Compartmentalized Acyl-CoA Metabolism in Skeletal Muscle Regulates Systemic Glucose Homeostasis

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. Acsl1M−/− mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1M−/− mice ran only 48% as far as controls. At the time that Acsl1M−/− 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 Acsl1M−/− 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.

[1]  P. Sachs,et al.  Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients , 2013, Journal of Inherited Metabolic Disease.

[2]  S. Jackowski,et al.  Compartmentalization of Mammalian Pantothenate Kinases , 2012, PloS one.

[3]  M. Watt,et al.  Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. , 2012, American journal of physiology. Endocrinology and metabolism.

[4]  E. Ravussin,et al.  Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. , 2012, Cell metabolism.

[5]  Herman I. May,et al.  Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis , 2012, Nature.

[6]  L. Nybo,et al.  Enhanced Fatty Acid Oxidation and FATP4 Protein Expression after Endurance Exercise Training in Human Skeletal Muscle , 2012, PloS one.

[7]  R. Coleman,et al.  Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments. , 2012, American journal of physiology. Endocrinology and metabolism.

[8]  M. Okamoto,et al.  Brain glycogen decreases during prolonged exercise. , 2011, The Journal of physiology.

[9]  C. Hoppel,et al.  Mitochondrial Carnitine Palmitoyltransferase 1a (CPT1a) Is Part of an Outer Membrane Fatty Acid Transfer Complex* , 2011, The Journal of Biological Chemistry.

[10]  R. Coleman,et al.  Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy , 2011, Molecular and Cellular Biology.

[11]  K. Frayn Fat as a fuel: emerging understanding of the adipose tissue–skeletal muscle axis , 2010, Acta physiologica.

[12]  Olga Ilkayeva,et al.  Adipose acyl-CoA synthetase-1 directs fatty acids toward beta-oxidation and is required for cold thermogenesis. , 2010, Cell metabolism.

[13]  C. Rock,et al.  Pantothenate Kinase 1 Is Required to Support the Metabolic Transition from the Fed to the Fasted State , 2010, PloS one.

[14]  P. A. Wood,et al.  Mitochondrial fatty acid oxidation disorders: pathophysiological studies in mouse models , 2010, Journal of Inherited Metabolic Disease.

[15]  R. Coleman,et al.  Acyl-coenzyme A synthetases in metabolic control , 2010, Current opinion in lipidology.

[16]  Gary W. Cline,et al.  Glycerol-3-Phosphate Acyltransferase 1 Deficiency in ob/ob Mice Diminishes Hepatic Steatosis but Does Not Protect Against Insulin Resistance or Obesity , 2010, Diabetes.

[17]  R. Coleman,et al.  Acyl-CoA synthesis, lipid metabolism and lipotoxicity. , 2010, Biochimica et biophysica acta.

[18]  Richard Barnett Diabetes , 1904, The Lancet.

[19]  Shuli Wang,et al.  Liver-specific Loss of Long Chain Acyl-CoA Synthetase-1 Decreases Triacylglycerol Synthesis and β-Oxidation and Alters Phospholipid Fatty Acid Composition* , 2009, The Journal of Biological Chemistry.

[20]  G. Steinberg Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exercise. , 2009, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[21]  K. Sahlin,et al.  Control of lipid oxidation during exercise: role of energy state and mitochondrial factors , 2008, Acta physiologica.

[22]  Elias Chaibub Neto,et al.  Genetic Networks of Liver Metabolism Revealed by Integration of Metabolic and Transcriptional Profiling , 2008, PLoS genetics.

[23]  M. Hunt,et al.  Short- and medium-chain carnitine acyltransferases and acyl-CoA thioesterases in mouse provide complementary systems for transport of β-oxidation products out of peroxisomes , 2008, Cellular and Molecular Life Sciences.

[24]  P. Watkins Very-long-chain Acyl-CoA Synthetases* , 2008, Journal of Biological Chemistry.

[25]  G. Shulman,et al.  Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance , 2007, Proceedings of the National Academy of Sciences.

[26]  J. van der Greef,et al.  Metabolomics (liver and blood profiling) in a mouse model in response to fasting: a study of hepatic steatosis. , 2007, Biochimica et biophysica acta.

[27]  R. Cortright,et al.  Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance. , 2007, American journal of physiology. Endocrinology and metabolism.

[28]  T. Stellingwerff,et al.  Significant intramyocellular lipid use during prolonged cycling in endurance-trained males as assessed by three different methodologies. , 2007, American journal of physiology. Endocrinology and metabolism.

[29]  G. Bray,et al.  Family History of Diabetes Links Impaired Substrate Switching and Reduced Mitochondrial Content in Skeletal Muscle , 2007, Diabetes.

[30]  R. Rector,et al.  Metabolic inflexibility in skeletal muscle: a prelude to the cardiometabolic syndrome? , 2006, Journal of the cardiometabolic syndrome.

[31]  Bente Kiens,et al.  Skeletal muscle lipid metabolism in exercise and insulin resistance. , 2006, Physiological reviews.

[32]  David Millington,et al.  Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance , 2004, Nature Medicine.

[33]  N. Secher,et al.  Cerebral perturbations provoked by prolonged exercise , 2004, Progress in Neurobiology.

[34]  F. A. Wijburg,et al.  Disorders of mitochondrial fatty acyl-CoA β-oxidation , 1999, Journal of Inherited Metabolic Disease.

[35]  U. Müller,et al.  Beta1 integrins regulate myoblast fusion and sarcomere assembly. , 2003, Developmental cell.

[36]  W. Kraus,et al.  Fatty Acid Homeostasis and Induction of Lipid Regulatory Genes in Skeletal Muscles of Peroxisome Proliferator-activated Receptor (PPAR) α Knock-out Mice , 2002, The Journal of Biological Chemistry.

[37]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[38]  T. M. Lewin,et al.  Acyl-CoA Synthetase Isoforms 1, 4, and 5 Are Present in Different Subcellular Membranes in Rat Liver and Can Be Inhibited Independently* , 2001, The Journal of Biological Chemistry.

[39]  D. Zheng,et al.  Muscle Glucose Transporter (GLUT 4) Gene Expression during Exercise , 2000, Exercise and sport sciences reviews.

[40]  L. Mandarino,et al.  Fuel selection in human skeletal muscle in insulin resistance: a reexamination. , 2000, Diabetes.

[41]  M. Rennie,et al.  Protein and amino acid metabolism during and after exercise and the effects of nutrition. , 2000, Annual review of nutrition.

[42]  W. Wahli,et al.  Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting , 1999 .

[43]  J. Schaffer,et al.  Localization of adipocyte long-chain fatty acyl-CoA synthetase at the plasma membrane. , 1999, Journal of lipid research.

[44]  W. Wahli,et al.  Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. , 1999, The Journal of clinical investigation.

[45]  A H van Gennip,et al.  Disorders of mitochondrial fatty acyl-CoA beta-oxidation. , 1999, Journal of inherited metabolic disease.

[46]  W. Kohrt,et al.  The regulation of carbohydrate and fat metabolism during and after exercise. , 1998, Frontiers in bioscience : a journal and virtual library.

[47]  J. Auwerx,et al.  Coordinate Regulation of the Expression of the Fatty Acid Transport Protein and Acyl-CoA Synthetase Genes by PPARα and PPARγ Activators* , 1997, The Journal of Biological Chemistry.

[48]  G. Dohm,et al.  Protein degradation during endurance exercise and recovery. , 1987, Medicine and science in sports and exercise.

[49]  W. Winder,et al.  Epinephrine, glucose, and lactate infusion in exercising adrenodemedullated rats. , 1987, Journal of applied physiology.

[50]  C. Franzini-armstrong,et al.  Myology: Basic and clinical , 1986 .

[51]  R. Bell,et al.  Limited palmitoyl-CoA penetration into microsomal vesicles as evidenced by a highly latent ethanol acyltransferase activity. , 1978, The Journal of biological chemistry.

[52]  J. Passonneau,et al.  A comparison of three methods of glycogen measurement in tissues. , 1974, Analytical biochemistry.

[53]  J. Folch,et al.  A simple method for the isolation and purification of total lipides from animal tissues. , 1957, The Journal of biological chemistry.