Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis
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Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis. / Li, Lei O; Grevengoed, Trisha J; Paul, David S; Ilkayeva, Olga; Koves, Timothy R; Pascual, Florencia; Newgard, Christopher B; Muoio, Deborah M; Coleman, Rosalind A.
In: Diabetes, Vol. 64, No. 1, 01.2015, p. 23-35.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis
AU - Li, Lei O
AU - Grevengoed, Trisha J
AU - Paul, David S
AU - Ilkayeva, Olga
AU - Koves, Timothy R
AU - Pascual, Florencia
AU - Newgard, Christopher B
AU - Muoio, Deborah M
AU - Coleman, Rosalind A
N1 - © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
KW - Animals
KW - Blood Glucose
KW - Cell Compartmentation
KW - Cerebral Cortex
KW - Coenzyme A
KW - Coenzyme A Ligases
KW - Fasting
KW - Fatty Acids
KW - Female
KW - Gluconeogenesis
KW - Homeostasis
KW - Hypoglycemia
KW - Liver
KW - Male
KW - Metabolomics
KW - Mice, Knockout
KW - Muscle, Skeletal
KW - Oxidation-Reduction
KW - Physical Endurance
KW - Pregnancy
KW - Signal Transduction
U2 - 10.2337/db13-1070
DO - 10.2337/db13-1070
M3 - Journal article
C2 - 25071025
VL - 64
SP - 23
EP - 35
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 1
ER -
ID: 146698721