Rinsho Shinkeigaku (Clinical Neurology)

The 45th Annual Meeting of the Japanese Society of Neurology

The pathomechanism and the direction of therapy development in view of cDNA microarray

Ichizo Nishino, M.D., Ph.D., Yukiko K. Hayashi, M.D., Ph.D. and Satoru Noguchi, Ph.D.

Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP)

We recently developed a new cDNA microarry encompassing more than 5,000 genes expressed in human skeletal muscle. We successfully identified the differences at the gene expression profiles among Duchenne muscular dystrophy patients. Using our microarray, we catalogued gene expression during myogenic differentiation. The resultant expression patterns were classified into eight groups by hierarchical cluster analysis. Among them, clusters 6, 7, and 8 contain genes which show high expression level at the later differentiation stage and encode mainly sarocmere and extracellular matrix proteins. We used genes in these clusters as markers for regeneration. We identified that these regeneration-associated genes were not necessarily upregulated in Fukuyama congenital muscular dystrophy (FCMD) even though necrosis-associated genes were highly upregulated, suggesting the insufficient regenerating capability in FCMD. We have also characterized genes regulated by IGF-I simulation. We subject cascade specific inhibitors and IGF-I to human myotubes and performed gene expression profiling using our cDNA microarray. We found that PI3K/Akt-1 cascade first activates transcriptional factors such as MyoD, myogenin, and MEF2C, and then genes in clusters 6, 7, and 8, which have E-box and MEF-box where these transcriptional factors associate. We expect to develop a new therapeutic method by elucidating the molecular mechanism of muscular dystrophy and the effect of IGF-I and anti-myostatin treatments.

(CLINICA NEUROL, 44: 905|907, 2004)
key words: cDNA microarray, muscular dystrophy, IGF-I, Akt-1, signal cascade

(Received: 14-May-04)