Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects

Glycogen synthase is activated by protein phosphatase type-1 (PP-1). The spontaneous PP-1 activity accounts for only a small fraction of total PP-1 activity, which can be exposed by trypsin digestion of inhibitor proteins in the presence of Mn2+. We determined total PP-1 activity in muscle biopsies...

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Bibliographic Details
Published in:The Journal of clinical investigation 1991-11, Vol.88 (5), p.1540-1545
Main Authors: NYOMBA, B. L, BRAUTIGAN, D. L, SCHLENDER, K. K, WEI WANG, BOGARDUS, C, MOTT, D. M
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Blotting, Western
Catalysis
Endocrinopathies
Glycogen Synthase - analysis
Humans
Insulin Resistance
Manganese - pharmacology
Medical sciences
Muscles - enzymology
Phosphoprotein Phosphatases - analysis
Phosphorylase Phosphatase - deficiency
Trypsin - pharmacology
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Summary:Glycogen synthase is activated by protein phosphatase type-1 (PP-1). The spontaneous PP-1 activity accounts for only a small fraction of total PP-1 activity, which can be exposed by trypsin digestion of inhibitor proteins in the presence of Mn2+. We determined total PP-1 activity in muscle biopsies from insulin-sensitive and -resistant nondiabetic Pima Indians. Inhibitor-2 sensitive PP-1 represented 90% of total phosphatase activity. Spontaneous and total PP-1 activities were reduced in insulin resistant subjects (P less than 0.05-0.01), suggesting that the reduced PP-1 activity is not the result of inhibition by trypsin-labile phosphatase regulatory subunits. This difference was further investigated by Western blots using two different antibodies. An antibody raised against the rabbit muscle PP-1 catalytic subunit was used to analyze muscle extracts concentrated by DEAE-Sepharose adsorption. An antibody raised against a peptide derived from the COOH-terminal end of the PP-1 catalytic subunit was used to analyze crude muscle extracts. Both antibodies recognized a PP-1 catalytic subunit of approximately 33 kD, which unexpectedly was more abundant in insulin-resistant subjects (P less than 0.05-0.01). The increase in the tissue PP-1 protein content may be a response to compensate for the impairment in the enzyme activity.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI115464