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Effect of unloading on type I myosin heavy chain gene regulation in rat soleus muscle

Department of Physiology and Biophysics, University of California, Irvine, California

Submitted 1 October 2004 ; accepted in final form 8 December 2004

Slow-twitch soleus, a weight-bearing hindlimb muscle, predominantly expresses the type I myosin heavy chain (MHC) isoform. However, under unloading conditions, a transition in MHC expression occurs from slow type I toward the fast-type isoforms. Transcriptional processes are believed to be involved in this adaptation. To test the hypothesis that the downregulation of MHC₁ in soleus muscle following unloading is controlled through cis element(s) in the proximal region of the promoter, the MHC₁ promoter was injected into soleus muscles of control rats and those subjected to 7 days of hindlimb suspension. Mutation analyses of six putative regulatory elements within the –408-bp region demonstrated that three elements, an A/T-rich, the proximal muscle-type CAT (e3), and an E-box (–63 bp), play an important role in the basal level of MHC₁ gene activity in the control soleus and function as unloading-responsive elements. Gel mobility shift assays revealed a diminished level of complex formation of the e3 and E-box probes with nuclear extract from hindlimb suspension soleus compared with control soleus. Supershift assays indicated that transcriptional enhancer factor 1 and myogenin factors bind the e3 and E-box elements, respectively, in the control soleus. Western blots showed that the relative concentrations of the transcriptional enhancer factor 1 and myogenin factors were significantly attenuated in the unloaded soleus compared with the control muscle. We conclude that the downregulation of MHC₁ in response to unloading is due, in part, to a significant decrease in the concentration of these transcription factors available for binding the positive regulatory elements.

direct gene transfer; promoter; gel mobility shift assay; pre-messenger ribonucleic acid

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