This proposal will improve our understanding of the structural and mechanical changes in muscles and muscle cells after contracture that occur after upper motor neuron lesion. Upper motor neuron lesions such as spinal cord injury, cerebral palsy, and head injury often result in muscle spasticity and associated contractures. Many times the only treatment for the long-term contracture is surgical tendon transfer or release, which is highly invasive and does not necessarily restore muscle function. While there is no question of the clinical impact of muscle contractures, the underlying basis for the mechanical changes in muscle contractures are largely unknown. Such an understanding is critical if rational therapeutic treatments are to be developed to treat muscle contractures. The objectives of this proposal are to provide objective data that define the mechanical alterations in muscle from patients with contractures and to begin to identify the structural basis for these mechanical alterations. In the long term, based on an understanding of the structural alterations in human muscle after contracture, we will design therapeutic interventions to reduce or reverse these changes and restore muscle properties to normal. Muscle properties from patients with contractures will be measured during surgery and cellular properties measured in vitro after surgery to determine the extent to which the changes in passive mechanical properties are due to the giant intramuscular protein, titin and other extracellular proteins such as collagen.
The specific aims of this proposal are: (1) To measure sarcomere length in wrist flexor muscles prior to and after surgical release in human subjects with contractures, (2) To quantify the intrinsic passive mechanical properties of single cells and fiber bundles from human muscles after contracture, and (3) To determine the relationship between single fiber micromechanical properties and titin protein expression in normal and """"""""contracture"""""""" human skeletal muscle fibers. This three year proposal is based on preliminary data that have been obtained from actual human muscles after contracture due to upper motor neuron lesion. In addition to increasing our understanding of muscle after contracture, these experiments will provide information that is relevant to understanding mechanisms that lead to muscle adaptation in response to other decreased-use paradigms such as immobilization and weightlessness. ? ?
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