Contractures are a common and disabling musculoskeletal complication of neurological and neuromuscular disease. Contractures can be congenital, acquired through muscle imbalance on a joint, or acquired through chronic/progressive muscle disuse or disease. The muscular dystrophies frequently show contractures, and these often limit the ability for ambulation and effective use of limbs, in some cases despite relatively preserved muscle mass. Some of these are due to muscle imbalance, however many of the dystrophies show contractures at specific joints, suggesting a developmental or tissue remodeling process as underlying the contracture. In this research proposal, we test the hypothesis that remodeling at the myotendinous junction (MTJ) and/or ectopic expression of MTJ-like features at non-MTJ sites in muscle, are a major cause underlying contractures. The MTJ is a very dynamic site where two distinct cell lineages and tissues, tendon and muscle, must form very specific yet strong interactions. The MTJ also bears much of the force generated by muscle, and must maintain cell-extracellular matrix contacts under substantial load bearing. Further, accumulating evidence suggests that much of muscle growth occurs at the MTJ, making constant remodeling another feature of this unique myofiber specialization. Despite the critical role of the MTJ, little is known of the molecular nature of this subcellular specialization of the myofiber/tendon. Here, we pursue three aims. The first is a """"""""genome anatomy"""""""" of MTJ pre- and post-maturation, via genome-wide expression profiling of MTJ, tendon, and adjacent myofiber.
The second aim i s to compare the developmental series in aim 1 with a regeneration series, to define the extent to which regeneration recapitulates post-natal development/growth. The third is then to use the data warehouse accumulated in aims 1 and 2 to dissect the pathophysiology of muscular dystrophy remodeling at the MTJ, and to test the hypothesis that ectopic expression of MTJ components in the muscle belly is associated with contractures. All profiles with the MTJ expression signatures will be released to the public via our existing Oracle Web database. The MTJs will be isolated by laser capture microscopy well established in the laboratory.
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| Bakay, Marina; Wang, Zuyi; Melcon, Gisela et al. (2006) Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain 129:996-1013 |
| Melcon, Gisela; Kozlov, Serguei; Cutler, Dedra A et al. (2006) Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum Mol Genet 15:637-51 |
