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

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 - 2015/1/1

Y1 - 2015/1/1

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. Acsl1M2/2 mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1M2/2 mice ran only 48%as far as controls. At the time that Acsl1M2/2 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 Acsl1M2/2 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 b-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. Acsl1M2/2 mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1M2/2 mice ran only 48%as far as controls. At the time that Acsl1M2/2 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 Acsl1M2/2 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 b-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

SN - 0012-1797

VL - 64

SP - 23

EP - 35

JO - Diabetes

JF - Diabetes

IS - 1

ER -