Contraction-induced skeletal muscle FAT/CD36 trafficking and FA uptake is AMPK independent
Bibliographic record
Abstract
The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contracted, ex vivo. In separate studies, FAT/CD36 translocation and FA uptake in response to muscle contractions were investigated in the perfused rat hindlimb. Exercise induced a similar increase in skeletal muscle cell surface membrane FAT/CD36 content in WT (+34%) and AMPK KD (+37%) mice. In contrast, 5-aminoimidazole-4-carboxamide ribonucleoside only induced an increase in cell surface FAT/CD36 content in WT (+29%) mice. Furthermore, in the perfused rat hindlimb, muscle contraction induced a rapid (1 min, +15%) and sustained (10 min, +24%) FAT/CD36 relocation to cell surface membranes. The increase in cell surface FAT/CD36 protein content with muscle contractions was associated with increased FA uptake, both in EDL and SOL muscle from WT and AMPK KD mice and in the perfused rat hindlimb. This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, AMPK could be important in regulation of FAT/CD36 distribution in other physiological situations. The aim of this study was to investigate the molecular mechanisms regulating FA translocase CD36 (FAT/CD36) translocation and FA uptake in skeletal muscle during contractions. In one model, wild-type (WT) and AMP-dependent protein kinase kinase dead (AMPK KD) mice were exercised or extensor digitorum longus (EDL) and soleus (SOL) muscles were contracted, ex vivo. In separate studies, FAT/CD36 translocation and FA uptake in response to muscle contractions were investigated in the perfused rat hindlimb. Exercise induced a similar increase in skeletal muscle cell surface membrane FAT/CD36 content in WT (+34%) and AMPK KD (+37%) mice. In contrast, 5-aminoimidazole-4-carboxamide ribonucleoside only induced an increase in cell surface FAT/CD36 content in WT (+29%) mice. Furthermore, in the perfused rat hindlimb, muscle contraction induced a rapid (1 min, +15%) and sustained (10 min, +24%) FAT/CD36 relocation to cell surface membranes. The increase in cell surface FAT/CD36 protein content with muscle contractions was associated with increased FA uptake, both in EDL and SOL muscle from WT and AMPK KD mice and in the perfused rat hindlimb. This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, AMPK could be important in regulation of FAT/CD36 distribution in other physiological situations. During submaximal exercise, plasma FAs are an important source of energy, accounting for ∼60% of total substrate utilization in human subjects (1Roepstorff C. Steffensen C.H. Madsen M. Stallknecht B. Kanstrup I.L. Richter E.A. Kiens B. Gender differences in substrate utilization during submaximal exercise in endurance-trained subjects.Am. J. Physiol. Endocrinol. Metab. 2002; 282: E435-E447Crossref PubMed Scopus (202) Google Scholar, 2Stellingwerff T. Boon H. Jonkers R.A. Senden J.M. Spriet L.L. Koopman R. van Loon L.J. Significant intramyocellular lipid use during prolonged cycling in endurance-trained males as assessed by three different methodologies.Am. J. Physiol. Endocrinol. Metab. 2007; 292: E1715-E1723Crossref PubMed Scopus (65) Google Scholar, 3Romijn J.A. Coyle E.F. Sidossis L.S. Gastaldelli A. Horowitz J.F. Endert E. Wolfe R.R. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration.Am. J. Physiol. 1993; 265: E380-E391PubMed Google Scholar). Increases in FA utilization during exercise are facilitated by a rapid and sustained upregulation of skeletal muscle FA uptake by 5–15-fold (1Roepstorff C. Steffensen C.H. Madsen M. Stallknecht B. Kanstrup I.L. Richter E.A. Kiens B. Gender differences in substrate utilization during submaximal exercise in endurance-trained subjects.Am. J. Physiol. Endocrinol. Metab. 2002; 282: E435-E447Crossref PubMed Scopus (202) Google Scholar, 4Burguera B. Proctor D. Dietz N. Guo Z. Joyner M. Jensen M.D. Leg free fatty acid kinetics during exercise in men and women.Am. J. Physiol. Endocrinol. Metab. 2000; 278: E113-E117Crossref PubMed Google Scholar). This increase in skeletal muscle FA uptake during exercise results from a coordinated increase in rates of FA delivery, surface membrane FA transport, and intracellular substrate flux through mitochondrial β-oxidation or storage as intracellular lipids [for review, see (5Kiens B. Skeletal muscle lipid metabolism in exercise and insulin resistance.Physiol. Rev. 2006; 86: 205-243Crossref PubMed Scopus (336) Google Scholar)]. Skeletal muscle expresses multiple lipid binding proteins [for review, see (6Glatz J.F. Luiken J.J. Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease.Physiol. Rev. 2010.; 90: 367-417Crossref PubMed Scopus (516) Google Scholar)], such as the membrane-bound FA binding protein (7Stremmel W. Strohmeyer G. Borchard F. Kochwa S. Berk P.D. Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes.Proc. Natl. Acad. Sci. USA. 1985; 82: 4-8Crossref PubMed Scopus (289) Google Scholar), the FA transport proteins (FATP1 and FATP4) (8Schaffer J.E. Lodish H.F. Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein.Cell. 1994; 79: 427-436Abstract Full Text PDF PubMed Scopus (741) Google Scholar, 9Stahl A. Hirsch D.J. Gimeno R.E. Punreddy S. Ge P. Watson N. Patel S. Kotler M. Raimondi A. Tartaglia L.A. Identification of the major intestinal fatty acid transport protein.Mol. Cell. 1999; 4: 299-308Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar), and the FA translocase CD36 (FAT/CD36) (10Abumrad N.A. el-Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36.J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar), all of which have been implicated in the transsarcolemmal transport of FA uptake (9Stahl A. Hirsch D.J. Gimeno R.E. Punreddy S. Ge P. Watson N. Patel S. Kotler M. Raimondi A. Tartaglia L.A. Identification of the major intestinal fatty acid transport protein.Mol. Cell. 1999; 4: 299-308Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar, 11Bonen A. Han X.X. Habets D.D. Febbraio M. Glatz J.F. Luiken J.J. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar, D. Han X.X. J. Glatz J.F. Luiken J.J. J.J. Bonen A. of fatty acid binding protein in fatty acid transport and PubMed Scopus Google Scholar). The role of FAT/CD36 in long-chain FA plasma membrane transport is by uptake of the acid acid in muscle from with partial or total in FAT/CD36 protein T. T. T. T. F. in human long-chain fatty acid uptake is by FAT/CD36 Full Text Full Text PDF PubMed Google Scholar, T. T. M. CD36 and long-chain fatty acid uptake in the J. 2002; PubMed Scopus Google Scholar, S. T. S. T. F. C. H. A. CD36 long-chain fatty acid transport in human of long-chain fatty acid in subjects with CD36 Cell. 1999; PubMed Google Scholar). Furthermore, FA uptake in and skeletal muscle as as is in CD36 mice with wild-type (WT) A. Han X.X. Habets D.D. Febbraio M. Glatz J.F. Luiken J.J. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar, Febbraio M. N.A. uptake and utilization of long chain fatty acids in muscle and of CD36 Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). FAT/CD36 and other lipid binding proteins as regulators of FA transport by from intracellular to the plasma membrane in skeletal muscle in response to both muscle contractions J. P. Luiken J.J. Glatz J.F. Kiens B. not increase content in rat muscle Cell. PubMed Scopus Google Scholar, A. Luiken J.J. Glatz J.F. regulation of fatty acid uptake the of fatty acid Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google and of the AMP-dependent protein kinase by 5-aminoimidazole-4-carboxamide ribonucleoside J. P. Luiken J.J. Glatz J.F. Kiens B. not increase content in rat muscle Cell. PubMed Scopus Google Scholar). Furthermore, CD36 mice were to was that the increase in FA uptake was in CD36 mice with WT A. Han X.X. Habets D.D. Febbraio M. Glatz J.F. Luiken J.J. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar). In FA uptake skeletal muscle was increased during of J. AMPK not in muscle in J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar). a role of AMPK in the regulation of FAT/CD36 FA However, and have that FAT/CD36 translocation and in FA uptake are the rat is perfused with an of the kinase and of AMPK increase in plasma membrane FAT/CD36 content and FA uptake in Physiol. PubMed Scopus Google Scholar). The the for in to the FAT/CD36 and the FA uptake in skeletal the aim of this study was to investigate the molecular mechanisms regulating FAT/CD36 translocation in skeletal muscle during contractions. were from investigate the role of AMPK in the regulation of FAT/CD36 mice a AMPK by the and skeletal kinase as J. M. A role for protein kinase in and transport in skeletal Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The mice were a from J. of mice (AMPK KD) and WT mice of were and were from of mice and WT mice. In to the investigated the of FAT/CD36 translocation in relation to FA uptake and in skeletal the perfused rat were a and and were by the and with the for the of for and of rat and skeletal muscle was as in J. Kiens B. Richter E.A. of contraction of and in rat skeletal J. Physiol. Physiol. PubMed Scopus Google Scholar, M. G. P. M. A. protein in skeletal muscle J. Physiol. Google Scholar). The muscles were and free of and The muscles were and three a in and A of the was and for of The was for The was to and the was in of and for The which of was and the were through and in a for The was in with the of and and for by The was for The was and the was in with and a a and for in an were a and from the of the The of the was in with and and with the were A of to and was with and to of and The were a by for min, and for The was and A of was and for of protein to mice were three separate to to the mice were to in the for and were exercised by and the mice were a or an exercised mice were by and the muscles were and for as mice were an with a of with or were from the min, and min, mice were by and the muscles were and for as mice were with and the extensor digitorum longus (EDL) and soleus (SOL) muscles were to for muscle as Bonen A. D.J. acid and are in J. Physiol. Endocrinol. Metab. 2002; 282: PubMed Scopus Google Scholar, D.J. of in rat soleus muscle in response to J. Physiol. Endocrinol. Metab. 2000; PubMed Google Scholar). FA metabolism were Bonen A. D.J. acid and are in J. Physiol. Endocrinol. Metab. 2002; 282: PubMed Scopus Google Scholar, D.J. of in rat soleus muscle in response to J. Physiol. Endocrinol. Metab. 2000; PubMed Google Scholar). EDL and SOL muscles were in and acid acid was in and a was to the total to the with or the EDL and SOL muscle was for contraction the and of EDL and SOL muscles were with and to a in a an of min, the was with the with of FA metabolism was in the or of In contraction FA metabolism was in of EDL and SOL This contraction was been to FA metabolism in muscles D.J. Bonen A. contraction and and J. Physiol. PubMed Google Scholar). the of the contraction muscles were in and FA uptake was as the of to N. R. S. skeletal muscle fatty acid Physiol. PubMed Scopus Google and of acid and in the as Bonen A. D.J. acid and are in J. Physiol. Endocrinol. Metab. 2002; 282: PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar, D.D. E. B. Kiens B. Jensen Richter E.A. Bonen A. role for to in the regulation of long-chain fatty acid uptake PubMed Scopus Google Scholar). During muscle FAT/CD36 translocation to the plasma membrane been in rat muscle J. P. Luiken J.J. Glatz J.F. Kiens B. not increase content in rat muscle Cell. PubMed Scopus Google Scholar, A. Luiken J.J. Glatz J.F. regulation of fatty acid uptake the of fatty acid Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and the increase of FAT/CD36 in the plasma membrane been associated with an increase in FA transport A. Luiken J.J. Glatz J.F. regulation of fatty acid uptake the of fatty acid Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. J. Han X.X. L.A. Glatz J.F. transport of the membrane fatty acid transporters FAT/CD36 and with and and fatty acid and in rat skeletal Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the from muscle contractions been that AMPK could be a major of FAT/CD36 translocation in skeletal muscle A. Han X.X. Habets D.D. Febbraio M. Glatz J.F. Luiken J.J. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar, J. P. Luiken J.J. Glatz J.F. Kiens B. not increase content in rat muscle Cell. PubMed Scopus Google Scholar). In the that is not essential in regulation of FAT/CD36 during muscle FAT/CD36 protein content increased in cell surface and in the intracellular in both WT and AMPK KD mice of exercise the similar in to translocation exercise J. Jensen P. J.F. Richter E.A. of not muscle uptake during exercise in J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar). In the study by and were not increased in AMPK KD muscles during exercise the J. Jensen P. J.F. 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A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar, J. AMPK not in muscle in J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar, J. B. J.A. skeletal muscle not long-chain fatty acid uptake is PubMed Scopus Google Scholar). was that of increased FA uptake skeletal and muscle during a J. AMPK not in muscle in J. Physiol. Endocrinol. Metab. PubMed Scopus Google Scholar, J. B. J.A. skeletal muscle not long-chain fatty acid uptake is PubMed Scopus Google Scholar). the of AMPK FA uptake in skeletal SOL and EDL muscle from WT and AMPK KD mice and FA uptake ex vivo. FA uptake was similar in AMPK KD mice and WT in SOL and EDL both and during muscle contraction muscles were with FA uptake increased only in WT This suggests that AMPK could be a of FA uptake in skeletal to the of muscle were to the or and AMPK KD) induced increase in FA uptake was FAT/CD36 was in the perfused that increase in FA uptake was in CD36 mice with WT A. Han X.X. Habets D.D. Febbraio M. Glatz J.F. Luiken J.J. A null mutation in skeletal muscle FAT/CD36 reveals its essential role in insulin- and fatty acid J. Physiol. Endocrinol. Metab. 2007; 292: PubMed Scopus Google Scholar). this is similar in EDL and SOL muscle to be a of in FAT/CD36 translocation with ex FA uptake is the perfused rat to the of muscle contractions induced a rapid FAT/CD36 translocation that muscle contractions increased FA uptake in the perfused rat hindlimb, as differences in the rat that during muscle FA uptake and FAT/CD36 translocation in skeletal muscle are rapid and of The of increased FA with the rapid increase in FA uptake in the study the that plasma FA uptake in skeletal muscle is not for FA during the of muscle in human subjects B. van long-chain fatty acid content during exercise in J. Physiol. 1999; Google Scholar). the in the is that mechanisms other AMPK are in the regulation of FAT/CD36 translocation and FA uptake in skeletal In of and Regulation of FA uptake and by AMPK and is intensity in J. Physiol. Endocrinol. Metab. 2006; PubMed Scopus Google and AMPK is not in the regulation of muscle FA uptake and during muscle J. Physiol. Endocrinol. Metab. PubMed Scopus Google have that increased FA uptake and FA during muscle contractions of AMPK Furthermore, that be a of FAT/CD36 translocation and FA uptake increase in plasma membrane FAT/CD36 content and FA uptake in Physiol. PubMed Scopus Google Scholar). However, in the FAT/CD36 translocation in and AMPK that AMPK are essential for FAT/CD36 translocation or FA uptake during contraction in rat muscle the from the study AMPK as a of FAT/CD36 translocation other physiological the of FAT/CD36 translocation and in FA uptake in AMPK suggests that AMPK is not the of FA uptake in skeletal In to muscle is an for regulating metabolism and FAT/CD36 translocation and FA been that both and protein kinase were the of muscle contractions E.A. S. translocation of protein kinase in rat skeletal PubMed Scopus Google Scholar, Richter E.A. Regulation and of protein kinase of rat skeletal Physiol. 2007; PubMed Scopus Google Scholar). In with P. H. and B. and is an of protein kinase in regulation of substrate metabolism in skeletal J. Physiol. Physiol. PubMed Scopus Google that a of induced translocation of FAT/CD36 from intracellular to cell surface in and this was associated with an increase in FA uptake in the perfused rat hindlimb. In and that the increase in FA uptake in the perfused rat for the of and AMPK in regulating FA uptake and in Physiol. PubMed Scopus Google Scholar). one could that the rapid and sustained FAT/CD36 translocation and increase in FA uptake during muscle contraction could be by in However, been to increase uptake J.F. Richter E.A. uptake in soleus J. Physiol. Endocrinol. Metab. 2007; PubMed Scopus Google Scholar), a AMPK in be In P. H. and B. and E.A. S. translocation of protein kinase in rat skeletal PubMed Scopus Google have that other such as protein kinase are during muscle contractions E.A. S. translocation of protein kinase in rat skeletal PubMed Scopus Google Scholar), and that the role of in to FAT/CD36 translocation and FA metabolism In exercise induced a relocation of FAT/CD36 from intracellular to cell surface in skeletal muscle from both WT and AMPK KD mice. Furthermore, muscle contractions in induced a rapid and sustained FAT/CD36 relocation in the perfused rat to of In both the in cell surface FAT/CD36 protein was associated with an increase in FA This suggests that AMPK is not essential in regulation of FAT/CD36 translocation and FA uptake in skeletal muscle during contractions. However, induced a FAT/CD36 translocation in an AMPK could be important in the regulation of FAT/CD36 distribution The are to A. Richter and F. P. for and during the of this The the of B. and 5-aminoimidazole-4-carboxamide ribonucleoside AMP-dependent protein kinase acid protein kinase extensor digitorum longus kinase FA translocase CD36 FA transport protein soleus wild-type
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".