Regulation of glycogen metabolism in cultured human muscles by the glycogen phosphorylase inhibitor CP-91149

• Published in: Biochemical journal Vol. 378; no. Pt 3; pp. 1073 - 1077
• Main Authors: Lerín, Carlos, Montell, Eulàlia, Nolasco, Teresa, García-Rocha, Mar, Guinovart, Joan J, Gómez-Foix, Anna M
• Format: Journal Article
• Language: English
• Published: England 15.03.2004
• Subjects: Amides - pharmacology; Cells, Cultured; Enzyme Inhibitors - pharmacology; Glycogen - metabolism; Glycogen Phosphorylase - antagonists & inhibitors; Glycogen Phosphorylase - metabolism; Glycogen Synthase - metabolism; Humans; Indoles - pharmacology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20030971

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.