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Modulation of insulin-like growth factor 1 function by C-terminal E-peptides during muscle differentiation and myofibrillogenesis

Final Activity Report Summary - IGF1_EP_TN06 (Modulation of Insulin-like Growth Factor 1 function by C-terminal E-peptides during muscle differentiation and myofibrillogenesis)

Muscle weakness and disruption of muscle cytoarchitecture are associated with several myopathies, many of which still of unknown genetic cause, as well as with muscle atrophy occurring with aging, cancer, inflammation or after myocardial infarction. Insulin-like Growth Factor I (IGF1) is a member of the insulin-like superfamily of peptides and a critical regulator of body growth regulation and tissue homeostasis.

IGF1 function has proven to be critical to enhance skeletal muscle mass and function and to hasten muscle degeneration associated to genetic diseases, inflammation and aging. The way IGF1 regulates such events is likely to involve activation and proliferation of muscle precursors, stimulation of muscle differentiation and remodelling of muscle contractile apparatus. However, the actual role played by IGF1 in regulating such events and the molecular components of its pathway have not been fully elucidated.

IGF1 is produced as multiple isoforms characterized by the presence of additional sequences located at the amino terminus (N-terminal signal peptides) as well as at the carboxyl terminus of the core mature hormone (C-terminal E-peptides). We have hypothesized that the C-terminal E-peptides exert critical functions on muscle differentiation, either independently or in combination with IGF1. This study set out to assess the regulatory effects of IGF1 on the assembly and maintenance of the contractile machinery and to test the potential function exerted by IGF1 E-peptides on muscle differentiation, either alone or in combination with the mature hormone.

The results indicate that IGF1-treatment enhances muscle cells differentiation and induces formation of robust cytoskeletal structures, an effect that is augmented by concurrent stimulation with some of the C-terminal E-peptides. It is possible that such effects are mediated through modulation of IGF1 canonical signalling pathway involving the IGF1-Receptor, since the levels of activation of downstream regulators, such as Akt, are markedly influenced by the stimulation with E-peptides. However further studies will be required to evaluate whether E-peptides modulate IGF1 signalling by concurrent activation of alternative parallel pathways.