In the previous project period, we proposed that calcineurin and CaMK serve as nodal points in signal transduction pathways by which specific patterns of motor nerve activity lead to changes in gene expression that establish specialized metabolic and physiologic properties in adult skeletal myofibers. Our basic mechanistic model has been supported by evidence from our own lab, and from others, but features of the model remain conjectural or controversial, and the mechanisms we have described so far provide only a partial view of the relevant biological processes. In the next project period, we propose new experiments that seek to achieve a more complete understanding of the molecular basis for fiber type determination in mammalian skeletal muscles. To this end, we will address the following specific aims: 1) To define the set of specific molecular signals that are necessary and sufficient to promote complete fiber type transformation in skeletal muscles of adult transgenic mice; 2) To define quantitative relationships between specific patterns of neural activity and the activation state of specific signaling cascades in skeletal myofibers of intact animals; 3) To define other signaling molecules and pathways pertinent to transcriptional regulation of fiber type-specific genes.
These aims are distinctive within the field of muscle biology for several reasons. Activity-dependent inter-conversion of specialized skeletal muscle subtypes was observed many decades ago, but identifying the molecular mechanisms that underlie this physiologically important response has been an elusive goal. Our recent hypothesis that calcineurin is important to the process has stimulated a fresh look at the problem. The subsequent experiments we propose are hypothesis-driven and focused, and major conclusions will be buttressed by results from both reductionisticand integrative approaches. We have incorporated new experimental methods so as to capitalize on recent technological advances. Finally, the knowledge to be gained may provide opportunities for development of new therapeutic measures to alter the specialized properties of skeletal myofibers, for the benefit of patients with primary and secondary myopathies or with metabolic diseases in which skeletal muscle plays an important role.
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