Viral expression of insulin-like growth factor I E-peptides increases skeletal muscle mass but at the expense of strength

• Published in: American journal of physiology: endocrinology and metabolism Vol. 306; no. 8; pp. E965 - E974
• Main Authors: Brisson, Becky K, Spinazzola, Janelle, Park, SooHyun, Barton, Elisabeth R
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 15.04.2014
• Subjects: 3T3 Cells; Animals; Cellular biology; Dependovirus; Gene Transfer Techniques; Genetic Vectors; Human growth; Insulin-Like Growth Factor I - genetics; Insulin-like growth factors; Mice; Mice, Inbred C57BL; Muscle Strength - genetics; Muscle, Skeletal - anatomy & histology; Muscle, Skeletal - metabolism; Musculoskeletal system; Organ Size - genetics; Peptide Fragments - genetics; Phosphorylation; Physiology; Protein expression; adeno-associated viral vectors; IGF-I; E-peptides; skeletal muscle; hypertrophy
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00008.2014

Insulin-like growth factor I (IGF-I) is a protein that regulates and promotes growth in skeletal muscle. The IGF-I precursor polypeptide contains a COOH-terminal extension called the E-peptide. Alternative splicing in the rodent produces two isoforms, IA and IB, where the mature IGF-I in both isoforms is identical yet the E-peptides, EA and EB, share less than 50% homology. Recent in vitro studies show that the E-peptides can enhance IGF-I signaling, leading to increased myoblast cell proliferation and migration. To determine the significance of these actions in vivo and to evaluate if they are physiologically beneficial, EA and EB were expressed in murine skeletal muscle via viral vectors. The viral constructs ensured production of E-peptides without the influence of additional IGF-I through an inactivating mutation in mature IGF-I. E-peptide expression altered ERK1/2 and Akt phosphorylation and increased satellite cell proliferation. EB expression resulted in significant muscle hypertrophy that was IGF-I receptor dependent. However, the increased mass was associated with a loss of muscle strength. EA and EB have similar effects in skeletal muscle signaling and on satellite cells, but EB is more potent at increasing muscle mass. Although sustained EB expression may drive hypertrophy, there are significant physiological consequences for muscle.