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

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.

authors

  • Metzger, Friedrich
  • Sajid, Waseem
  • Saenger, Stefanie
  • Staudenmaier, Christian
  • van der Poel, Chris
  • Sobottka, Bettina
  • Schuler, Angelika
  • Sawitzky, Mandy
  • Poirier, Raphael
  • Tuerck, Dietrich
  • Schick, Eginhard
  • Schaubmar, Andreas
  • Hesse, Friederike
  • Amrein, Kurt
  • Loetscher, Hansruedi
  • Lynch, Gordon S
  • Hoeflich, Andreas
  • De Meyts, Pierre
  • Schoenfeld, Hans-Joachim

publication date

  • June 3, 2011