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Regulation of Glycogen Metabolism in Cultured Human Muscles by the Glycogen Phosphorylase Inhibitor CP-91149

Regulation of Glycogen Metabolism in Cultured Human Muscles by the Glycogen Phosphorylase Inhibitor CP-91149

Carlos Lerín, Eulàlia Montell, Teresa Nolasco, Mar García-Rocha, Joan J Guinovart, Anna M Gómez-Foix

Biochem J. 2004 Mar 15;378(Pt 3):1073-7.

PMID: 14651477

Abstract:

Pharmacological inhibition of liver GP (glycogen phosphorylase), which is currently being studied as a treatment for Type II (non-insulin-dependent) diabetes, may affect muscle glycogen metabolism. In the present study, we analysed the effects of the GP inhibitor CP-91149 on non-engineered or GP-overexpressing cultured human muscle cells. We found that CP-91149 treatment decreased muscle GP activity by (1) converting the phosphorylated AMP-independent a form into the dephosphorylated AMP-dependent b form and (2) inhibiting GP a activity and AMP-mediated GP b activation. Dephosphorylation of GP was exerted, irrespective of incubation of the cells with glucose, whereas inhibition of its activity was synergic with glucose. As expected, CP-91149 impaired the glycogenolysis induced by glucose deprivation. CP-91149 also promoted the dephosphorylation and activation of GS (glycogen synthase) in non-engineered or GP-overexpressing cultured human muscle cells, but exclusively in glucose-deprived cells. However, this inhibitor did not activate GS in glucose-deprived but glycogen-replete cells overexpressing PTG (protein targeting to glycogen), thus suggesting that glycogen inhibits the CP-91149-mediated activation of GS. Consistently, CP-91149 promoted glycogen resynthesis, but not its overaccumulation. Hence, treatment with CP-91149 impairs muscle glycogen breakdown, but enhances its recovery, which may be useful for the treatment of Type II (insulin-dependent) diabetes.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP186392405	CP-91149		186392-40-5	Price

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