Difference between revisions of "Smith 2012 Biochem J"
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{{Publication | {{Publication | ||
|title=Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Identification of a novel malonyl-CoA IC50 for CPT-I: implications for predicting ''in vivo'' fatty acid oxidation rates. Biochem J 448: 13-20. | |title=Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Identification of a novel malonyl-CoA IC50 for CPT-I: implications for predicting ''in vivo'' fatty acid oxidation rates. Biochem J 448:13-20. | ||
|info=[http://www.ncbi.nlm.nih.gov/pubmed/22928974 PMID: 22928974] | |info=[http://www.ncbi.nlm.nih.gov/pubmed/22928974 PMID: 22928974] | ||
|authors=Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP | |authors=Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP | ||
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|journal=Biochem J | |journal=Biochem J | ||
|abstract=Published values regarding the sensitivity (IC50) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted ''in vivo'' rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC50 (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC50 (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the ''in vivo'' disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes. | |abstract=Published values regarding the sensitivity (IC50) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted ''in vivo'' rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC50 (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC50 (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the ''in vivo'' disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes. | ||
|keywords=Type 2 diabetes, | |keywords=Type 2 diabetes, Skeletal muscle, Fatty acid oxidation | ||
|mipnetlab=CA Guelph Holloway GP | |mipnetlab=CA Guelph Holloway GP, CA Toronto Perry CG, US NC Durham Koves TR, US NC Greenville Neufer PD | ||
}} | }} | ||
{{Labeling | {{Labeling | ||
| | |area=Respiration | ||
|diseases=Diabetes | |||
|organism=Rat | |organism=Rat | ||
|tissues=Skeletal muscle | |tissues=Skeletal muscle | ||
|preparations=Permeabilized tissue, Isolated | |preparations=Permeabilized tissue, Isolated mitochondria | ||
|topics=Fatty acid | |||
|couplingstates=LEAK, OXPHOS | |couplingstates=LEAK, OXPHOS | ||
| | |instruments=Oxygraph-2k | ||
}} | }} | ||
Latest revision as of 14:46, 28 March 2018
| Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Identification of a novel malonyl-CoA IC50 for CPT-I: implications for predicting in vivo fatty acid oxidation rates. Biochem J 448:13-20. |
Smith BK, Perry CG, Koves TR, Wright DC, Smith JC, Neufer PD, Muoio DM, Holloway GP (2012) Biochem J
Abstract: Published values regarding the sensitivity (IC50) of CPT-I (carnitine palmitoyltransferase I) to M-CoA (malonyl-CoA) inhibition in isolated mitochondria are inconsistent with predicted in vivo rates of fatty acid oxidation. Therefore we have re-examined M-CoA inhibition kinetics under various P-CoA (palmitoyl-CoA) concentrations in both isolated mitochondria and PMFs (permeabilized muscle fibres). PMFs have an 18-fold higher IC50 (0.61 compared with 0.034 μM) in the presence of 25 μM P-CoA and a 13-fold higher IC50 (6.3 compared with 0.49 μM) in the presence of 150 μM P-CoA compared with isolated mitochondria. M-CoA inhibition kinetics determined in PMFs predicts that CPT-I activity is inhibited by 33% in resting muscle compared with >95% in isolated mitochondria. Additionally, the ability of M-CoA to inhibit CPT-I appears to be dependent on P-CoA concentration, as the relative inhibitory capacity of M-CoA is decreased with increasing P-CoA concentrations. Altogether, the use of PMFs appears to provide an M-CoA IC50 that better reflects the predicted in vivo rates of fatty acid oxidation. These findings also demonstrate that the ratio of [P-CoA]/[M-CoA] is critical for regulating CPT-I activity and may partially rectify the in vivo disconnect between M-CoA content and CPT-I flux within the context of exercise and Type 2 diabetes. • Keywords: Type 2 diabetes, Skeletal muscle, Fatty acid oxidation
• O2k-Network Lab: CA Guelph Holloway GP, CA Toronto Perry CG, US NC Durham Koves TR, US NC Greenville Neufer PD
Labels: MiParea: Respiration
Pathology: Diabetes
Organism: Rat Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue, Isolated mitochondria
Regulation: Fatty acid Coupling state: LEAK, OXPHOS
HRR: Oxygraph-2k
