Glycogen metabolism in muscle

Figure 7.5 Glycogen metabolism in muscle (compare with Figure 6.22)...

Fig. 7.18. Regulation of glycogen metabolism in muscle. Phosphorylase kinase stands at the center of regulation of glycogen metabolism. Phosphorylase kinase may exist in an active, phosphorylated form and an inactive, unphosphorylated form. Phosphorylation of phosphorylase kinase is triggered by hormonal signals (e.g. adrenahne) and takes place via an activation of protein kinase A in the cAMP pathway. In the absence of hormonal stimulation, phosphorylase kinase can also be activated by an increase in cytosolic Ca. The active phosphorylase kinase stimulates glycogen degradation and inhibits glycogen synthesis, in that, on the one side, it activates glycogen phosphorylase by phosphorylation, and on the other side, it inactivates glycogen synthase by phosphorylation.

Recently Exton and co-workers [93] have proposed that adrenergic responsiveness in skeletal muscle is regulated by thyroid hormones at two levels, i.e., 1) stimulation of /3-adrenergic receptors and adenylate cyclase activity and 2) increased activity of phosphoprotein phosphatases. Such results would explain the effect of thyroid hormones on glycogen metabolism in muscle although the primary mechanism of these actions remains unknown. 

Figures 15-11 and 15-12 provide a model for the regulation of glycogen metabolism in muscle. This model is consistent with many of the known facts, but alternative interpretations are equally plausible. Only two of the external stimuli that affect muscle glycogen metabolism are considered in these figures.

Donahue, M. J., Yacoub, N. J. and Harris, B. G. (1982) Correlation of muscle activity with glycogen metabolism in muscle of Ascaris suum. Am. J. Physiol. 242 R514-R521. 

Describe the major compositional features of phosphorylase kinase and its activation by protein kinase A (PKA). Explain the effects of calmodulin and Ca on glycogen metabolism in muscle and liver. 

Inherited deficiencies in specific enzymes of glycogen metabolism in both liver and muscle are the causes of glycogen storage diseases. 

The current state of Ser/Thr phosphorylation of a protein is determined by the relative activity of Ser/Thr-specific protein kinase and protein phosphatase. It is therefore imderstandable that the cell has had to develop special mechanisms to balance the two activities with one another, and, when needed, to allow kinase or phosphatase activity to dominate. One of the best investigated examples of coordinated activity of protein kinases and protein phosphatases is the regulation of glycogen metabolism in skeletal muscle. Glycogen metabolism is an example of how two different signals, namely a cAMP signal and a Ca signal meet in one metabolic pathway and control the activity of one and the same enzyme. 

Groop L. The effect of (steroid) immunosuppression on skeletal muscle glycogen metabolism in patients after kid- 292. ney transplantation. Transplantation 1996 61(6) 889-93. 

During glycogen degradation in muscle, the main aim is to produce energy quickly and so the glucose 6-phosphate is metabolized immediately via glycolysis. This tissue does not contain glucose 6-phosphatase. 

Antoniw, J. F., Nimmo, H. G., teaman, S. J., and Cohen, P. (1977). Comparison of the Substrate Specificities of Protein Phosphatases Involved in the Regulation of Glycogen Metabolism in Rabbit Skeletal Muscle. Biochem J 162 423. 

As noted previously, like skeletal muscle, glycogen depletion in liver during endurance exercise is much less in trained animals and in animals who have had free fatty acids artificially elevated. No evidence exists that the mechanism proposed by Randle to account for the inhibition of carbohydrate metabolism in muscle by oxidation of fatty acids is operative in the liver. Thus other factors must be responsible for the slower rate of liver glycogen depletion in these situations. Such factors may include a smaller increase in catecholamine levels, a smaller reduction in insulin levels, and a smaller reduction in blood flow to the liver during exercise (19,20). 

Protein phosphatase-1 (Mg +/ATP-dependent phosphatase multisubstrate protein phosphatase M.W. of catalytic subunit is 35,000 major enzyme in regulation of glycogen metabolism in skeletal muscle dephosphorylates glycogen phosphorylase, jS-subunit of phosphorylase kinase, and at least three sites of glycogen synthase regulated by inhibitor-1, inhibitor-2, and GSK-3 -t- Mg +- ATP). 

Possible mechanism for regulation of glycogen metabolism in skeletal muscle by changes in cytosolic calcium. Increased glycogen breakdown may be coordinated with muscle contractions, as indicated here. The actual control scheme is probably more complicated, since phosphoprotein phosphatases are also involved. Interactions with cAMP-activated reactions, which also may complicate regulation, are not included. 

Whether glycogen synthase is a substrate for phosphorylase kinase in vivo is unclear. [Modified and reproduced with permission from P. Cohen, Protein phosphorylation and the control of glycogen metabolism in skeletal muscle. Philos. Trans. R. Soc. Land. (Biol.) 302, 13 (1983).]... 

Protein phosphatases-1, 2 A, 2B, and 2C occur in mammalian liver and, as in skeletal muscle, possess essentially all of the phosphatase activity toward enzymes and regulatory proteins of glycogen metabolism. In liver, however, the ratios of the activities of phosphatase-2A and 2C to that of phosphatase-1 are seven-fold higher than in muscle. Although protein phosphatase-I sediments with glycogen particles in both tissues, a much smaller fraction is glycogen-associated in liver than in muscle. The specific activity of phosphatase-2B is lower in liver than in muscle. Protein phosphatase inhibitors-1 and 2 have been identified in liver, where they appear to function as they do in muscle. A disinhibitor protein (M. W. 9,000) of liver can block the effects of inhibitors-1 and 2 on phosphatase-1. 

Serotonin appears to be an important regulator of glycogen metabolism in most parasitic helminths. In flatworms, such as Fasciota hepatica or Schistosoma mansoni, serotonin stimulates both glycogen breakdown and muscle contraction in nematodes, such as A. suum, only glycogen breakdown is affected. In F. hepatica, the serotonin... 

Fig. 43.6. Effects of epinephrine on fuel metabolism and pancreatic endocrine function. Epinephrine (Epi) stimulates glycogen breakdown in muscle and liver, gluconeogenesis in liver, and lipolysis in adipose tissue. Epinephrine further reinforces these effects because it increases the secretion of glucagon, a hormone that shares many of the same effects as epinephrine. Epi also inhibits insulin release but stimulates glucagon release from the pancreas.

Compare the effects of glucagon and epinephrine on glycogen metabolism in liver and in muscle. 

Activity Like the chemically and physiologically related (R)- noradrenaline (/f)-A., as an adrenal hormone, increases the degradation of glycogen in the liver and of fat in adipose tissue as well as the oxidative metabolism in muscle. As neutrotransmitter of the adrenergic nerve system (R)-A. increases heart rate as a sympathicomimetic, constricts blood vessels of the skin, mucous membranes, and abdominal viscera, and dilates vessels of the skeletal musculature and liver. The relaxation of smooth musculature in the intestine or bronchi effected by (R)-A. leads to a reduction of peristalsis (intestinal movements) or to dilatation of the bronchi. (S)-A. is about 12 times less active than (R)-adrenaline. 

Fructose metabolism in muscle is illustrated in Fig. 22.2. Fructose is phosphorylated by hcxokina.sc to fructose 6-phosphatc. The fructose 6-phosphate is then used for glycogenesis or, when the glycogen reserves are fuU, energy metabolism via glycolysis. 

Robbins, P.W., Lipman, F. Recent observations on the mechanism of glycogen synthesis in muscle. Ciba Symposium on Regulation of Cell Metabolism, p. 188-193 (1959)... 

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