Résumé :
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Muscle-derived BDNF has long been thought to serve as a retrograde trophic factor for innervating motor neurons throughout their lifespan. However, our recent studies have shown that BDNF is not enriched at the neuromuscular junction in adult skeletal muscle, and instead, is highly expressed in satellite cells (J. Neurosci., 26: 5739, 2006). Furthermore, we have shown that BDNF depletion results in precocious differentiation of myoblasts in culture. These findings suggest a role for BDNF in myogenic differentiation. In order to expand on these findings, and determine whether BDNF plays a similar role in vivo, we designed a series of complementary experiments to elucidate the role of BDNF in muscle development, regeneration and disease. First, we generated a mouse in which BDNF is specifically depleted in skeletal muscle. Characterization of the muscle-specific BDNF knockout mouse showed abnormal neuromuscular junction formation, and fiber-type switching. Next, we compared regeneration of wild-type and BDNF-depleted muscle following cardiotoxin injury. BDNF-depleted muscle showed delayed regeneration, as indicated by delayed appearance of centrally nucleated fibers and developmental myosin heavy chains (MyHC). Finally, given the therapeutic importance of regeneration for treating various muscle diseases, we examined the expression profile of BDNF in dystrophic muscles from mdx mice. Compared to wild-type, aged mdx muscles consistently displayed greater levels of BDNF. Interestingly, high levels of BDNF correlate with the age at which regeneration becomes defective in mdx muscle, resulting in rapid deterioration and early death compared to wild-type. These findings demonstrate that muscle-derived BDNF is important for regulating: i) the organization of the post-synaptic compartment of muscle fibers; ii) the pattern of MyHC isoform expressed; and iii) the regenerative potential of muscle. Based on these findings, BDNF manipulation may represent an important theraputic tool to alleviate the dystrophic muscle pathology. This work is supported by CIHR, AFM and MDA (USA).
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