Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise

Hayley M O'Neill, James S Lally, Sandra Galic, Thomas Pulinilkunnil, Rebecca J Ford, Jason R B Dyck, Bryce J van Denderen, Bruce E Kemp, Gregory R Steinberg

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Abstract

During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions.

Original languageEnglish
Article numbere12444
JournalPhysiological Reports
Volume3
Issue number7
DOIs
Publication statusPublished - Jul 2015

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Acetyl-CoA Carboxylase
Skeletal Muscle
Fatty Acids
Phosphorylation
Malonyl Coenzyme A
Muscle Contraction
AMP-Activated Protein Kinases
Muscles
Protein Isoforms
Carnitine O-Palmitoyltransferase
Acyl Coenzyme A
Metformin
Running
Mitochondria
Pharmacology
Enzymes

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O'Neill, H. M., Lally, J. S., Galic, S., Pulinilkunnil, T., Ford, R. J., Dyck, J. R. B., ... Steinberg, G. R. (2015). Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. Physiological Reports, 3(7), [e12444]. https://doi.org/10.14814/phy2.12444
O'Neill, Hayley M ; Lally, James S ; Galic, Sandra ; Pulinilkunnil, Thomas ; Ford, Rebecca J ; Dyck, Jason R B ; van Denderen, Bryce J ; Kemp, Bruce E ; Steinberg, Gregory R. / Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. In: Physiological Reports. 2015 ; Vol. 3, No. 7.
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title = "Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise",
abstract = "During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions.",
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O'Neill, HM, Lally, JS, Galic, S, Pulinilkunnil, T, Ford, RJ, Dyck, JRB, van Denderen, BJ, Kemp, BE & Steinberg, GR 2015, 'Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise' Physiological Reports, vol. 3, no. 7, e12444. https://doi.org/10.14814/phy2.12444

Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. / O'Neill, Hayley M; Lally, James S; Galic, Sandra; Pulinilkunnil, Thomas; Ford, Rebecca J; Dyck, Jason R B; van Denderen, Bryce J; Kemp, Bruce E; Steinberg, Gregory R.

In: Physiological Reports, Vol. 3, No. 7, e12444, 07.2015.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise

AU - O'Neill, Hayley M

AU - Lally, James S

AU - Galic, Sandra

AU - Pulinilkunnil, Thomas

AU - Ford, Rebecca J

AU - Dyck, Jason R B

AU - van Denderen, Bryce J

AU - Kemp, Bruce E

AU - Steinberg, Gregory R

N1 - © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

PY - 2015/7

Y1 - 2015/7

N2 - During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions.

AB - During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl-CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT-1); the primary enzyme controlling fatty acyl-CoA flux into mitochondria for oxidation. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl-CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans-ACC2-knock-in [ACC2-KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock-in [ACCD-KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2-KI mice had normal exercise capacity and whole-body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl-CoA. Similar results were observed in ACCD-KI mice. Fatty acid oxidation was also maintained in muscles from ACC2-KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions.

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DO - 10.14814/phy2.12444

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