Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992) Nature (London) 360, 588 -591]. This outcome has led to the concept that ectopic expression of a ''synaptic scaffold'' of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx͞CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, ␣-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx͞CT but not in mdx muscles. mdx͞CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx͞CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD. D uchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations or deletions in the dystrophin gene that abrogate dystrophin protein expression (1-3). Loss of dystrophin protein in DMD (4) or in the mdx mouse model for DMD (5) also leads to the reduced expression of a complex of membrane proteins that either bind to or associate with dystrophin. Among these are cytoplasmic membrane-associated proteins, including syntrophins and dystrobrevins, and transmembrane glycoproteins, including the dystroglycans and sarcoglycans (for review, see ref. 6). Through a series of intermolecular interactions, this complex of proteins ultimately links laminins in the extracellular matrix to the actin cytoskeleton. Mutations in genes encoding most of these proteins cause some form of muscular dystrophy. Mutations in dystrophin cause DMD (7) and Becker muscular dystrophy (8), mutations in sarcoglycans cause forms of limb-girdle muscular dystrophy (for review, see ref. 9), mutations in laminin ␣2 cause a form of congenital muscular dystrophy (10), and mutations in dystrobrevin (11), dystroglycan (12) and proteins that alter dystroglycan glycosylation (13, 14) cause muscular dystrophy.Although the loss of dystrophin reduces the expression of dystrophin-associated proteins along myofibers, most of these proteins are still highly concentrated at the neuromuscular junction (5). In addition, utrophin, a protein homologue of dystrophin ...
Recently, there have been a number of studies demonstrating that overexpression of molecules in skeletal muscle can inhibit or ameliorate aspects of muscular dystrophy in the mdx mouse, a model for Duchenne muscular dystrophy. Several such studies involve molecules that increase the expression of dystroglycan, an important component of the dystrophin-glycoprotein complex. To test whether dystroglycan itself inhibits muscular dystrophy in mdx mice, we created dystroglycan transgenic mdx mice (DG/mdx). The alpha and beta chains of dystroglycan were highly overexpressed along the sarcolemmal membrane in most DG/mdx muscles. Increased dystroglycan expression, however, did not correlate with increased expression of utrophin or sarcoglycans, but rather caused their decreased expression. In addition, the percentage of centrally located myofiber nuclei and the level of serum creatine kinase activity were not decreased in DG/mdx mice relative to mdx animals. Therefore, dystroglycan overexpression does not cause the concomitant overexpression of a utrophin-glycoprotein complex in mdx muscles and has no effect on the development of muscle pathology associated with muscular dystrophy.
Chronic tissue response to microelectrode implants stands in the way as a major challenge to development of many neural prosthetic applications. The long term tissue response is mostly due to the movement of interconnects and the resulting mechanical stress between the electrode and the surrounding neural tissue. Remotely activated floating micro-stimulators are one possible method of eliminating the interconnects. As a method of energy transfer to the micro-stimulator, we proposed to use a laser beam at near infrared (NIR) wavelengths. FLAMES of various sizes were fabricated with integrated silicon PIN photodiodes. Sizes varied from 120 (Width) × 300 (Length) × 100 (Height) μm to 200 × 500 × 100μm. Devices were bench tested using 850nm excitation from a Ti:Sapphire laser. To test this method, the voltage field of the FLAMES was experimentally tested in saline solution pulsed with a NIR laser beam. The voltage generated is around 196mV in peak at the cathodic contact as a response to a single pulse. When a train of laser pulses was applied at 100Hz, the peak voltage at the cathodic contact remained around 141mV suggesting the feasibility of this approach for applications with pulse frequencies up to 100Hz.
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