IGF1_EP_TN06 · Modulation of insulin-like growth factor 1 function by C-terminal E-peptides during muscle differentiation and myofibrillogenesis
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-11-01 → 2008-10-31
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
Muscle weakness and loss of muscle cytoarchitecture are associated with several myopathies, many of which still of unknown genetic cause, and with other pathologic states, such as the muscle atrophy that results from aging, cancer or cardiac infarction (cardiac cachexia). Because of the changes in our life habits and in the average life expectancy of our societies, treating muscle weakness by increasing muscle mass or by boosting the regenerative potential of muscle tissue is becoming a major goal for the clinical industry as well as for healthcare agencies. Insulin Growth Factor 1 (IGF1) can play an important role in improving muscle function during diseased states or along the aging process. In fact, it can increase the regenerative potential of muscle tissue and/or stimulate local hypertrophy, an event that ultimately requires for active remodelling of the contractile apparatus.However, IGF1 regulation is particularly complex, since different isoforms of the pro-hormone have been described, differing in their C-terminal E-peptides. Overall, little is known about the events controlled by alternative IGF1 isoforms specifically in muscle cells, or their importance for remodelling/stability of myofibrillar apparatus. Elucidating any direct effect exerted by IGF1 E-peptides on muscle differentiation and myofibrillogenesis, or how they influence the modes of function of IGF1, is crucial for our understanding of this system and for our capacity to modulate it to attenuate age- or disease-associated muscle weakness.We propose the following aims:1. To characterise the events under the control of IGF1 specifically in muscle cells;2. To assess the role of IGF1 E-peptides on muscle cells, either as direct effectors or as modulators of IGF1 function;3. To define the contribution of IGF1 signalling to the stability and remodelling of the myofibrillar apparatus in skeletal muscle fibres.
Original text from CORDIS.
Participants
- EUROPEAN MOLECULAR BIOLOGY LABORATORY · HEIDELBERGCoordinatorGermany
Links
Data: CORDIS, © European Union