise nor CHO availability affected the phosphorylation of p38MAPK Thr180/Tyr182 or CaMKII Thr268 or mRNA expression of p53, Tfam, CPT-1, CD36, or PDK4. Data demonstrate that when exercise is commenced with muscle glycogen 300 mmol/kg dry wt, further graded reductions of 100 mmol/kg dry weight impair exercise capacity but do not augment skeletal muscle cell signaling. NEW & NOTEWORTHY We provide novel data demonstrating that when exercise is commenced with muscle glycogen below 300 mmol/kg dry wt (as achieved with the sleep-low, train-low model) further graded reductions in preexercise muscle glycogen of 100 mmol/kg dry wt reduce exercise capacity at 80% peak power output by 20–50% but do not augment skeletal muscle cell signaling.
Publisher: Wiley
Date: 08-03-2018
DOI: 10.1111/ACEL.12735
Publisher: Portland Press Ltd.
Date: 14-07-2015
DOI: 10.1042/CS20150246
Abstract: Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000329279
Abstract: Glycogen was first identified in muscle over a century and a half ago. Even though we have known of its existence and its role in metabolism for a long time, recognition of its ability to directly and indirectly modulate signaling and the adaptation to exercise is far more recent. Acute exercise induces a number of changes within the body (i.e. sympathetic nervous system activation and elevation of plasma free fatty acids) and muscle (increased AMP-activated protein kinase activity and fat metabolism) that may underlie the long- term adaptation to training. These changes are also affected by glycogen depletion. This review discusses the effect of exercise in a glycogen-depleted state on metabolism and signaling and how this affects the adaptation to exercise. Although 'training low' may increase cellular markers associated with training and enhance functions such as fat oxidation at sub- maximal exercise intensities, how this translates to performance is unclear. Further research is warranted to identify situations both in health and athletic performance where training with low glycogen levels may be beneficial. In the meantime, athletes and coaches need to weigh the pros and cons of training with low carbohydrate within a periodized training program.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2019
DOI: 10.1249/JES.0000000000000173
Abstract: The mechanistic target of rapamycin (mTOR) is a central regulator of muscle protein synthesis, and its activation has long been attributed to its translocation to the lysosome. Here, we present a novel model of mTOR activation in skeletal muscle where the translocation of mTOR and the lysosome toward the cell membrane is a key process in mTOR activation.
Publisher: Frontiers Media SA
Date: 27-10-2015
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
No related grants have been discovered for Andrew Philp.