Discordant Expression of Utrophin and Its Transcript in Human and Mouse Skeletal Muscles

In order to determine the mechanisms regulating utrophin expression in human skeletal muscle, we examined the expression and distribution of utrophin and its transcript in biopsies from normal subjects as well as from Duchenne muscular dystrophy (DMD) and polymyositis (PM) patients. We first determined by immunoblotting that in comparison to biopsies from normal subjects, utrophin levels were indeed higher in muscle samples from both DMD and PM patients as previously shown. By contrast, levels of utrophin mRNAs as determined by both RT-PCR assays and in situ hybridization, were identical in muscle samples obtained from normal subjects versus DMD and PM patients. In these experiments, we also noted that while utrophin transcripts had a clear tendency to accumulate within the postsynaptic sarcoplasm of normal human muscle fibers, the extent of synaptic accumulation was considerably less than that which we recently observed in mouse muscle fibers. The distribution of utrophin transcripts in synaptic and extra synaptic compartments of muscle fibers obtained from DMD and PM patients was similar to that seen along muscle fibers from normal subjects. Finally, we also monitored expression of utrophin and its transcripts during regeneration of mouse muscle induced to degenerate by cardiotoxin injections. In these regenerating muscles, we observed by both immunoblotting and immunofluorescence, a large increase (4- to 7-fold) in the levels of utrophin. In agreement with our results obtained with human muscle, the increase in utrophin levels in regenerating mouse muscle was not accompanied by parallel changes in the abundance of utrophin transcripts. Taken together, these results indicate that the levels of utrophin and its transcript in muscle are discordantly regulated under certain conditions thereby highlighting the important contribution of post-transcriptional regulatory mechanisms in the control of utrophin levels in skeletal muscle fibers.