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Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

Publication ,  Journal Article
Li, LO; Grevengoed, TJ; Paul, DS; Ilkayeva, O; Koves, TR; Pascual, F; Newgard, CB; Muoio, DM; Coleman, RA
Published in: Diabetes
January 2015

The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis.

Duke Scholars

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

January 2015

Volume

64

Issue

1

Start / End Page

23 / 35

Location

United States

Related Subject Headings

  • Signal Transduction
  • Pregnancy
  • Physical Endurance
  • Oxidation-Reduction
  • Muscle, Skeletal
  • Mice, Knockout
  • Metabolomics
  • Male
  • Liver
  • Hypoglycemia
 

Citation

APA
Chicago
ICMJE
MLA
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Li, L. O., Grevengoed, T. J., Paul, D. S., Ilkayeva, O., Koves, T. R., Pascual, F., … Coleman, R. A. (2015). Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. Diabetes, 64(1), 23–35. https://doi.org/10.2337/db13-1070
Li, Lei O., Trisha J. Grevengoed, David S. Paul, Olga Ilkayeva, Timothy R. Koves, Florencia Pascual, Christopher B. Newgard, Deborah M. Muoio, and Rosalind A. Coleman. “Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.Diabetes 64, no. 1 (January 2015): 23–35. https://doi.org/10.2337/db13-1070.
Li LO, Grevengoed TJ, Paul DS, Ilkayeva O, Koves TR, Pascual F, et al. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. Diabetes. 2015 Jan;64(1):23–35.
Li, Lei O., et al. “Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.Diabetes, vol. 64, no. 1, Jan. 2015, pp. 23–35. Pubmed, doi:10.2337/db13-1070.
Li LO, Grevengoed TJ, Paul DS, Ilkayeva O, Koves TR, Pascual F, Newgard CB, Muoio DM, Coleman RA. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. Diabetes. 2015 Jan;64(1):23–35.

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

January 2015

Volume

64

Issue

1

Start / End Page

23 / 35

Location

United States

Related Subject Headings

  • Signal Transduction
  • Pregnancy
  • Physical Endurance
  • Oxidation-Reduction
  • Muscle, Skeletal
  • Mice, Knockout
  • Metabolomics
  • Male
  • Liver
  • Hypoglycemia