To study how the functional output of skeletal muscle might be augmented in senescent animals, we propose to manipulate the expression of putative muscle growth and neurotrophic factors. These will include insulin-like growth factor (IGFs) I and II, receptors for thyroid hormone (THRs) and retinoic acid receptors (RXRs) which affect skeletal muscle fibers, as well as neurotrophins such as brain derived neurotrophic factor (BDNF), the neurotrophins (NT3, 4, 5) and nerve growth factor (NGF) which may affect neuromuscular innervation. Expression of these factors in skeletal muscle fiber will be accomplished in two ways. Virus mediated gene transfer employing the avian retroviral system (described by our collaborator Dr. Steve Hughes (Unit 4)) will be used to introduce the genes encoding these factors into muscles of interest at selected times (from embryonic life through old age) and locations (axial vs. limb musculature; rostral vs. caudal musculature). Functional and structural analysis of muscle and of its innervation will be performed at various times after transfection. Should this approach yield data which prove difficult to analyze due to resultant animal-to-animal heterogeneity, muscle and neuromuscular phenotype will be analyzed in transgenic mouse lines in which expression of these genes is driven by myosin light chain (MLC) regulatory elements. In this way we hope to study how advancing age leads to declines in muscle function, and determine whether and how the cumulative effects of senescence on skeletal muscle function may be altered by intervention.
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