PMID- 25071025
OWN - NLM
STAT- MEDLINE
DCOM- 20150311
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 64
IP  - 1
DP  - 2015 Jan
TI  - Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic 
      glucose homeostasis.
PG  - 23-35
LID - 10.2337/db13-1070 [doi]
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  approximately 40 mg/dL, whereas glucose concentrations in controls were 
       approximately 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 beta-oxidation. This compartmentalization of 
      acyl-CoAs resulted in both an excessive glucose requirement and severely 
      compromised systemic glucose homeostasis.
CI  - (c) 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.
FAU - Li, Lei O
AU  - Li LO
AD  - Department of Nutrition, University of North Carolina, Chapel Hill, NC.
FAU - Grevengoed, Trisha J
AU  - Grevengoed TJ
AD  - Department of Nutrition, University of North Carolina, Chapel Hill, NC.
FAU - Paul, David S
AU  - Paul DS
AD  - Department of Nutrition, University of North Carolina, Chapel Hill, NC.
FAU - Ilkayeva, Olga
AU  - Ilkayeva O
AD  - Sarah W. Stedman Nutrition and Metabolism Center, and Departments of Medicine and 
      Pharmacology and Cancer Biology, Duke University, Durham, NC.
FAU - Koves, Timothy R
AU  - Koves TR
AD  - Sarah W. Stedman Nutrition and Metabolism Center, and Departments of Medicine and 
      Pharmacology and Cancer Biology, Duke University, Durham, NC.
FAU - Pascual, Florencia
AU  - Pascual F
AD  - Department of Nutrition, University of North Carolina, Chapel Hill, NC.
FAU - Newgard, Christopher B
AU  - Newgard CB
AD  - Sarah W. Stedman Nutrition and Metabolism Center, and Departments of Medicine and 
      Pharmacology and Cancer Biology, Duke University, Durham, NC.
FAU - Muoio, Deborah M
AU  - Muoio DM
AD  - Sarah W. Stedman Nutrition and Metabolism Center, and Departments of Medicine and 
      Pharmacology and Cancer Biology, Duke University, Durham, NC.
FAU - Coleman, Rosalind A
AU  - Coleman RA
AD  - Department of Nutrition, University of North Carolina, Chapel Hill, NC 
      rcoleman@unc.edu.
LA  - eng
GR  - T32HL069768/HL/NHLBI NIH HHS/United States
GR  - DK59935/DK/NIDDK NIH HHS/United States
GR  - P30DK56350/DK/NIDDK NIH HHS/United States
GR  - AG028930/AG/NIA NIH HHS/United States
GR  - DK058398/DK/NIDDK NIH HHS/United States
GR  - R01 DK059935/DK/NIDDK NIH HHS/United States
GR  - P01 DK058398/DK/NIDDK NIH HHS/United States
GR  - R01 AG028930/AG/NIA NIH HHS/United States
GR  - T32 HL069768/HL/NHLBI NIH HHS/United States
GR  - P30 DK056350/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140728
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Blood Glucose)
RN  - 0 (Fatty Acids)
RN  - EC 6.2.1.- (ACSL1 protein, mouse)
RN  - EC 6.2.1.- (Coenzyme A Ligases)
RN  - SAA04E81UX (Coenzyme A)
SB  - IM
MH  - Animals
MH  - Blood Glucose/*metabolism
MH  - Cell Compartmentation/physiology
MH  - Cerebral Cortex/metabolism
MH  - Coenzyme A/metabolism
MH  - Coenzyme A Ligases/*genetics/*metabolism
MH  - Fasting/metabolism
MH  - Fatty Acids/metabolism
MH  - Female
MH  - Gluconeogenesis/*physiology
MH  - Homeostasis/physiology
MH  - Hypoglycemia/genetics/metabolism
MH  - Liver/metabolism
MH  - Male
MH  - Metabolomics
MH  - Mice, Knockout
MH  - Muscle, Skeletal/*enzymology
MH  - Oxidation-Reduction
MH  - Physical Endurance/physiology
MH  - Pregnancy
MH  - Signal Transduction/physiology
PMC - PMC4274800
EDAT- 2014/07/30 06:00
MHDA- 2015/03/12 06:00
PMCR- 2016/01/01
CRDT- 2014/07/30 06:00
PHST- 2014/07/30 06:00 [entrez]
PHST- 2014/07/30 06:00 [pubmed]
PHST- 2015/03/12 06:00 [medline]
PHST- 2016/01/01 00:00 [pmc-release]
AID - db13-1070 [pii]
AID - 1070 [pii]
AID - 10.2337/db13-1070 [doi]
PST - ppublish
SO  - Diabetes. 2015 Jan;64(1):23-35. doi: 10.2337/db13-1070. Epub 2014 Jul 28.