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Title: Evaluation of the role of paracrine/autocrine IGF-1 system in skeletal muscle adaptation
Author: Owino, Dorcas Vivian Apiyo
ISNI:       0000 0001 3462 0839
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2003
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Muscle is highly responsive to changes in functional demand, with overload and increased activity leading to hypertrophy, while decreased load, dennervation and joint immobilization can cause muscle atrophy. It has also been long appreciated that the mechanism of load-dependent muscle hypertrophy and atrophy are locally regulated and now increasing evidence suggests a role for locally expressed insulin-like growth factor I (IGF-1). Although it is accepted that overload and stretch are likely to mediate skeletal hypertrophy by an increase in local IGF-1, it is not clear to what extent changes in local IGF-1 gene expression are regulated in response to ageing and neuronal injury, which lead to muscle atrophy. There is even less information on how the two local IGF-1 isoforms, IGF-lEa and MGF are differentially regulated. This thesis presents the hypothesis that muscle response to mechanical and electrical stimuli can be determined by changes in local IGF-1 expression based on the premise that insulin-like growth factor (IGF-1), functioning in an autocrine/paracrine mode, is an important mediator of skeletal muscle adaptation. The experiments focused on the central role of local isoforms of muscle IGF-1, IGF-lEa and MGF, in muscle hypertrophy, atrophy and loss of skeletal muscle strength during senescence and in response to spinal injury. In summary, the experiments suggested that local modulation of IGF-1, particularly transcription of autocrine splice variant MGF, is stimulated by mechanical loading as well as some component of neuromuscular activity. A recurring observation was that the two IGF-1 isoforms were differentially regulated in response to loading, senescence and neuronal injury both in muscle and spinal cord tissue. In addition, it appeared that absence of neuromuscular activity affects the expression of IGF-1 gene, as passive cycling of spinal transected muscle did not appear to activate MGF expression in muscle. The results of this thesis supports evidence that IGF-1 is a positive regulator of muscle growth, but its downregulation may not directly determine muscle atrophy. However, as it is likely that the signalling pathways that control proteolysis and protein synthesis converge downstream, there is a possibility that indirect modulation of IGF-1 signalling may enhance the process of muscle atrophy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available