Insulin-like growth factor I (
IGF-I) is a key regulator of muscle development and growth. The pre-pro-
peptide produced by the Igf1 gene undergoes several post-translational processing steps to result in a secreted mature
protein, which is thought to be the obligate
ligand for the
IGF-I receptor (IGF-IR). However, the significance of the additional forms and
peptides produced from Igf1 is not clear. For instance, the C-terminal extensions called the E-
peptides that are part of
pro-IGF-I, have been implicated in playing roles in cell growth, including cell proliferation and migration and muscle
hypertrophy in an IGF-IR independent manner. However, the activity of these
peptides has been controversial. IGF-IR independent actions suggest the existence of an E-
peptide receptor, yet such a
protein has not been discovered. We propose a new concept: there is no E-
peptide receptor, rather the E-
peptides coordinate with
IGF-I to modulate activity of the IGF-IR. Growing evidence reveals that the presence of an E-
peptide alters
IGF-I activity, whether as part of
pro-IGF-I, or as a separate
peptide. In this review, we will examine the past literature on
IGF-I processing and E-
peptide actions in skeletal muscle, address the previous attempts to separate
IGF-I and E-
peptide effects, propose a new model for
IGF-I/E-
peptide synergy, and suggest future experiments to test if the E-
peptides truly modulate
IGF-I activity.