Publications by authors named "Joaquín Pérez-Schindler"

17 Publications

  • Page 1 of 1

Over-expression of a retinol dehydrogenase (SRP35/DHRS7C) in skeletal muscle activates mTORC2, enhances glucose metabolism and muscle performance.

Sci Rep 2018 01 12;8(1):636. Epub 2018 Jan 12.

Departments of Anesthesia and of Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031, Basel, Switzerland.

SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C dehydrogenase/ reductase family 7. Here we show that its over-expression in mouse skeletal muscles induces enhanced muscle performance in vivo, which is not related to alterations in excitation-contraction coupling but rather linked to enhanced glucose metabolism. Over-expression of SRP-35 causes increased phosphorylation of Akt, triggering plasmalemmal targeting of GLUT4 and higher glucose uptake into muscles. SRP-35 signaling involves RARα and RARγ (non-genomic effect), PI3K and mTORC2. We also demonstrate that all-trans retinoic acid, a downstream product of the enzymatic activity of SRP-35, mimics the effect of SRP-35 in skeletal muscle, inducing a synergistic effect with insulin on AKT phosphorylation. These results indicate that SRP-35 affects skeletal muscle metabolism and may represent an important target for the treatment of metabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-18844-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766524PMC
January 2018

Exercise and high-fat feeding remodel transcript-metabolite interactive networks in mouse skeletal muscle.

Sci Rep 2017 10 18;7(1):13485. Epub 2017 Oct 18.

MRC-ARUK Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, B152TT, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-14081-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647435PMC
October 2017

Overload-mediated skeletal muscle hypertrophy is not impaired by loss of myofiber STAT3.

Am J Physiol Cell Physiol 2017 Sep 28;313(3):C257-C261. Epub 2017 Jun 28.

Department of Orthopaedic Surgery, University of California, San Diego, California; and

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00100.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625092PMC
September 2017

Single inhibition of either PDE3 or PDE4 unmasks β2-adrenoceptor-mediated inotropic and lusitropic effects in the left but not right ventricular myocardium of rat.

Eur J Pharmacol 2015 Oct 11;765:429-36. Epub 2015 Sep 11.

Department of Pharmacology, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain. Electronic address:

Cyclic nucleotide phosphodiesterase (PDE)3 and PDE4 provide the major PDE activity in cardiac myocytes and shape β1-adrenoceptor-dependent cardiac cAMP signaling but their role in regulating β2-adrenoceptor-mediated responses is less well known. We investigated potential differences in PDE3 and PDE4 activities between right (RV) and left (LV) ventricular myocardium, and their role in regulating β2-adrenoceptor effects. PDE3 activity in the microsomal fraction was lower in RV than in LV but was the same in the cytosolic fraction. However, no significant difference between RV and LV was found when the PDE4 activity was studied. β2-adrenoceptor activation increased inotropism and lusitropism in LV when measured in the presence of either the PDE3 inhibitor cilostamide, the PDE4 inhibitor rolipram or a non-selective PDE inhibitor IBMX. However, the joint inhibition of both PDE3 and PDE4 was necessary in RV to uncover β2-adrenoceptor-induced inotropic and lusitropic effects. Our results indicate different regulation of β2-adrenoceptor-mediated contractility by PDE3 and PDE4 in RV and LV of the rat heart. In the case of PDE3 due to a different contribution of the enzyme in the microsomal fraction whereas in the case of PDE4 it can be attributed to differences in the intracellular distribution and coupling to β2-adrenoceptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2015.09.001DOI Listing
October 2015

Rapamycin does not prevent increases in myofibrillar or mitochondrial protein synthesis following endurance exercise.

J Physiol 2015 Sep;593(18):4275-84

Neurobiology, Physiology and Behaviour, University of California, Davis, CA, USA.

The present study aimed to investigate the role of the mechanistic target of rapamycin complex 1 (mTORC1) in the regulation of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis following endurance exercise. Forty-two female C57BL/6 mice performed 1 h of treadmill running (18 m min(-1) ; 5° grade), 1 h after i.p. administration of rapamycin (1.5 mg · kg(-1) ) or vehicle. To quantify skeletal muscle protein fractional synthesis rates, a flooding dose (50 mg · kg(-1) ) of l-[ring-(13) C6 ]phenylalanine was administered via i.p. injection. Blood and gastrocnemius muscle were collected in non-exercised control mice, as well as at 0.5, 3 and 6 h after completing exercise (n = 4 per time point). Skeletal muscle MyoPS and MitoPS were determined by measuring isotope incorporation in their respective protein pools. Activation of the mTORC1-signalling cascade was measured via direct kinase activity assay and immunoblotting, whereas genes related to mitochondrial biogenesis were measured via a quantitative RT-PCR. MyoPS increased rapidly in the vehicle group post-exercise and remained elevated for 6 h, whereas this response was transiently blunted (30 min post-exercise) by rapamycin. By contrast, MitoPS was unaffected by rapamycin, and was increased over the entire post-exercise recovery period in both groups (P < 0.05). Despite rapid increases in both MyoPS and MitoPS, mTORC1 activation was suppressed in both groups post-exercise for the entire 6 h recovery period. Peroxisome proliferator activated receptor-γ coactivator-1α, pyruvate dehydrogenase kinase 4 and mitochondrial transcription factor A mRNA increased post-exercise (P < 0.05) and this response was augmented by rapamycin (P < 0.05). Collectively, these data suggest that endurance exercise stimulates MyoPS and MitoPS in skeletal muscle independently of mTORC1 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP271219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594297PMC
September 2015

Regulation of skeletal muscle mitochondrial function by nuclear receptors: implications for health and disease.

Clin Sci (Lond) 2015 Oct;129(7):589-99

MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/CS20150246DOI Listing
October 2015

PDE2 activity differs in right and left rat ventricular myocardium and differentially regulates β2 adrenoceptor-mediated effects.

Exp Biol Med (Maywood) 2015 Sep 27;240(9):1205-13. Epub 2014 Nov 27.

Department of Pharmacology, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain

The important regulator of cardiac function, cAMP, is hydrolyzed by different cyclic nucleotide phosphodiesterases (PDEs), whose expression and activity are not uniform throughout the heart. Of these enzymes, PDE2 shapes β1 adrenoceptor-dependent cardiac cAMP signaling, both in the right and left ventricular myocardium, but its role in regulating β2 adrenoceptor-mediated responses is less well known. Our aim was to investigate possible differences in PDE2 transcription and activity between right (RV) and left (LV) rat ventricular myocardium, as well as its role in regulating β2 adrenoceptor effects. The free walls of the RV and the LV were obtained from Sprague-Dawley rat hearts. Relative mRNA for PDE2 (quantified by qPCR) and PDE2 activity (evaluated by a colorimetric procedure and using the PDE2 inhibitor EHNA) were determined in RV and LV. Also, β2 adrenoceptor-mediated effects (β2-adrenoceptor agonist salbutamol + β1 adrenoceptor antagonist CGP-20712A) on contractility and cAMP concentrations, in the absence or presence of EHNA, were studied in the RV and LV. PDE2 transcript levels were less abundant in RV than in LV and the contribution of PDE2 to the total PDE activity was around 25% lower in the microsomal fraction of the RV compared with the LV. β2 adrenoceptor activation increased inotropy and cAMP levels in the LV when measured in the presence of EHNA, but no such effects were observed in the RV, either in the presence or absence of EHNA. These results indicate interventricular differences in PDE2 transcript and activity levels, which may distinctly regulate β2 adrenoceptor-mediated contractility and cAMP concentrations in the RV and in the LV of the rat heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1535370214560969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935361PMC
September 2015

Understanding the acetylome: translating targeted proteomics into meaningful physiology.

Am J Physiol Cell Physiol 2014 Nov 3;307(9):C763-73. Epub 2014 Sep 3.

Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, California.

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 diverse metabolic systems have led to the current hypothesis that acetylation may be a fundamental mechanism to fine-tune metabolic adaptation in skeletal muscle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00399.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216940PMC
November 2014

Nutritional strategies to support concurrent training.

Eur J Sport Sci 2015 27;15(1):41-52. Epub 2014 Aug 27.

a School of Sport, Exercise and Rehabilitation Sciences , University of Birmingham , Birmingham , UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17461391.2014.950345DOI Listing
November 2015

The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet.

Diabetologia 2014 Nov 13;57(11):2405-12. Epub 2014 Aug 13.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056, Basel, Switzerland.

Aims/hypothesis: Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo.

Methods: Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining.

Results: Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α-PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle.

Conclusions/interpretation: Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-014-3352-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657154PMC
November 2014

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling.

Proc Natl Acad Sci U S A 2013 Dec 25;110(50):20314-9. Epub 2013 Nov 25.

Biozentrum, University of Basel, 4056 Basel, Switzerland.

Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1312039110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864298PMC
December 2013

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A.

Proc Natl Acad Sci U S A 2013 May 6;110(21):8738-43. Epub 2013 May 6.

Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1212976110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666691PMC
May 2013

Pathophysiological relevance of the cardiac β2-adrenergic receptor and its potential as a therapeutic target to improve cardiac function.

Eur J Pharmacol 2013 Jan 23;698(1-3):39-47. Epub 2012 Nov 23.

Biozentrum, University of Basel, Klingelbergstrasse 50/70, Basel 4056, Switzerland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2012.11.001DOI Listing
January 2013

The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α in the regulation of skeletal muscle function and oxidative metabolism.

Mol Cell Biol 2012 Dec 1;32(24):4913-24. Epub 2012 Oct 1.

Biozentrum, University of Basel, Basel, Switzerland.

Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.00877-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510532PMC
December 2012

Regulation of contractility and metabolic signaling by the β2-adrenergic receptor in rat ventricular muscle.

Life Sci 2011 May 3;88(19-20):892-7. Epub 2011 Apr 3.

Department of Pharmacology, Faculty of Medicine, University of Murcia, Murcia, Spain.

Aims: 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.

Main Methods: 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.

Key Findings: 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).

Significance: 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2011.03.020DOI Listing
May 2011

Pyruvate suppresses PGC1alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes.

Am J Physiol Cell Physiol 2010 Aug 21;299(2):C240-50. Epub 2010 Apr 21.

Division of Molecular Physiology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.

Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha)-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 beta-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 PGC1alpha (72%) protein content as well as PGC1alpha (48%) and PGC1beta (122%) mRNA. The decrease in PGC1alpha was compensated for by an increase in the PGC1alpha-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 PGC1alpha 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00438.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928631PMC
August 2010

The training stimulus experienced by the leg muscles during cycling in humans.

Exp Physiol 2009 Jun 13;94(6):684-94. Epub 2009 Feb 13.

Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, UK.

Considerable variability exists between people in their health- and performance-related adaptations to conventional endurance training. We hypothesized that some of this variability might be due to differences in the training stimulus received by the working muscles. In 71 young sedentary women we observed large variations in the ratio of one-leg cycling muscle aerobic capacity (V(O2peak)) to two-leg cycling whole-body maximal oxygen uptake (V(O2max); Ratio(1:2); range 0.58-0.96). The variability in Ratio(1:2) was primarily due to differences between people in one-leg V(O2peak) (r = 0.71, P < 0.0005) and was not related to two-leg V(O2max) (r = 0.15, P = 0.209). Magnetic resonance imaging (n = 30) and muscle biopsy sampling (n = 20) revealed that one-leg V(O2peak) was mainly determined by muscle volume (r = 0.73, P < 0.0005) rather than muscle fibre type or oxidative capacity. A high one-leg V(O2peak) was associated with favourable lipoprotein profiles (P = 0.033, n = 24) but this was not the case for two-leg V(O2max). Calculations based on these data suggest that conventional two-leg exercise at 70% V(O2max) requires subjects with the lowest Ratio(1:2) to work their legs at 60% of single-leg V(O2peak), whilst those with the highest Ratio(1:2) work their legs at only 36% of maximum. It was concluded that endurance training carried out according to current guidelines will result in highly variable training stimuli for the leg muscles and variable magnitudes of adaptation. These conclusions have implications for the prescription of exercise to improve health and for investigations into the genetic basis of muscle adaptations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/expphysiol.2008.045658DOI Listing
June 2009