Comprehensive Physiology Wiley Online Library

Regulation of Glucose Metabolism in Skeletal Muscle

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Abstract

The sections in this article are:

1 Glucose Phosphorylation by Hexokinase
2 Glycogen Metabolism
2.1 Enzymes of Glycogen Metabolism
2.2 Structural Organization of Glycogen Metabolism
2.3 Coordinate Regulation of Glycogen Metabolism
2.4 Signaling Pathways for Hormonal Regulation of Glycogen Metabolism
3 Regulation of Glycolysis
4 Metabolism of Pyruvate
5 Energy Yield of Glycolysis and Glucose Oxidation
6 Regulation of Glucose Oxidation
6.1 Pyruvate Dehydrogenase
6.2 Control of Flux Through the Tricarboxylic Acid Cycle
6.3 Glucose Fatty Acid Cycle
7 Metabolism of Glucose via the Hexosamine Pathway
8 Summary
Figure 1. Figure 1.

Steps of glycogen synthesis and breakdown in skeletal muscle. Key enzymes are indicated in bold type. UTP, uridine triphosphate; UDP‐glucose, uridine diphosphoglucose; UDPG pyrophosphorylase, uridine diphosphoglucose pyrophosphorylase; Pi, inorganic phosphate; PPi, inorganic pyrophosphate.

Figure 2. Figure 2.

Phosphorylation and dephosphorylation reactions in the regulation of glycogen synthesis. PP1G, protein phosphatase‐1G; PKA, AMP‐dependent protein kinase A; GS, glycogen synthase; CaMPK, calmodulin‐dependent protein kinase; PhK, phosphorylase kinase; GsK, glycogen synthase kinase.

Figure 3. Figure 3.

Phosphorylation and dephosphorylation reactions leading to stimulation of glycogenolysis. AC, adenylate cyclase; PKA, AMP‐dependent protein kinase; PhK, phosphorylase kinase; Pha and Phb, phosphorylases a and b; PP1G, protein phosphatase‐1G.

Figure 4. Figure 4.

The tricarboxylic acid (TCA) cycle. Only acetyl CoA can be oxidized by the TCA cycle. Intermediates such as glutamine, aspartate, and branched‐chain amino acids, which can give rise to TCA cycle intermediates, must first be converted to oxaloacetate, which is removed from the cycle and converted to pyruvate [via phosphoenolpyruvate (PEP)] and finally to acetyl CoA. The main flux‐generating steps are citrate synthase (2), NAD+‐isocitrate dehydrogenase (3), and 2‐oxoglutarate dehydrogenase (4) reactions. These enzymes are regulated in a coordinated manner. Low NADH:NAD+ and ATP:ADP ratios increase flux through the cycle to a large extent by allosteric effects on these three enzymes. Capacity of the cycle is also determined by the content of intermediates and, hence, the availability of oxaloacetate for condensation with acetyl CoA. Isocitrate dehydrogenase, 2‐oxoglutarate dehydrogenase, and pyruvate dehydrogenase are activated by physiological calcium concentrations. In skeletal and cardiac muscle, the increase in mitochondrial calcium in response to catecholamines and neural stimulation/muscle contraction increases the generation of acetyl CoA from pyruvate by effects on pyruvate dehydrogenase and the rate of acetyl CoA oxidation by the cycle.Key to numbered enzymes

Pyruvate dehydrogenase

Citrate synthase

NAD‐isocitrate dehydrogenase

2‐Oxoglutarate dehydrogenase

Succinyl CoA synthase

Succinate dehydrogenase

Malate dehydrogenase

Figure 5. Figure 5.

Regulation of the pyruvate dehydrogenase (PDH) complex by reversible phosphorylation. The products of the reaction, acetyl CoA and NADH, in addition to activating the kinase and thereby increasing the proportion of inactive PDH phosphate, allosterically inhibit the activity of the dephosphorylated enzyme. Activation of PDH in response to catecholamines and enhanced muscle contraction in skeletal muscle and heart is mediated by calcium. Calcium also mediates the stimulatory effects of insulin on PDH in adipose tissue but not in skeletal muscle. Pi, inorganic phosphate.

Figure 6. Figure 6.

The hexosamine pathway of glucose metabolism. Glutamine‐fructose‐6‐phosphate amidotransferase (GFAT) is the first and rate‐limiting step in this pathway.



Figure 1.

Steps of glycogen synthesis and breakdown in skeletal muscle. Key enzymes are indicated in bold type. UTP, uridine triphosphate; UDP‐glucose, uridine diphosphoglucose; UDPG pyrophosphorylase, uridine diphosphoglucose pyrophosphorylase; Pi, inorganic phosphate; PPi, inorganic pyrophosphate.



Figure 2.

Phosphorylation and dephosphorylation reactions in the regulation of glycogen synthesis. PP1G, protein phosphatase‐1G; PKA, AMP‐dependent protein kinase A; GS, glycogen synthase; CaMPK, calmodulin‐dependent protein kinase; PhK, phosphorylase kinase; GsK, glycogen synthase kinase.



Figure 3.

Phosphorylation and dephosphorylation reactions leading to stimulation of glycogenolysis. AC, adenylate cyclase; PKA, AMP‐dependent protein kinase; PhK, phosphorylase kinase; Pha and Phb, phosphorylases a and b; PP1G, protein phosphatase‐1G.



Figure 4.

The tricarboxylic acid (TCA) cycle. Only acetyl CoA can be oxidized by the TCA cycle. Intermediates such as glutamine, aspartate, and branched‐chain amino acids, which can give rise to TCA cycle intermediates, must first be converted to oxaloacetate, which is removed from the cycle and converted to pyruvate [via phosphoenolpyruvate (PEP)] and finally to acetyl CoA. The main flux‐generating steps are citrate synthase (2), NAD+‐isocitrate dehydrogenase (3), and 2‐oxoglutarate dehydrogenase (4) reactions. These enzymes are regulated in a coordinated manner. Low NADH:NAD+ and ATP:ADP ratios increase flux through the cycle to a large extent by allosteric effects on these three enzymes. Capacity of the cycle is also determined by the content of intermediates and, hence, the availability of oxaloacetate for condensation with acetyl CoA. Isocitrate dehydrogenase, 2‐oxoglutarate dehydrogenase, and pyruvate dehydrogenase are activated by physiological calcium concentrations. In skeletal and cardiac muscle, the increase in mitochondrial calcium in response to catecholamines and neural stimulation/muscle contraction increases the generation of acetyl CoA from pyruvate by effects on pyruvate dehydrogenase and the rate of acetyl CoA oxidation by the cycle.Key to numbered enzymes

Pyruvate dehydrogenase

Citrate synthase

NAD‐isocitrate dehydrogenase

2‐Oxoglutarate dehydrogenase

Succinyl CoA synthase

Succinate dehydrogenase

Malate dehydrogenase



Figure 5.

Regulation of the pyruvate dehydrogenase (PDH) complex by reversible phosphorylation. The products of the reaction, acetyl CoA and NADH, in addition to activating the kinase and thereby increasing the proportion of inactive PDH phosphate, allosterically inhibit the activity of the dephosphorylated enzyme. Activation of PDH in response to catecholamines and enhanced muscle contraction in skeletal muscle and heart is mediated by calcium. Calcium also mediates the stimulatory effects of insulin on PDH in adipose tissue but not in skeletal muscle. Pi, inorganic phosphate.



Figure 6.

The hexosamine pathway of glucose metabolism. Glutamine‐fructose‐6‐phosphate amidotransferase (GFAT) is the first and rate‐limiting step in this pathway.

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Yolanta T. Kruszynska, Theodore P. Ciaraldi, Robert R. Henry. Regulation of Glucose Metabolism in Skeletal Muscle. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 579-607. First published in print 2001. doi: 10.1002/cphy.cp070218