| Muscle weakness is a common clinical phenomena observed following bed rest, surgery, cast immobilization or chronic disease. The consequences of muscle dysfunction are far reaching and can include functional impairments, decreased motor control, reduced fitness and long term disability. As such, the maintenance and recovery of muscle function presents an important challenge to the field of rehabilitation sciences. The overall objective of this dissertation was to investigate the potential of virus-mediated gene transfer of insulin-like growth factor-I (IGF-I) to maintain skeletal muscle size and function during cast immobilization and reambulation. A combination of magnetic resonance imaging (MRI), in vitro force measurements, immunohistochemical assays and real time-PCR techniques were performed in an animal model of cast immobilization to explore this objective. We investigated both the impact of IGF-I overexpression in the anterior compartment and posterior compartment hindlimb muscles.;Our findings demonstrate that local overexpression of IGF-I results in significant increases in muscle mass, muscle fiber size and concomitant increases in muscle force production under normal loading conditions in both slow twitch and fast twitch muscles. In addition, the relative gains in muscle size and force production are maintained during cast immobilization and reambulation. Thirdly, muscles overexpressing IGF-I show protection from muscle damage during early reambulation and evidence of enhanced muscle regeneration during later reambulation. Additionally, IGF-I receptor and binding proteins demonstrate concomitant molecular responses with IGF-I protein and mRNAs overexpression during cast immobilization and reambulation. Collectively, findings from this series of studies show that viral delivery of IGF-I can protect skeletal muscle from the deleterious effects of immobilization/disuse and accelerate the subsequent restoration of muscle function. These findings may also set the stage for possible clinical applications of gene therapy to ameliorate muscle weakness and atrophy and expedite muscle recovery following disuse or in chronic diseases associated with muscle wasting (e.g. cancer, AIDS). |
