Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Li, LO; Grevengoed, TJ; Paul, DS; Ilkayeva, O; Koves, TR; Pascual, F; Newgard, CB; Muoio, DM; Coleman, RA
Published Date
- January 2015
Published In
Volume / Issue
- 64 / 1
Start / End Page
- 23 - 35
PubMed ID
- 25071025
Pubmed Central ID
- PMC4274800
Electronic International Standard Serial Number (EISSN)
- 1939-327X
Digital Object Identifier (DOI)
- 10.2337/db13-1070
Language
- eng
Conference Location
- United States