The obligatory role of carnitine palmitoyltransferase-I (CPT-I) in mediating mitochondrial lipid transport is well established, a process attenuated by malonyl-CoA (M-CoA). However, the necessity of reducing M-CoA concentrations to promote lipid oxidation has recently been challenged, suggesting external regulation on CPT-I. Since previous work in hepatocytes suggests the involvement of the intermediate filament fraction of the cytoskeleton in regulating CPT-I, we investigated in skeletal muscle if CPT-I sensitivity for M-CoA inhibition could be regulated by the intermediate filaments, and whether AMP-activated protein kinase (AMPK) could be involved in this process. Chemical disruption (3,3′-iminodipropionitrile, IDPN) of the intermediate filaments did not alter mitochondrial respiration or sensitivity for numerous substrates (palmitoyl-CoA, ADP, palmitoyl carnitine and pyruvate). In contrast, IDPN reduced CPT-I sensitivity for M-CoA inhibition in permeabilized muscle fibers, identifying M-CoA kinetics as a specific target for intermediate filament regulation. Importantly, exercise mimicked the effect of IDPN on M-CoA sensitivity, suggesting that intermediate filament disruption in vivo is physiologically important for CPT-I regulation. To ascertain a potential mechanism, since AMPK is activated during exercise, AMPK β1β2-KO mice were utilized in an attempt to ablate the observed exercise response. Unexpectedly, these mice displayed drastic attenuation in resting M-CoA sensitivity, such that exercise and IDPN could not further alter M-CoA sensitivity. These data suggest that AMPK is not required for the regulation of the intermediate filament interaction with CPT-I. Altogether, these data highlight that M-CoA sensitivity is important for regulating mitochondrial lipid transport. Moreover, M-CoA sensitivity appears to be regulated by intermediate filament interaction with CPT-I, a process that is important when metabolic homeostasis is challenged.
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February 2017
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Docking simulation predicts that the binding of CD81 extracellular domain-2 (EC2) to the RGD-binding site of integrin alphaVbeta3. CD81 EC2 (in red), integrin alphaV (in light green), and integrin beta3 (in purple). Please see pp. 589–596 for more information. Image provided by Yoshikazu Takada.
Research Article|
February 03 2017
Controlling skeletal muscle CPT-I malonyl-CoA sensitivity: the importance of AMPK-independent regulation of intermediate filaments during exercise
Paula M. Miotto;
1Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Rd East, Guelph, Ontario, Canada N1G 2W1
Correspondence: Paula M. Miotto (pmiotto@uoguelph.ca) or Graham P. Holloway (ghollowa@uoguelph.ca)
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Gregory R. Steinberg;
Gregory R. Steinberg
2Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
3Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5
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Graham P. Holloway
1Department of Human Health and Nutritional Sciences, University of Guelph, 50 Stone Rd East, Guelph, Ontario, Canada N1G 2W1
Correspondence: Paula M. Miotto (pmiotto@uoguelph.ca) or Graham P. Holloway (ghollowa@uoguelph.ca)
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Publisher: Portland Press Ltd
Received:
October 05 2016
Revision Received:
November 28 2016
Accepted:
December 08 2016
Accepted Manuscript online:
December 08 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (4): 557–569.
Article history
Received:
October 05 2016
Revision Received:
November 28 2016
Accepted:
December 08 2016
Accepted Manuscript online:
December 08 2016
Citation
Paula M. Miotto, Gregory R. Steinberg, Graham P. Holloway; Controlling skeletal muscle CPT-I malonyl-CoA sensitivity: the importance of AMPK-independent regulation of intermediate filaments during exercise. Biochem J 15 February 2017; 474 (4): 557–569. doi: https://doi.org/10.1042/BCJ20160913
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