Separation of Fast from Slow Anabolism by Site-specific PEGylation of Insulin-like Growth Factor I (IGF-I)

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2011 Apr 5

PMID 21460230

Citations 18

Authors

Friedrich Metzger

Waseem Sajid

Stefanie Saenger

Christian Staudenmaier

Chris van der Poel

Bettina Sobottka

Angelika Schuler

Mandy Sawitzky

Raphael Poirier

Dietrich Tuerck

Eginhard Schick

Andreas Schaubmar

Friederike Hesse

Kurt Amrein

Hansruedi Loetscher

Gordon S Lynch

Andreas Hoeflich

Pierre De Meyts

Hans-Joachim Schoenfeld

Affiliations

Soon will be listed here.

Abstract

Insulin-like growth factor I (IGF-I) has important anabolic and homeostatic functions in tissues like skeletal muscle, and a decline in circulating levels is linked with catabolic conditions. Whereas IGF-I therapies for musculoskeletal disorders have been postulated, dosing issues and disruptions of the homeostasis have so far precluded clinical application. We have developed a novel IGF-I variant by site-specific addition of polyethylene glycol (PEG) to lysine 68 (PEG-IGF-I). In vitro, this modification decreased the affinity for the IGF-I and insulin receptors, presumably through decreased association rates, and slowed down the association to IGF-I-binding proteins, selectively limiting fast but maintaining sustained anabolic activity. Desirable in vivo effects of PEG-IGF-I included increased half-life and recruitment of IGF-binding proteins, thereby reducing risk of hypoglycemia. PEG-IGF-I was equipotent to IGF-I in ameliorating contraction-induced muscle injury in vivo without affecting muscle metabolism as IGF-I did. The data provide an important step in understanding the differences of IGF-I and insulin receptor contribution to the in vivo activity of IGF-I. In addition, PEG-IGF-I presents an innovative concept for IGF-I therapy in diseases with indicated muscle dysfunction.

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