PGC-1α increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4

2008 ◽  
Vol 35 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Carley R. Benton ◽  
Yuko Yoshida ◽  
James Lally ◽  
Xiao-Xia Han ◽  
Hideo Hatta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Positive Association ◽  
Strong Relationship ◽  
Muscle Lactate ◽  
Hindlimb Muscles ◽  
Metabolic Genes ◽  
Lactate Uptake ◽  
Strong Positive Association

We examined the relationship between PGC-1α protein; the monocarboxylate transporters MCT1, 2, and 4; and CD147 1) among six metabolically heterogeneous rat muscles, 2) in chronically stimulated red (RTA) and white tibialis (WTA) muscles (7 days), and 3) in RTA and WTA muscles transfected with PGC-1α-pcDNA plasmid in vivo. Among rat hindlimb muscles, there was a strong positive association between PGC-1α and MCT1 and CD147, and between MCT1 and CD147. A negative association was found between PGC-1α and MCT4, and CD147 and MCT4, while there was no relationship between PGC-1α or CD147 and MCT2. Transfecting PGC-1α-pcDNA plasmid into muscle increased PGC-1α protein (RTA +23%; WTA +25%) and induced the expression of MCT1 (RTA +16%; WTA +28%), but not MCT2 and MCT4. As a result of the PGC-1α-induced upregulation of MCT1 and its chaperone CD147 (+29%), there was a concomitant increase in the rate of lactate uptake (+20%). In chronically stimulated muscles, the following proteins were upregulated, PGC-1α in RTA (+26%) and WTA (+86%), MCT1 in RTA (+61%) and WTA (+180%), and CD147 in WTA (+106%). In contrast, MCT4 protein expression was not altered in either RTA or WTA muscles, while MCT2 protein expression was reduced in both RTA (−14%) and WTA (−10%). In these studies, whether comparing oxidative capacities among muscles or increasing their oxidative capacities by PGC-1α transfection and chronic muscle stimulation, there was a strong relationship between the expression of PGC-1α and MCT1, and PGC-1α and CD147 proteins. Thus, MCT1 and CD147 belong to the family of metabolic genes whose expression is regulated by PGC-1α in skeletal muscle.

Lactate shuttles in Nature

2002 ◽  
Vol 30 (2) ◽  
pp. 258-264 ◽  
Author(s):  
G. A. Brooks
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Cell Signalling ◽  
Supporting Cell ◽  
Lactate Oxidation ◽  
Lactate Shuttle ◽  
Lactate Uptake ◽  
Lactate Exchange ◽  
Cell Cell

Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilized continuously under fully aerobic conditions. ‘Cell-cell’ and ‘intracellular lactate shuttle’ concepts describe the roles of lactate in the delivery of oxidative and gluconeogenic substrates, as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges between white-glycolytic and red-oxidative fibres within a working muscle bed, between working skeletal muscle and heart, and between tissues of net lactate release and gluconeogenesis. Lactate exchange between astrocytes and neurons that is linked to glutamatergic signalling in the brain is an example of a lactate shuttle supporting cell-cell signalling. Lactate uptake by mitochondria and pyruvate-lactate exchange in peroxisomes are examples of intracellular lactate shuttles. Lactate exchange between sites of production and removal is facilitated by monocarboxylate transport proteins, of which there are several isoforms, and, probably, also by scaffolding proteins. The mitochondrial lactate-pyruvate transporter appears to work in conjunction with mitochondrial lactate dehydrogenase, which permits lactate to be oxidized within actively respiring cells. Hence mitochondria function to establish the concentration and proton gradients necessary for cells with high mitochondrial densities (e.g. cardiocytes) to take up and oxidize lactate. Arteriovenous difference measurements on working cardiac and skeletal muscle beds as well as NMR spectral analyses of these tissues show that lactate is formed and oxidized within the cells of formation in vivo. Glycolysis and lactate oxidation within cells permits high flux rates and the maintenance of redox balance in the cytosol and mitochondria. Other examples of intracellular lactate shuttles include lactate uptake and oxidation in sperm mitochondria and the facilitation of β-oxidation in peroxisomes by pyruvate-lactate exchange. An ancient origin to the utility of lactate shuttling is implied by the observation that mitochondria of Saccharomyces cerevisiae contain flavocytochrome b2, a lactate-cytochrome c oxidoreductase that couples lactate dehydrogenation to the reduction of cytochrome c. The presence of cell-cell and intracellular lactate shuttles gives rise to the notion that glycolytic and oxidative pathways can be viewed as linked, as opposed to alternative, processes, because lactate, the product of one pathway, is the substrate for the other.

scholarly journals A Transgenic Mouse Model to Study Glucose Transporter 4myc Regulation in Skeletal Muscle

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 1935-1940 ◽  
Author(s):  
Jonathan D. Schertzer ◽  
Costin N. Antonescu ◽  
Philip J. Bilan ◽  
Swati Jain ◽  
Xudong Huang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Glucose Transporter ◽  
Fold Increase ◽  
Essential Elements ◽  
Glucose Disposal ◽  
Vesicle Membrane ◽  
Muscle Creatine Kinase ◽  
Hindlimb Muscles

Skeletal muscle is the major site for dietary glucose disposal, taking up glucose via glucose transporter 4 (GLUT4). Although subcellular fractionation studies demonstrate that insulin increases GLUT4 density in sarcolemma and transverse tubules, fractionation cannot discern GLUT4 vesicle-membrane association from insertion and exofacial exposure. Clonal muscle cultures expressing exofacially tagged GLUT4 have allowed quantification of GLUT4 exposure at the cell surface, its exocytosis, endocytosis, and partner proteins. We hypothesized that transgenic expression of GLUT4myc in skeletal muscles would provide a useful model to investigate GLUT4 biology in vivo. A homozygous mouse colony was generated expressing GLUT4myc driven by the muscle creatine kinase (MCK) promoter. GLUT4 protein levels were about 3-fold higher in hindlimb muscles of MCK-GLUT4myc transgenic mice compared with littermates (P < 0.05). Insulin (12 nm, 30 min) induced a 2.1-fold increase in surface GLUT4myc detected by immunofluorescence of the exofacial myc epitope in nonpermeabilized muscle fiber bundles (P < 0.05). Glucose uptake and surface GLUT4myc levels were 3.5- and 3-fold higher, respectively, in giant membrane vesicles blebbed from hindlimb muscles of insulin-stimulated transgenic mice compared with unstimulated counterparts (P < 0.05). Muscle contraction also elevated both parameters, an effect partially additive to insulin’s. GLUT4myc immunoprecipitation with anti-myc antibodies avoids interfering with associated intracellular binding proteins. Tether, containing a UBX domain, for GLUT4 coimmunoprecipitated with GLUT4myc and insulin stimulation significantly decreased such association (P < 0.05). MCK-GLUT4myc transgenic mice are thus useful to quantify exofacial GLUT4 exposure at the sarcolemma and GLUT4 binding partners in skeletal muscle, essential elements in the investigation of muscle GLUT4 regulation in physiological and pathological states in vivo.

scholarly journals PGC-1^|^alpha; increases skeletal muscle lactate uptake by increasing the expression of MCT1 but not MCT2 or MCT4

2009 ◽  
Vol 58 (1) ◽  
pp. 49-49
Author(s):  
YUKO YOSHIDA ◽  
CARLEY R. BENTON ◽  
JAMES LALLY ◽  
XIAO-XIA HAN ◽  
HIDEO HATTA ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Lactate ◽  
Lactate Uptake

The effect of nutritional status on protein degradation and components of the calpain system in skeletal muscle of weaned wether lambs

1997 ◽  
Vol 129 (4) ◽  
pp. 471-477 ◽  
Author(s):  
B. C. THOMSON ◽  
B. J. HOSKING ◽  
R. D. SAINZ ◽  
V. H. ODDY
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Nutritional Status ◽  
Protein Degradation ◽  
Hind Limb ◽  
Positive Association ◽  
Negative Association ◽  
Stepwise Gradient ◽  
Calpain System

The association between the rate of protein degradation and the components of the calpain system in lambs fed at sub-maintenance, maintenance and supra-maintenance levels of nutrition was investigated. Weights of the cold carcass, liver, kidney, pluck and m. semitendinosus increased with nutritional level (P<0·05). The rate of protein degradation in the hind-limb was determined using an in vivo arterio-venous method. Blood flow, protein gain and protein synthesis across the hind-limb increased with nutritional status (P<0·05). There was an increase in the amount of protein synthesised per unit of RNA (mg RNA/g protein) with improved nutritional status. The rate of protein degradation across the hind-limb increased between the sub-maintenance and maintenance treatments (P<0·05) but there was no further increase above maintenance (P>0·10). The activity of the components of the calpain system was determined after separation on a DEAE-Sepharose column with a stepwise gradient with increasing NaCl concentrations. Although there were no significant effects of nutritional status on the components of the calpain system, there was a negative association between the rate of protein degradation and the activity of μ-calpain (R2=0·61; P<0·005) and a weak positive association between calpastatin activity and protein gain (R2=0·44; P<0·05).

Effects of intense swimming and tetanic electrical stimulation on skeletal muscle ions and metabolites

1987 ◽  
Vol 63 (6) ◽  
pp. 2331-2339 ◽  
Author(s):  
M. I. Lindinger ◽  
G. J. Heigenhauser ◽  
L. L. Spriet
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Creatine Phosphate ◽  
Hindlimb Muscles ◽  
Pass Perfusion ◽  
Ion Movements ◽  
Glycogen Breakdown ◽  
White Gastrocnemius ◽  
Stimulation Of

The purpose of this study was to compare changes in ions and metabolites in four different rat hindlimb muscles in response to intense swimming exercise in vivo (263 +/- 33 s) (SWUM), and to 5 min (300 s) of tetanic electrical stimulation of artificially perfused rat hindlimbs (STIM). With both swimming and electrical stimulation, soleus (SOL) contents of creatine phosphate (CP), ATP, and glycogen changed the least, whereas the largest decreases in these metabolites occurred in the white gastrocnemius (WG). Lactate (La-) accumulation and glycogen breakdown were significantly greater in SWUM hindlimb muscles compared with STIM. The high arterial La- concentration [( La-] = 20 meq.l-1) in SWUM may have contributed to elevated muscle [La-], whereas one-pass perfusion kept arterial [La-] below 2 meq.l–1 in STIM. In SWUM, intracellular [Na+] increased significantly in the plantaris (PL), red gastrocnemius (RG), and WG, but not in SOL. [Cl-] increased, and [K+], [Ca2+], and [Mg2+] decreased in all muscles. In STIM, intracellular [K+], [Mg2+], and [Ca2+] decreased significantly, whereas [Na+] and [Cl-] increased in all muscles. Differences in the magnitude of ion and fluid fluxes between groups can be explained by the different methods of hindlimb perfusion. In conclusion, STIM is a useful model of in vivo energy metabolism and permits mechanisms of transsarcolemmal ion movements to be studied.

Wear in Retrieved Charnley Acetabular Sockets

1996 ◽  
Vol 210 (3) ◽  
pp. 197-207 ◽  
Author(s):  
R M Hall ◽  
A Unsworth ◽  
P Siney ◽  
B M Wroblewski
Keyword(s):  
Laboratory Experiments ◽  
Significant Proportion ◽  
Positive Association ◽  
Ordinary Least Squares ◽  
Rate Of Change ◽  
Wear Volume ◽  
Least Squares Regression ◽  
Initial Penetration ◽  
Strong Positive Association

One hundred and twenty-nine Charnley acetabular components were acquired at the time of revision surgery and a tribological investigation undertaken. The relative occurrence of pitting in the unworn and worn regions of the sockets suggest that most of the cement ingress occurs during the early part of the service life. The penetration depth of the explanted sockets was determined using the shadowgraph technique. Observation of the profiles in the wear planes suggest that, in general, the creep component was not a significant proportion of the overall change in the inner bore of the socket. Using weighted ordinary least squares regression, in which the intercept was not assumed to be zero, mean penetration and wear volume rates of 0.20 (SE = 0.02) mm/year and 55 (SE = 5) mm3/year, respectively, were recorded and are in agreement with other retrieval studies. In neither case was the intercept found to be significantly different from zero. A mean clinical wear factor, kclinical, equal to 2.1 (SE = 0.2) × 10-6 mm3/N m was calculated which is considerably larger than that found in laboratory experiments which purport to reflect in vivo conditions. In this analysis, a significant positive intercept was observed [96 (SE = 36) mm3] and may be evidence of the small initial penetration due to creep reported in simulator experiments. A strong positive association between kclinical and the arithmetical mean roughness, Ra, of the femoral head was also demonstrated although the rate of change was not as great as that cited for laboratory experiments.

scholarly journals Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor α (PPARα)

2002 ◽  
Vol 366 (3) ◽  
pp. 839-846 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Mary C. SUGDEN
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Skeletal Muscles ◽  
Pyruvate Dehydrogenase Kinase ◽  
Glucose Disposal ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anterior Tibialis

In insulin deficiency, increased lipid delivery and oxidation suppress skeletal-muscle glucose oxidation by inhibiting pyruvate dehydrogenase complex (PDC) activity via enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4, which phosphorylates (and inactivates) PDC. Signalling via peroxisome-proliferator-activated receptor α (PPARα) is an important component of the mechanism enhancing hepatic and renal PDK4 protein expression. Activation of PPARα in gastrocnemius, a predominantly fast glycolytic (FG) muscle, also increases PDK4 expression, an effect that, if extended to all muscles, would be predicted to drastically restrict whole-body glucose disposal. Paradoxically, chronic activation of PPARα by WY14,643 treatment improves glucose utilization by muscles of insulin-resistant high-fat-fed rats. In the resting state, oxidative skeletal muscles are quantitatively more important for glucose disposal than FG muscles. We evaluated the participation of PPARα in regulating PDK4 protein expression in slow oxidative (SO) skeletal muscle (soleus) and fast oxidative-glycolytic (FOG) skeletal muscle (anterior tibialis) containing a high proportion of oxidative fibres. In the fed state, acute (24h) activation of PPARα by WY14,643 in vivo failed to modify PDK4 protein expression in soleus, but modestly enhanced PDK4 protein expression in anterior tibialis. Starvation enhanced PDK4 protein expression in both muscles, with the greater response in anterior tibialis. WY14,643 treatment in vivo during starvation did not further enhance upregulation of PDK4 protein expression in either muscle type. Enhanced PDK4 protein expression after starvation was retained in SO and FOG skeletal muscles of PPARα-deficient mice. Our data indicate that PDK4 protein expression in oxidative skeletal muscle is regulated by a lipid-dependent mechanism that is not obligatorily dependent on signalling via PPARα.

Lactate removal is not enhanced in nonstimulated perfused skeletal muscle after endurance training

2001 ◽  
Vol 90 (4) ◽  
pp. 1307-1313 ◽  
Author(s):  
Ken D. Sumida ◽  
Casey M. Donovan
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Glycogen Synthesis ◽  
Venous Blood ◽  
Muscle Lactate ◽  
Bicarbonate Buffer ◽  
Muscle Glycogen Synthesis ◽  
Lactate Removal ◽  
Lactate Uptake ◽  
And Control

The effects of endurance training (running 40 m/min, 10% grade for 60 min, 5 days/wk for 8 wk) on skeletal muscle lactate removal was studied in rats by utilizing the isolated hindlimb perfusion technique. Hindlimbs were perfused (single-pass) with Krebs-Henseleit bicarbonate buffer, fresh bovine erythrocytes (hematocrit ∼30%), 10 mM lactate, and [U-14C]lactate (30,000 dpm/ml). Arterial and venous blood samples were collected every 10 min for the duration of the experiment to assess lactate uptake. During perfusions, no significant differences in skeletal muscle lactate uptake were observed between trained (7.31 ± 0.20 μmol/min) and control hindlimbs (6.98 ± 0.43 μmol/min). In support, no significant differences were observed for [14C]lactate uptake in trained (22,776 ± 370 dpm/min) compared with control hindlimbs (21,924 ± 1,373 dpm/min). Concomitant with these observations, no significant differences were observed between groups for oxygen consumption (4.93 ± 0.18 vs. 4.92 ± 0.13 μmol/min), net skeletal muscle glycogen synthesis (7.1 ± 0.4 vs. 6.5 ± 0.3 μmol · 40 min−1 · g−1), or14CO2 production (2,203 ± 185 vs. 2,098 ± 155 dpm/min), trained and control, respectively. These findings indicate that endurance training does not affect lactate uptake or alter the metabolic fate of lactate in quiescent skeletal muscle.

Functional and biochemical characterization of soleus muscle in Down syndrome mice: insight into the muscle dysfunction seen in the human condition

2012 ◽  
Vol 303 (12) ◽  
pp. R1251-R1260 ◽  
Author(s):  
Patrick M. Cowley ◽  
Stefan Keslacy ◽  
Frank A. Middleton ◽  
Lara R. DeRuisseau ◽  
Bo Fernhall ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Down Syndrome ◽  
Protein Expression ◽  
Muscle Weakness ◽  
Soleus Muscle ◽  
Citrate Synthase ◽  
Human Condition ◽  
Muscle Dysfunction ◽  
Ts65dn Mouse

Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may be a useful model to examine DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of nonfatigued Ts65Dn soleus, but a 12% reduction in force was observed during recovery from fatiguing contractions compared with WT muscle ( P < 0.05). Indicators of oxidative stress and mitochondrial oxidative capacity were assessed to reveal potential mechanisms of DS-associated muscle weakness. Protein expression of copper-zinc superoxide dismutase (SOD1), a triplicated gene in persons with DS and Ts65Dn mice, was increased 25% ( P < 0.05) in Ts65Dn soleus. Nontriplicated antioxidant protein expression was similar between groups. Lipid peroxidation was unaltered in Ts65Dn animals, but protein oxidation was 20% greater compared with controls ( P < 0.05). Cytochrome- c oxidase expression was 22% lower in Ts65Dn muscle ( P < 0.05), while expression of citrate synthase was similar between groups. Microarray analysis revealed alteration of numerous pathways in Ts65Dn muscle, including proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, despite biochemical and gene expression differences in soleus muscle of Ts65Dn animals, the functional properties of skeletal muscle likely contribute a minor part to the in vivo muscle weakness.

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